1
|
Chen Y, Yu K, Jiang Z, Yang G. CRISPR-based genetically modified scaffold-free biomaterials for tissue engineering and regenerative medicine. Biomater Sci 2025; 13:3149-3175. [PMID: 40326747 DOI: 10.1039/d5bm00194c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2025]
Abstract
CRISPR-based genetically modified scaffold-free biomaterials, including extracellular vehicles, cell sheets, cell aggregates, organoids and organs, have attracted significant attention in the fields of regenerative medicine and tissue engineering in recent years. With a wide range of applications in gene therapy, modeling disease, tissue regeneration, organ xenotransplantation, modeling organogenesis as well as gene and drug screening, they are at a critical juncture from clinical trials to therapeutic applications. Xenografts have already been tested on non-human primates and humans. However, we have to admit that a series of obstacles still need to be addressed, such as immune response, viral infection, off-target effects, difficulty in mass production, and ethical issues. Therefore, future research should pay more attention to improving their safety, accuracy of gene editing, flexibility of production, and ethical rationality. This review summarizes various types of CRISPR-based genetically modified scaffold-free biomaterials, including their preparation procedures, applications, and possible improvements.
Collapse
Affiliation(s)
- Yunxuan Chen
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China.
| | - Ke Yu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China.
| | - Zhiwei Jiang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China.
| | - Guoli Yang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China.
| |
Collapse
|
2
|
Zacchi F, Abida W, Antonarakis ES, Bryce AH, Castro E, Cheng HH, Shandhu S, Mateo J. Recent and Future Developments in the Use of Poly (ADP-ribose) Polymerase Inhibitors for Prostate Cancer. Eur Urol Oncol 2025; 8:818-828. [PMID: 39638687 DOI: 10.1016/j.euo.2024.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 10/30/2024] [Accepted: 11/20/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND AND OBJECTIVE Advanced prostate cancer (PCa) is enriched for alterations in DNA damage repair genes; poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a class of drugs that have demonstrated effectiveness in PCa, particularly in tumors with alterations in BRCA1/2 and other homologous recombination repair (HRR) genes, acting through a synthetic lethal mechanism. To prevent or delay drug resistance, and to expand the patient population that can benefit from this class of drug, combination treatment strategies have been developed in preclinical and clinical studies. METHODS This review examines the latest developments in clinical trials testing PARPi for advanced PCa and their emerging role in earlier disease settings. Furthermore, it discusses the critical role of careful patient selection and identification of additional biomarkers to enhance treatment efficacy. KEY FINDINGS AND LIMITATIONS Two PARPi (olaparib and rucaparib) have been approved as monotherapy in metastatic castration-resistant PCa, thereby establishing the first biomarker-guided drug indications in PCa. Several combinations of PARPi with androgen receptor pathway inhibitors have now also been approved. Anemia and fatigue are the main adverse events associated with this drug class in clinical trials; gastrointestinal toxicities are common but usually manageble. CONCLUSIONS AND CLINICAL IMPLICATIONS PARPi are active against PCa with HRR mutations, especially in those with germline or somatic BRCA1/2 mutations. There is still a need to further optimize patient stratification strategies, particularly for combination approaches. Future research should focus on refining predictive biomarkers, improving treatment delivery strategies, and exploring the potential benefits of PARPi in earlier stages of the disease. PATIENT SUMMARY Here, we summarize the results from clinical trials testing different poly (ADP-ribose) polymerase inhibitors (PARPi), a novel targeted drug class, in prostate cancer. Overall, the data from these trials confirm the efficacy of this drug class in those metastatic prostate cancers that show specific gene alterations, such as mutations in the BRCA1/2 genes. Several studies combining PARPi with other standard drugs for prostate cancer suggest that there may be efficacy in larger patient populations, but some of these data still need validation in longer follow-up analyses.
Collapse
Affiliation(s)
- Francesca Zacchi
- Section of Innovation Biomedicine-Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, Verona, Italy
| | - Wassim Abida
- Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Emmanuel S Antonarakis
- Department of Medicine, University of Minnesota, Masonic Cancer Center, Minneapolis, MN, USA
| | - Alan H Bryce
- Department of Medical Oncology and Developmental Therapeutics, City of Hope, Goodyear, AZ, USA
| | - Elena Castro
- Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Heather H Cheng
- Department of Medicine, Division of Hematology and Oncology, University of Washington, Seattle, WA, USA; Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Shahneen Shandhu
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Joaquin Mateo
- Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
| |
Collapse
|
3
|
Andersson J, Cowland S, Vestergaard M, Yang Y, Liu S, Fang X, Mukund S, Ghimire-Rijal S, Carter C, Chung G, Jacso T, Sarvary I, Hughes PE, Gouliaev A, Payton M, Belmontes B, Caenepeel S, Franch T, Glad S, Husemoen B, Nielsen SJ. MTA-cooperative PRMT5 inhibitors from cofactor-directed DNA-encoded library screens. Proc Natl Acad Sci U S A 2025; 122:e2425052122. [PMID: 40377999 DOI: 10.1073/pnas.2425052122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/31/2025] [Indexed: 05/18/2025] Open
Abstract
Methylthioadenosine phosphorylase (MTAP) gene deletions are frequent in human cancers. Loss of MTAP leads to significantly increased cellular levels of methylthioadenosine (MTA), a cellular metabolite and specific inhibitor of the cell-essential enzyme Protein Arginine Methyltransferase-5 (PRMT5). Using a cofactor-directed screening strategy and DNA-encoded libraries, we identify a class of PRMT5 inhibitors that cooperatively inhibit PRMT5 in the presence of MTA. An optimized inhibitor, AM-9934, selectively inhibits PRMT5 in MTAP-deleted cells and in transplanted tumors while sparing MTAP-expressing counterparts, leading to specific suppression of viability in MTAP-deleted cells. Structural studies show that AM-9934 occupies the arginine substrate pocket of MTA-bound PRMT5. This study introduces a broadly applicable method for directed DNA-encoded library screening toward a desired mechanistic outcome and highlights MTA-selective PRMT5 inhibition as an attractive therapeutic strategy with a potentially broad therapeutic index in patients with MTAP-deleted cancers.
Collapse
Affiliation(s)
| | | | | | | | | | - Xie Fang
- Amgen Research, South San Francisco, CA 94080
| | | | | | | | | | | | | | | | | | | | | | | | | | - Sanne Glad
- Amgen Research, Copenhagen DK-2100, Denmark
| | | | | |
Collapse
|
4
|
Yap TA, LoRusso P, Miller RE, Kristeleit R, Paulovich AG, McMorn S, Oplustil O'Connor L, Lombardi B, Marco-Casanova P, Gangl ET, Patel B, O'Connor MJ, Dean E, Zviezdin R, Plummer R. The DNA-PK inhibitor AZD7648 alone or combined with pegylated liposomal doxorubicin in patients with advanced cancer: results of a first-in-human Phase I/IIa study. Br J Cancer 2025:10.1038/s41416-025-03053-x. [PMID: 40382524 DOI: 10.1038/s41416-025-03053-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 04/15/2025] [Accepted: 05/01/2025] [Indexed: 05/20/2025] Open
Abstract
BACKGROUND Upregulation of DNA-dependent protein kinase (DNA-PK) is associated with poor prognosis and decreased response to DNA-damaging agents across cancer types. A Phase I/IIa study (NCT03907969) investigated the highly potent, selective DNA-PK inhibitor AZD7648 as monotherapy or combined with pegylated liposomal doxorubicin (PLD) in patients with advanced cancer. METHODS Thirty patients received escalating doses of AZD7648 as monotherapy (n = 14), starting at 5 mg QD, or with PLD 40 mg/m2 (n = 16). The primary objective was safety and tolerability. RESULTS AZD7648 monotherapy was administered at 5-160 mg BID. The most frequent class of adverse events was gastrointestinal disorders (9/14 patients, 64.3%); one patient (160 mg BID) experienced dose-limiting toxicities (DLTs). No responses to AZD7648 monotherapy were observed. The maximum dose of combination therapy was AZD7648 40 mg QD days 1-7 + PLD every 28 days. 13/16 patients (81.3%) experienced gastrointestinal disorders and 11/16 (68.8%) patients had anaemia. Three patients experienced DLTs (two at AZD7648 20 mg QD 7 days + PLD; one at AZD7648 30 mg QD 7 days + PLD). Limited efficacy was observed, with one RECIST partial response. DISCUSSION Toxicity of AZD7648 + PLD was greater than expected and antitumour activity was limited, leading to early study termination.
Collapse
Affiliation(s)
- Timothy A Yap
- University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | | | - Rowan E Miller
- University College London Hospitals NHS Foundation Trust, London, UK
| | - Rebecca Kristeleit
- Department of Oncology, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
| | | | | | | | | | | | - Eric T Gangl
- Clinical Pharmacology and Safety Sciences, Biopharmaceuticals R&D, AstraZeneca, Waltham, MA, USA
| | | | | | - Emma Dean
- Oncology R&D, AstraZeneca, Cambridge, UK
| | | | - Ruth Plummer
- Newcastle University and Northern Centre for Cancer Care, Newcastle Hospitals NHS Trust, Newcastle Upon Tyne, UK
| |
Collapse
|
5
|
Pedretti F, Abdalfttah M, Pellegrino B, Mateo F, Martínez-Sanz P, Herencia-Ropero A, Òdena A, Clavell-Revelles P, Casali G, Domènech H, Monserrat L, Papić D, Mas Malavila A, Pascual-Reguant A, Eixarch H, Guzmán M, Rodríguez O, Grueso J, Simonetti S, Fasani R, Nuciforo P, Espejo C, Florian S, Pujana MÁ, Nonell L, Seoane J, Valge-Archer V, O'Connor MJ, Nieto JC, Heyn H, Balmaña J, Llop-Guevara A, Serra V. Harnessing STING Signaling and Natural Killer Cells Overcomes PARP Inhibitor Resistance in Homologous Recombination-Deficient Breast Cancer. Cancer Res 2025; 85:1888-1908. [PMID: 40067927 DOI: 10.1158/0008-5472.can-24-2531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 12/10/2024] [Accepted: 03/06/2025] [Indexed: 05/16/2025]
Abstract
Homologous recombination deficiency (HRD) contributes to genomic instability and leads to sensitivity to PARP inhibitors (PARPi). HRD also activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-interferon pathway, highlighting the need to understand the impact of cGAS-STING-IFN signaling on PARPi efficacy. In this study, we analyzed a cohort of 35 breast cancer patient-derived xenografts and mouse-derived allografts. PARPi sensitivity correlated with HRD, increased genomic instability, and activation of the cGAS-STING-IFN signaling pathway. Single-cell analyses showed that IFN signaling and IFN-based immune interactions were suppressed in preclinical models with acquired resistance to PARPi, lacking concomitant clonal expansion of functional CD8+ T cells. However, the combination of a PARPi and a novel STING agonist (STINGa) increased immune infiltration and resulted in superior antitumor activity in these tumors. Notably, the efficacy of PARPi monotherapy and the combination treatment with a STINGa was dependent on natural killer (NK) cells. In agreement, patients with breast cancer with BRCA1/BRCA2 mutations and good responses to PARPi showed higher abundancy of CD56+ NK cells in the tumor microenvironment and treatment-engaged CD56bright NK cells in the peripheral immune compartment, compared with those with poor responses. Therefore, these findings propose the combination of PARPis and a STINGa as a potential novel strategy to enhance the therapeutic response in patients with acquired PARPi resistance and highlight a pivotal role of NK cells in the PARPi antitumor activity. Significance: PARP inhibitor sensitivity is associated with cGAS-STING-IFN signaling, which can be harnessed by combining PARP inhibitors with STING agonists to overcome acquired resistance and requires NK cells to mediate antitumor immunity. See related commentary by Gohari et al., p. 1747.
Collapse
Affiliation(s)
- Flaminia Pedretti
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | | | - Benedetta Pellegrino
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Medical Oncology and Breast Unit, University Hospital of Parma, Parma, Italy
| | - Francesca Mateo
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain
| | - Paula Martínez-Sanz
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Andrea Herencia-Ropero
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Andreu Òdena
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Universitat de Barcelona (UB), Barcelona, Spain
| | - Pau Clavell-Revelles
- Bioinformatics Unit, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Giorgia Casali
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Heura Domènech
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Laia Monserrat
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Dražen Papić
- Institute of Pathology, Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Alba Mas Malavila
- Bioinformatics Unit, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | | | - Herena Eixarch
- Neurology-Neuroimmunology Department, Multiple Sclerosis Center of Catalonia, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Research Institute, Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
| | - Marta Guzmán
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Olga Rodríguez
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Judit Grueso
- Models of Cancer Therapies Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Sara Simonetti
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Roberta Fasani
- Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Paolo Nuciforo
- Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Carmen Espejo
- Neurology-Neuroimmunology Department, Multiple Sclerosis Center of Catalonia, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Research Institute, Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
| | - Stefan Florian
- Institute of Pathology, Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Miguel Ángel Pujana
- ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain
| | - Lara Nonell
- Bioinformatics Unit, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Joan Seoane
- Gene Expression and Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | | | | | - Juan C Nieto
- Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain
| | - Holger Heyn
- Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain
| | - Judith Balmaña
- Hereditary Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Department of Medical Oncology, Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Alba Llop-Guevara
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Violeta Serra
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| |
Collapse
|
6
|
Abraham JE, O'Connor LO, Grybowicz L, Alba KP, Dayimu A, Demiris N, Harvey C, Drewett LM, Lucey R, Fulton A, Roberts AN, Worley JR, Chhabra MA, Qian W, Brown J, Hardy R, Vallier AL, Chan S, Cidon MEU, Sherwin E, Chakrabarti A, Sadler C, Barnes J, Persic M, Smith S, Raj S, Borley A, Braybrooke JP, Staples E, Scott LC, Palmer CA, Moody M, Churn MJ, Pilger D, Zagnoli-Vieira G, Wijnhoven PWG, Mukesh MB, Roylance RR, Schouten PC, Levitt NC, McAdam K, Armstrong AC, Copson ER, McMurtry E, Galbraith S, Tischkowitz M, Provenzano E, O'Connor MJ, Earl HM. Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial. Nat Commun 2025; 16:4269. [PMID: 40360463 PMCID: PMC12075821 DOI: 10.1038/s41467-025-59151-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 04/11/2025] [Indexed: 05/15/2025] Open
Abstract
Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carboplatin that avoids enhanced toxicity but maintains anti-tumour activity. We investigated this schedule in a neoadjuvant, phase II-III, randomised controlled trial for gBRCAm breast cancers (ClinicalTrials.gov ID:NCT03150576; PARTNER). The research arm included carboplatin (Area Under the Curve 5, 3-weekly); paclitaxel (80 mg/m2, weekly) day 1, plus olaparib (150 mg twice daily) day 3-14 (4 cycles), followed by anthracycline-containing chemotherapy (3 cycles); control arm gave chemotherapy alone. The primary endpoint, pathological complete response rate, showed no statistical difference between research 64.1% (25/39); control 69.8% (30/43) (p = 0.59). However, estimated survival outcomes at 36-months demonstrated improved event-free survival: research 96.4%, control 80.1% (p = 0.04); overall survival: research 100%, control 88.2% (p = 0.04) and breast cancer specific survival: research 100%, control 88.2% (p = 0.04). There were no statistical differences in relapse-free survival and distant disease-free survival, both were: research 96.4%, control 87.9% (p = 0.20). Similarly, local recurrence-free survival and time to second cancer were both: research 96.4%, control 87.8% (p = 0.20). The PARTNER trial identified a safe, tolerable schedule combining neoadjuvant chemotherapy with olaparib. This combination demonstrated schedule-dependent overall survival benefit in early-stage gBRCAm breast cancer. This result needs confirmation in larger trials.
Collapse
Affiliation(s)
- Jean E Abraham
- Precision Breast Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom.
| | | | - Louise Grybowicz
- Cambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Karen Pinilla Alba
- Precision Breast Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom
| | - Alimu Dayimu
- Cambridge Clinical Trials Centre, Cancer Theme, University of Cambridge, Cambridge, United Kingdom
| | - Nikolaos Demiris
- Department of Statistics, Athens University of Economics and Business, Athens, Greece
| | - Caron Harvey
- Cambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Lynsey M Drewett
- Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom
| | - Rebecca Lucey
- Precision Breast Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom
| | - Alexander Fulton
- Precision Breast Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom
| | - Anne N Roberts
- Cambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Joanna R Worley
- Precision Breast Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
- Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom
| | - Ms Anita Chhabra
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Wendi Qian
- Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | | | - Richard Hardy
- Cambridge Clinical Trials Centre, Cancer Theme, University of Cambridge, Cambridge, United Kingdom
| | - Anne-Laure Vallier
- Cambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Steve Chan
- The City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
- Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, United Kingdom
| | - Maria Esther Una Cidon
- Royal Bournemouth General Hospital, University Hospitals Dorset NHS Foundation Trust, Bournemouth, United Kingdom
| | - Elizabeth Sherwin
- Ipswich Hospital, East Suffolk and North Essex NHS Foundation Trust, Ipswich, United Kingdom
| | | | - Claire Sadler
- Apconix Ltd, Alderley Edge, Cheshire, United Kingdom
| | | | - Mojca Persic
- University Hospital of Derby and Burton, Derby, United Kingdom
| | - Sarah Smith
- Bedford Hospital, Bedfordshire Hospitals NHS Foundation Trust, Bedford, United Kingdom
| | - Sanjay Raj
- University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
- Hampshire Hospitals NHS Foundation Trust, Hampshire, United Kingdom
| | | | - Jeremy P Braybrooke
- University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom
| | - Emma Staples
- Queens Hospital, Barking, Havering and Redbridge University Hospitals NHS Trust, Romford, United Kingdom
| | - Lucy C Scott
- Beatson West Of Scotland Cancer Centre, Glasgow, Scotland, United Kingdom
| | - Cheryl A Palmer
- Hinchingbrooke Hospital, North West Anglia NHS Foundation Trust, Huntingdon, United Kingdom
| | - Margaret Moody
- Macmillan Unit, West Suffolk Hospital NHS Foundation Trust, Bury St Edmunds, United Kingdom
| | - Mark J Churn
- Worcestershire Acute Hospitals NHS Trust, Worcester, United Kingdom
| | | | | | | | - Mukesh B Mukesh
- Colchester General Hospital, East Suffolk & North Essex NHS Trust, Colchester, United Kingdom
| | - Rebecca R Roylance
- University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Philip C Schouten
- Department of Histopathology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Nicola C Levitt
- Oxford University Hospital NHS Foundation Trust, Oxford, United Kingdom
| | - Karen McAdam
- Peterborough City Hospital, North West Anglia NHS Foundation Trust, Peterborough, United Kingdom
| | | | - Ellen R Copson
- Cancer Sciences Academic Unit, University of Southampton, Southampton, United Kingdom
| | | | | | - Marc Tischkowitz
- Department of Genomic Medicine, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Elena Provenzano
- Department of Histopathology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | | | - Helena M Earl
- Department of Oncology, University of Cambridge, Cambridge, United Kingdom
| |
Collapse
|
7
|
Boeszoermenyi A, Radeva DL, Schindler S, Valadares V, Padmanabha Das KM, Dubey A, Viennet T, Schmitt M, Kast P, Gelev VM, Stoyanov N, Burdzhiev N, Petrov O, Ficarro S, Marto J, Geffken EA, Dhe-Paganon S, Seo HS, Alexander ND, Cooley RB, Mehl RA, Kovacs H, Anklin C, Bermel W, Kuprov I, Takeuchi K, Arthanari H. Leveraging relaxation-optimized 1H- 13C F correlations in 4- 19F-phenylalanine as atomic beacons for probing structure and dynamics of large proteins. Nat Chem 2025:10.1038/s41557-025-01818-8. [PMID: 40325144 DOI: 10.1038/s41557-025-01818-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 03/28/2025] [Indexed: 05/07/2025]
Abstract
NMR spectroscopy of biomolecules provides atomic level information into their structure, dynamics and interactions with their binding partners. However, signal attenuation from line broadening caused by fast relaxation and signal overlap often limits the application of NMR to large macromolecular systems. Here we leverage the slow relaxation properties of 13C nuclei attached to 19F in aromatic 19F-13C spin pairs as well as the spin-spin coupling between the fluorinated 13C nucleus and the hydrogen atom at the meta-position to record two-dimensional 1H-13CF correlation spectra with transverse relaxation-optimized spectroscopy selection on 13CF. To accomplish this, we synthesized [4-19F13Cζ; 3,5-2H2ε] Phe, engineered for optimal relaxation properties, and adapted a residue-specific route to incorporate this residue globally into proteins and a site-specific 4-19F Phe encoding strategy. This approach resulted in narrow linewidths for proteins ranging from 30 kDa to 180 kDa, enabling interaction studies with small-molecule ligands without requiring specialized 19F-compatible probes.
Collapse
Affiliation(s)
- Andras Boeszoermenyi
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
| | - Denitsa L Radeva
- Faculty of Chemistry and Pharmacy, Sofia University, Sofia, Bulgaria
| | | | - Veronica Valadares
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Krishna M Padmanabha Das
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Abhinav Dubey
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Thibault Viennet
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
- Department of Chemistry | iNANO, Aarhus University, Aarhus, Denmark
| | - Max Schmitt
- Laboratory of Organic Chemistry, ETH Zurich, Zurich, Switzerland
| | - Peter Kast
- Laboratory of Organic Chemistry, ETH Zurich, Zurich, Switzerland
| | - Vladimir M Gelev
- Faculty of Chemistry and Pharmacy, Sofia University, Sofia, Bulgaria
| | - Nikolay Stoyanov
- Faculty of Chemistry and Pharmacy, Sofia University, Sofia, Bulgaria
| | - Nikola Burdzhiev
- Faculty of Chemistry and Pharmacy, Sofia University, Sofia, Bulgaria
| | - Ognyan Petrov
- Faculty of Chemistry and Pharmacy, Sofia University, Sofia, Bulgaria
| | - Scott Ficarro
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jarred Marto
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Ezekiel A Geffken
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Sirano Dhe-Paganon
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Hyuk-Soo Seo
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Nathan D Alexander
- Department of Biochemistry and Biophysics, Oregon State University, GCE4All Research Center, Corvallis, OR, USA
| | - Richard B Cooley
- Department of Biochemistry and Biophysics, Oregon State University, GCE4All Research Center, Corvallis, OR, USA
| | - Ryan A Mehl
- Department of Biochemistry and Biophysics, Oregon State University, GCE4All Research Center, Corvallis, OR, USA
| | | | | | | | - Ilya Kuprov
- School of Chemistry and Chemical Engineering, University of Southampton, Southampton, UK
- Department of Chemical and Biological Physics, Weizmann Institute of Science, Rehovot, Israel
| | - Koh Takeuchi
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
| | - Haribabu Arthanari
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
8
|
Julappagari M, Haque S, Tripathy S, Londhe S, Patel A, Banerjee R, Patra CR. Gold nanoparticles-based targeted delivery of rapamycin and Olaparib to breast cancer: An in vitro and in vivo approach. Bioorg Chem 2025; 158:108322. [PMID: 40073595 DOI: 10.1016/j.bioorg.2025.108322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 02/24/2025] [Accepted: 02/25/2025] [Indexed: 03/14/2025]
Abstract
Triple negative form of breast cancer (abbreviated as TNBC) is considered as the most aggressive form causing high mortality worldwide. Different treatment modalities such as chemotherapy, surgery, hormonal therapy and radiation therapy are employed for eliminating breast cancer, which are associated with many limitations. Therefore, considering the significance of metal nanoparticles in the biomedical sector, especially gold nanoparticles, in the current manuscript, we have designed and developed a combinatorial approach for synthesizing two types of gold (Au) nanoformulations (Au-Dex-MUA-Rapa, Au-Dex-MUA-Ola) using 11-mercaptoundecanoic acid (MUA), dexamethasone (Dex) (glucocorticoid receptor targeted molecule) along with rapamycin (Rapa: inhibitor of mTOR) or olaparib (Ola: inhibitor of PARP) against TNBC. These gold nanoformulations were characterized thoroughly using several analytical techniques such as TEM, spectroscopy, DLS, HPLC and ICPOES. The in vitro MTT assays (normal cells: HEK-293 and CHO) and ex vivo CAM assay displays the biocompatible properties of the conjugated gold nanoformulations. Further, the anticancer properties of the conjugated gold nanoformulations in TNBC cells (MDA-MB-231) were evaluated through several in vitro experiments along with plausible mechanism of action. The intraperitoneal administration of gold nanoformulations into the breast tumor bearing BALB/c mice inhibits the tumor growth and increases their survivability. Additionally, we have investigated the plausible mechanistic studies behind the anticancer properties of the conjugated gold nanoformulations. Finally, we have found the non-toxic nature of these nanoformulations at therapeutic dose. Considering the above results, the conjugated gold nanoformulations could be used as an alternative therapeutic strategy for the treatment of breast carcinoma in near future.
Collapse
Affiliation(s)
- Mamatha Julappagari
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India
| | - Shagufta Haque
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Sanchita Tripathy
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Swapnali Londhe
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Arti Patel
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India
| | - Rajkumar Banerjee
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
| | - Chitta Ranjan Patra
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
| |
Collapse
|
9
|
Renaudin X, Campalans A. Modulation of OGG1 enzymatic activities by small molecules, promising tools and current challenges. DNA Repair (Amst) 2025; 149:103827. [PMID: 40120404 DOI: 10.1016/j.dnarep.2025.103827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 03/04/2025] [Accepted: 03/09/2025] [Indexed: 03/25/2025]
Abstract
Oxidative DNA damage, resulting from endogenous cellular processes and external sources plays a significant role in mutagenesis, cancer progression, and the pathogenesis of neurological disorders. Base Excision Repair (BER) is involved in the repair of base modifications such as oxidations or alkylations as well as single strand breaks. The DNA glycosylase OGG1, initiates the BER pathway by the recognition and excision of 8oxoG, the most common oxidative DNA lesion, in both nuclear and mitochondrial DNA. Beyond DNA repair, OGG1 modulates transcription, particularly pro-inflammatory genes, linking oxidative DNA damage to broader biological processes like inflammation and aging. In cancer therapy, BER inhibition has emerged as a promising strategy to enhance treatment efficacy. Targeting OGG1 sensitizes cells to chemotherapies, radiotherapies, and PARP inhibitors, presenting opportunities to overcome therapy resistance. Additionally, OGG1 activators hold potential in mitigating oxidative damage associated with aging and neurological disorders. This review presents the development of several inhibitors and activators of OGG1 and how they have contributed to advance our knowledge in the fundamental functions of OGG1. We also discuss the new opportunities they provide for clinical applications in treating cancer, inflammation and neurological disorders. Finally, we also highlight the challenges in targeting OGG1, particularly regarding the off-target effects recently reported for some inhibitors and how we can overcome these limitations.
Collapse
Affiliation(s)
- Xavier Renaudin
- Université Paris-Saclay, iRCM/IBFJ, CEA, Genetic Stability, Stem Cells and Radiation, Fontenay-aux-Roses F-92260, France; Université Paris Cité, iRCM/IBFJ, CEA, Genetic Stability, Stem Cells and Radiation, Fontenay-aux-Roses F-92260, France
| | - Anna Campalans
- Université Paris-Saclay, iRCM/IBFJ, CEA, Genetic Stability, Stem Cells and Radiation, Fontenay-aux-Roses F-92260, France; Université Paris Cité, iRCM/IBFJ, CEA, Genetic Stability, Stem Cells and Radiation, Fontenay-aux-Roses F-92260, France.
| |
Collapse
|
10
|
Montaldo NP, Nilsen HL, Bordin DL. Targeting base excision repair in precision oncology. DNA Repair (Amst) 2025; 149:103844. [PMID: 40359788 DOI: 10.1016/j.dnarep.2025.103844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/27/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025]
Abstract
Targeting the DNA damage response (DDR) is a key strategy in cancer therapy, leveraging tumour-specific weaknesses in DNA repair pathways to enhance treatment efficacy. Traditional treatments, such as chemotherapy and radiation, use a broad, damage-inducing approach, whereas precision oncology aims to tailor therapies to specific genetic mutations or vulnerabilities. The clinical success of PARP inhibitors has renewed the interest in targeting DNA repair as a therapeutic strategy. Expanding the precision oncology toolbox by targeting the base excision repair (BER) pathway presents a promising avenue for cancer therapy, particularly in tumours that rely heavily on this pathway due to deficiencies in other DNA repair mechanisms. This review discusses how targeting BER could improve treatment outcomes, particularly in DDR-defective cancers. With ongoing advancements in biomarker discovery and drug development, BER-targeted therapies hold significant potential for refining precision oncology approaches.
Collapse
Affiliation(s)
- Nicola P Montaldo
- Department of Microbiology, Oslo University Hospital, Norway; Institute of Clinical Medicine, University of Oslo, Norway; CRESCO - Centre for embryology and healthy Development, University of Oslo, Norway
| | - Hilde Loge Nilsen
- Department of Microbiology, Oslo University Hospital, Norway; Institute of Clinical Medicine, University of Oslo, Norway; CRESCO - Centre for embryology and healthy Development, University of Oslo, Norway.
| | - Diana L Bordin
- Akershus University Hospital, Department of Clinical Molecular Biology, Unit for Precision Medicine, Lørenskog, Norway
| |
Collapse
|
11
|
Zhong L, Wang H, Lei C, Zou D. Bevacizumab combined with chemotherapy could be superior to chemotherapy alone in relapsed ovarian cancer after PARPi: evidence from a multi-center propensity score-matched analysis. J Gynecol Oncol 2025; 36:e36. [PMID: 39392165 PMCID: PMC12099040 DOI: 10.3802/jgo.2025.36.e36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 08/07/2024] [Accepted: 08/28/2024] [Indexed: 10/12/2024] Open
Abstract
OBJECTIVE A retrospective, multi-center propensity score-matched (PMS) analysis was conducted to investigate the efficacy and safety of the treatment strategy that combines bevacizumab and chemotherapy for patients with relapsed epithelial ovarian cancer (EOC) who previously received poly ADP-ribose polymerase inhibitors (PARPis). METHODS A total of 250 ovarian cancer (OC) patients relapsed after PARPi received chemotherapy with or without bevacizumab at 4 medical centers were enrolled in the study. For both treatments, Kaplan-Meier analysis and Cox regression were used to compare PFS. RESULTS In the multivariable analysis of 250 patients, the incorporation of bevacizumab into chemotherapy demonstrated a significant enhancement in PFS (hazard ratio [HR]=0.49; 95% confidence interval [CI]=0.34-0.72; p<0.001). Fifty-five patients were enrolled in Group A (bevacizumab combined with chemotherapy) and 55 were enrolled in Group B (chemotherapy alone regime) after PSM analysis. A statistically significant difference in PFS was observed between the 2 regimens (HR=0.62; 95% CI=0.40-0.97; p=0.036), suggesting that the bevacizumab combined with chemotherapy regimen confers superior clinical benefits. The median PFS was 11 months in Group A and 9 months in Group B. A significant variation was noted in PFS between patients without RCRS (HR=0.50; 95% CI=0.30-0.82) and the platinum-resistant subgroup (HR=0.31; 95% CI=0.14-0.68). Adverse effects of Grade 3-4 were more prevalent in Group A than in Group B. Additionally, instances of severe hypertension and bowel perforation were reported solely within Group A. CONCLUSION In patients diagnosed with EOC relapsed after PARPi, the regime of chemotherapy combined with bevacizumab is associated with better PFS.
Collapse
Affiliation(s)
- Lin Zhong
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
- Chongqing Specialized Medical Research Center of Ovarian Cancer, Chongqing, China
- Organoid Transformational Research Center, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Haixia Wang
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
- Chongqing Specialized Medical Research Center of Ovarian Cancer, Chongqing, China
- Organoid Transformational Research Center, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Cuirong Lei
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
- Chongqing Specialized Medical Research Center of Ovarian Cancer, Chongqing, China
- Organoid Transformational Research Center, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Dongling Zou
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
- Chongqing Specialized Medical Research Center of Ovarian Cancer, Chongqing, China
- Organoid Transformational Research Center, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China.
| |
Collapse
|
12
|
Zhu R, Eason K, Chin SF, Edwards PAW, Manzano Garcia R, Moulange R, Pan JW, Teo SH, Mukherjee S, Callari M, Caldas C, Sammut SJ, Rueda OM. Detecting homologous recombination deficiency for breast cancer through integrative analysis of genomic data. Mol Oncol 2025. [PMID: 40260608 DOI: 10.1002/1878-0261.70041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 02/25/2025] [Accepted: 03/30/2025] [Indexed: 04/23/2025] Open
Abstract
Homologous recombination deficiency (HRD) leads to genomic instability, and patients with HRD can benefit from HRD-targeting therapies. Previous studies have primarily focused on identifying HRD biomarkers using data from a single technology. Here we integrated features from different genomic data types, including total copy number (CN), allele-specific copy number (ASCN) and single nucleotide variants (SNV). Using a semi-supervised method, we developed HRD classifiers from 1404 breast tumours across two datasets based on their BRCA1/2 status, demonstrating improved HRD identification when aggregating different data types. Notably, HRD-positive tumours in ER-negative disease showed improved survival post-adjuvant chemotherapy, while HRD status strongly correlated with neoadjuvant treatment response. Furthermore, our analysis of cell lines highlighted a sensitivity to PARP inhibitors, particularly rucaparib, among predicted HRD-positive lines. Exploring somatic mutations outside BRCA1/2, we confirmed variants in several genes associated with HRD. Our method for HRD classification can adapt to different data types or resolutions and can be used in various scenarios to help refine patient selection for HRD-targeting therapies that might lead to better clinical outcomes.
Collapse
Affiliation(s)
- Rong Zhu
- School of Mathematics and Statistics, Beijing Institute of Technology, Beijing, China
- MRC Biostatistics Unit, University of Cambridge, UK
| | - Katherine Eason
- Cancer Research UK Cambridge Institute, University of Cambridge, UK
| | - Suet-Feung Chin
- Cancer Research UK Cambridge Institute, University of Cambridge, UK
| | | | | | | | | | | | - Sach Mukherjee
- MRC Biostatistics Unit, University of Cambridge, UK
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
- University of Bonn, Bonn, Germany
| | | | - Carlos Caldas
- School of Clinical Medicine, University of Cambridge, UK
| | - Stephen-John Sammut
- Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
- The Royal Marsden Hospital NHS Foundation Trust, London, UK
| | | |
Collapse
|
13
|
Hayes MN, Cohen-Gogo S, Kee L, Xiong X, Weiss A, Layeghifard M, Ladumor Y, Valencia-Sama I, Rajaselvam A, Kaplan DR, Villani A, Shlien A, Morgenstern DA, Irwin MS. DNA damage response deficiency enhances neuroblastoma progression and sensitivity to combination PARP and ATR inhibition. Cell Rep 2025; 44:115537. [PMID: 40220294 DOI: 10.1016/j.celrep.2025.115537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 02/03/2025] [Accepted: 03/17/2025] [Indexed: 04/14/2025] Open
Abstract
Sequencing of neuroblastoma (NB) tumors has revealed genetic alterations in genes involved in DNA damage response (DDR) pathways. However, roles for specific alterations of DDR genes in pediatric solid tumors remain poorly understood. To address this, mutations in the DDR pathway including Brca2, Atm, and Palb2 were incorporated into an established zebrafish MYCN transgenic model (Tg(dbh:EGFP-MYCN)). These mutations enhance NB formation and metastasis and result in upregulation of cell-cycle checkpoint and DNA damage repair signatures, revealing molecular vulnerabilities in DDR-deficient NB. DDR gene knockdown in zebrafish and human NB cells increases sensitivity to the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, and this effect is enhanced by inhibition of the ataxia telangiectasia and rad3-related (ATR) kinase. This work provides in vivo evidence demonstrating that alterations in certain DDR-pathway genes promote aggressive NB and supports combination PARP + ATR inhibitor therapy for NB patients with tumors harboring specific genetic alterations in DDR.
Collapse
Affiliation(s)
- Madeline N Hayes
- Developmental, Stem Cell and Cancer Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
| | - Sarah Cohen-Gogo
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Lynn Kee
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Xueting Xiong
- Developmental, Stem Cell and Cancer Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Alex Weiss
- Developmental, Stem Cell and Cancer Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Mehdi Layeghifard
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Yagnesh Ladumor
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | | | - Anisha Rajaselvam
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - David R Kaplan
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Neurosciences and Mental Health Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Anita Villani
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Adam Shlien
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Daniel A Morgenstern
- Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Meredith S Irwin
- Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
| |
Collapse
|
14
|
Nikolova S, Ma W, Sagoo GS, Punekar Y, Sheppard E. Cost-effectiveness of companion BRCA testing and adjuvant olaparib treatment in patients with BRCA-mutated high-risk HER2-negative early breast cancer. Front Oncol 2025; 15:1419071. [PMID: 40303990 PMCID: PMC12037560 DOI: 10.3389/fonc.2025.1419071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 03/19/2025] [Indexed: 05/02/2025] Open
Abstract
Background and objective As the healthcare industry evolves towards precision medicine, methods to assess the value of integrating companion diagnostics in clinical practice through adequate reimbursement levels are becoming essential. Cost-effectiveness analysis is an established tool used to inform the reimbursement of health technologies. Methods A decision-tree model was developed to estimate the incremental cost-effectiveness of companion BRCA testing and olaparib use versus no testing and the standard of care (SoC) for patients with BRCA-mutated high-risk HER2-negative early breast cancer from a UK NHS/PSS perspective. Results BRCA testing combined with treatment with adjuvant olaparib was associated with an incremental cost-effectiveness ratio (ICER) of £49,327 per quality-adjusted life-year (QALY) gained and an ICER of £86,349 per QALY gained for patients with triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 negative/hormone receptor-positive (HER2-/HR+) breast cancer, respectively, compared to no testing and treatment with SoC. This difference in ICER is due to significantly improved outcomes for patients with TNBC who were treated with targeted therapy. For both patient subgroups with early breast cancer, testing and olaparib improved patient outcomes and, despite its relatively high cost, the test and treat strategy was deemed to represent an acceptable use of resources. Conclusions The advancement of high-throughput sequencing technologies, coupled with the rise of targeted treatments in recent years, has facilitated a shift from conventional medical practices to individualized oncology therapeutic approaches. Our analysis presented the value of combining genetic sequencing and targeted therapy for patients with breast cancer carrying BRCA mutations and also provided the prototype of a testing model that can be utilized to promote precision medicine for better patient outcomes.
Collapse
Affiliation(s)
- Silviya Nikolova
- Health Economics and Outcomes Research (HEOR) Ltd, Cardiff, United Kingdom
| | | | - Gurdeep S. Sagoo
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom
| | - Yogesh Punekar
- IQVIA, EMEA Real World Methods & Evidence Generation, London, United Kingdom
| | | |
Collapse
|
15
|
Manickam R, Santhana S, Xuan W, Bisht KS, Tipparaju SM. Nampt: a new therapeutic target for modulating NAD + levels in metabolic, cardiovascular, and neurodegenerative diseases. Can J Physiol Pharmacol 2025. [PMID: 40203459 DOI: 10.1139/cjpp-2024-0400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
NAD+ is an important cofactor involved in regulating many biochemical processes in cells. An imbalance in NAD+/NADH ratio is linked to many diseases. NAD+ is depleted in diabetes, cardiovascular and neurodegenerative diseases, and in aging, and is increased in tumor cells. NAD+ is generated in cells via the de novo, Preiss-Handler, and salvage pathways. Most of the cellular NAD+ is generated through Nampt activation, a key rate-limiting enzyme that is involved in the salvage pathway. Restoration of NAD+/NADH balance offers therapeutic advantages for improving tissue homeostasis and function. NAD+ is known to benefit and restore the body's physiological mechanisms, including DNA replication, chromatin and epigenetic modifications, and gene expression. Recent studies elucidate the role of NAD+ in cells utilizing transgenic mouse models. Translational new therapeutics are positioned to utilize the NAD+ restoration strategies for overcoming the drawbacks that exist in the pharmacological toolkit. The present review highlights the significance of Nampt-NAD+ axis as a major player in energy metabolism and provides an overview with insights into future strategies, providing pharmacological advantages to address current and future medical needs.
Collapse
Affiliation(s)
- Ravikumar Manickam
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USA
| | - Sandhya Santhana
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USA
| | - Wanling Xuan
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USA
| | - Kirpal S Bisht
- Department of Chemistry, College of Arts and Sciences, University of South Florida, Tampa, FL 33620, USA
| | - Srinivas M Tipparaju
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USA
| |
Collapse
|
16
|
Lahiri S, Hamilton G, Moore G, Goehring L, Huang TT, Jensen RB, Rothenberg E. BRCA2 prevents PARPi-mediated PARP1 retention to protect RAD51 filaments. Nature 2025; 640:1103-1111. [PMID: 40140565 DOI: 10.1038/s41586-025-08749-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 02/06/2025] [Indexed: 03/28/2025]
Abstract
The tumour-suppressor protein BRCA2 has a central role in homology-directed DNA repair by enhancing the formation of RAD51 filaments on resected single-stranded DNA generated at double-stranded DNA breaks and stimulating RAD51 activity1,2. Individuals with BRCA2 mutations are predisposed to cancer; however, BRCA2-deficient tumours are often responsive to targeted therapy with PARP inhibitors (PARPi)3-6. The mechanism by which BRCA2 deficiency renders cells sensitive to PARPi but with minimal toxicity in cells heterozygous for BRCA2 mutations remains unclear. Here we identify a previously unknown role of BRCA2 that is directly linked to the effect of PARP1 inhibition. Using biochemical and single-molecule approaches, we demonstrate that PARPi-mediated PARP1 retention on a resected DNA substrate interferes with RAD51 filament stability and impairs RAD51-mediated DNA strand exchange. Full-length BRCA2 protects RAD51 filaments and counteracts the instability conferred by PARPi-mediated retention by preventing the binding of PARP1 to DNA. Extending these findings to a cellular context, we use quantitative single-molecule localization microscopy to show that BRCA2 prevents PARPi-induced PARP1 retention at homologous-recombination repair sites. By contrast, BRCA2-deficient cells exhibit increased PARP1 retention at these lesions in response to PARPi. These results provide mechanistic insights into the role of BRCA2 in maintaining RAD51 stability and protecting homologous-recombination repair sites by mitigating PARPi-mediated PARP1 retention.
Collapse
Affiliation(s)
- Sudipta Lahiri
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA
| | - George Hamilton
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
| | - Gemma Moore
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA
| | - Liana Goehring
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
| | - Tony T Huang
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA
| | - Ryan B Jensen
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.
| | - Eli Rothenberg
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA.
| |
Collapse
|
17
|
Li P, Wu D, Yu X. Targeting dePARylation in cancer therapy. DNA Repair (Amst) 2025; 148:103824. [PMID: 40056493 DOI: 10.1016/j.dnarep.2025.103824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/25/2025] [Accepted: 02/27/2025] [Indexed: 03/10/2025]
Abstract
Poly(ADP-ribosyl)ation (PARylation), a reversible post-translational modification mediated by poly(ADP-ribose) polymerases (PARPs), plays crucial roles in DNA replication and DNA damage repair. Since interfering PARylation induces selective cytotoxicity in tumor cells with homologous recombination defects, PARP inhibitors (PARPi) have significant clinical impacts in treating BRCA-mutant cancer patients. Likewise, dePARylation is also essential for optimal DNA damage response and genomic stability. This process is mediated by a group of dePARylation enzymes, such as poly(ADP-ribose) glycohydrolase (PARG). Currently, several novel PARG inhibitors have been developed and examined in preclinical and clinical studies, demonstrating promising anti-cancer activity distinct from PARP inhibitors. This review discusses the role of dePARylation in genome stability and the potential of PARG inhibitors in cancer therapy.
Collapse
Affiliation(s)
- Peng Li
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Duo Wu
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China
| | - Xiaochun Yu
- Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
| |
Collapse
|
18
|
Qureshi Z, Fatima E, Safi A, Khanzada M, Altaf F. Talazoparib for the Treatment of Metastatic Castration-resistant Prostate Cancer: A Narrative Review. Am J Clin Oncol 2025; 48:206-214. [PMID: 39761644 DOI: 10.1097/coc.0000000000001159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2025]
Abstract
Breast and prostate cancer are among the most commonly diagnosed cancers worldwide. Recent advances in tumor sequencing and gene studies have led to a paradigm shift from treatment centered on the type of tumor to therapy more focused on specific immune phenotype markers and molecular alterations. In this review, we discuss the utility and function of talazoparib concerning prostate cancer treatment and summarize recent and planned clinical trials on talazoparib. We searched medical databases for articles relating to the use of talazoparib in prostate cancer from inception. Poly ADP ribose polymerase (PARP) is a family of 17 necessary DNA repair enzymes responsible for base excision repair, single-strand break repair, and double-strand break repair. PARP inhibitors are a class of oral targeted therapies that compete for the NAD + binding site on PARP molecules. Talazoparib, a potent PARP inhibitor, has emerged as a significant therapeutic option in the treatment of metastatic castration-resistant prostate cancer (mCRPC), particularly for patients with specific genetic alterations. Its role as a PARP inhibitor makes it a targeted therapy, focusing on cancer cells with DNA repair deficiencies. Talazoparib's role as a biomarker-directed therapy in advanced prostate cancer has been increasingly recognized. The TALAPRO-1 demonstrated durable antitumor activity in mCRPC patients. TALAPRO-2 is a notable clinical trial, specifically examining the effectiveness of Talazoparib when used in combination therapies. Current investigations demonstrate a significant improvement in survival outcomes for the patients of mCRPC, making Talazoparib a promising intervention.
Collapse
Affiliation(s)
- Zaheer Qureshi
- The Frank H. Netter M.D. School of Medicine at Quinnipiac University, Bridgeport, CT
| | - Eeshal Fatima
- Department of Medicine, Services Institute of Medical Sciences
| | - Adnan Safi
- Department of Medicine, Lahore General Hospital
| | - Mikail Khanzada
- Department of Internal Medicine, Lahore Medical and Dental College, Lahore, Pakistan
| | - Faryal Altaf
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai/BronxCare Health System, New York, NY
| |
Collapse
|
19
|
Sheth AS, Chan KK, Liu S, Wan J, Angus SP, Rhodes SD, Mitchell DK, Davis C, Ridinger M, Croucher PJ, Zeidan AM, Wijeratne A, Qian S, Tran NT, Sierra Potchanant EA. PLK1 Inhibition Induces Synthetic Lethality in Fanconi Anemia Pathway-Deficient Acute Myeloid Leukemia. CANCER RESEARCH COMMUNICATIONS 2025; 5:648-667. [PMID: 40111122 PMCID: PMC12011380 DOI: 10.1158/2767-9764.crc-24-0260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 10/29/2024] [Accepted: 03/18/2025] [Indexed: 03/22/2025]
Abstract
SIGNIFICANCE This work demonstrates that FA pathway mutations, which are frequently observed in sporadic AML, induce hypersensitivity to PLK1 inhibition, providing rationale for a novel synthetic lethal therapeutic strategy for this patient population.
Collapse
Affiliation(s)
- Aditya S. Sheth
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ka-Kui Chan
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
| | - Sheng Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jun Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Steve P. Angus
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
| | - Steven D. Rhodes
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
| | - Dana K. Mitchell
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
| | - Christopher Davis
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
| | | | | | - Amer M. Zeidan
- Yale University and Yale Cancer Center, New Haven, Connecticut
| | - Aruna Wijeratne
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Shaomin Qian
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ngoc Tung Tran
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
| | - Elizabeth A. Sierra Potchanant
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
| |
Collapse
|
20
|
Moretto R, Germani MM, Carullo M, Conca V, Minelli A, Giordano M, Bruno R, Rossini D, Gusmaroli E, De Grandis MC, Antoniotti C, Salvatore L, Passardi A, Tamberi S, Scartozzi M, Pietrantonio F, Lonardi S, Ugolini C, Masi G, Cremolini C. Exploring the Prognostic and Predictive Impact of Genomic Loss of Heterozygosity and Homologous Recombination Deficiency Alterations in Patients With Metastatic Colorectal Cancer. JCO Precis Oncol 2025; 9:e2400567. [PMID: 40249885 DOI: 10.1200/po-24-00567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 12/20/2024] [Accepted: 03/10/2025] [Indexed: 04/20/2025] Open
Abstract
PURPOSE Genomic loss-of-heterozygosity (gLOH) consists in the loss of chromosomal regions and is associated with homologous recombination repair (HRR) system deficiency. We explored the role of gLOH and HRR-related gene alterations in metastatic colorectal cancer (mCRC). METHODS FoundationOne CDx assay was used to determine the percentage of gLOH and the presence of alterations in 27 HRR-related genes in archival chemo-naïve tumor tissues of patients with mCRC treated with first-line oxaliplatin- or irinotecan-based doublets and triplet ± anti-PD-L1. RESULTS Overall, 243 samples were analyzed. None of the nine deficient mismatch repair/microsatellite instability high tumors were gLOH-high, while 16 (7%) of 234 proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors were gLOH-high. In the pMMR/MSS population, six (3%) and 18 (8%) had at least a biallelic or monoallelic HRR-related gene alteration, respectively. Among patients receiving FOLFOXIRI alone (n = 68) or with an anti-PD-L1 (N = 90), higher benefit from the addition of the immune checkpoint inhibitor (ICI) was observed in the gLOH-high subgroup (n = 12), in terms of both progression-free survival (PFS; Pint = .02) and overall survival (OS; Pint = .03). No differences in PFS or OS were reported between patients treated with first-line oxaliplatin- (n = 40) versus irinotecan-based doublets (n = 25) or with the triplet FOLFOXIRI (n = 68) versus doublets (n = 65), according to the gLOH status. Among patients not receiving an anti-PD-L1, longer PFS was observed in the gLOH-low group (n = 138) versus the gLOH-high (n = 6) group (5.1 v 12.1 months; hazard ratio, 8.73 [95% CI, 3.64 to 20.9]; P < .001), and this was confirmed in the multivariate analysis (P < .001). No prognostic impact of monoallelic or biallelic HRR-related gene alterations was shown. CONCLUSION In pMMR/MSS mCRC, gLOH-high was associated with worse prognosis and higher benefit from the addition of anti-PD-L1 agents to chemotherapy. If confirmed in larger series, these results may inform the design of clinical trials.
Collapse
Affiliation(s)
- Roberto Moretto
- Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | - Marco Maria Germani
- Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Martina Carullo
- Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Veronica Conca
- Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Alessandro Minelli
- Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
- Clinical Oncology Unit, San Paolo Hospital, Civitavecchia, Italy
| | - Mirella Giordano
- Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Rossella Bruno
- Unit of Pathological Anatomy, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | - Daniele Rossini
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Eleonora Gusmaroli
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Caterina De Grandis
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Carlotta Antoniotti
- Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Lisa Salvatore
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Stefano Tamberi
- Oncology Unit, Ravenna Hospital, AUSL Romagna, Ravenna, Italy
| | - Mario Scartozzi
- Medical Oncology, University of Cagliari, Via Università, Cagliari, Italy
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Clara Ugolini
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy
| | - Gianluca Masi
- Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Chiara Cremolini
- Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| |
Collapse
|
21
|
Zhang N, Zhang W, Liu Y, Qiu H, Wu Q. Prevalence of breast cancer in ovarian cancer patients and its impact on patient survival: An analysis of the surveillance, epidemiology, and end results data. TUMORI JOURNAL 2025; 111:164-173. [PMID: 40077918 DOI: 10.1177/03008916251323224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2025]
Abstract
BACKGROUND Patients with high-grade serous ovarian carcinoma (HGSOC) often have a personal and/or family history of breast cancers. However, the clinical association and underlying molecular interaction between breast cancer and HGSOC is not well understood. In this study, the clinical characteristics and outcomes of HGSOC patients with or without breast cancer were compared. METHODS Eligible patient information was extracted from the Surveillance, Epidemiology, and End Results database. Kaplan-Meier and Cox proportional hazards regression models were used to determine survival outcomes and prognostic factors. RESULTS A total of 3065 HGSOC (ICD-O-3 code 8461/3) patients were identified from 1975 to 2020, among whom 239 (9.56%) had co-existing breast cancers. HGSOC with breast cancers tended to have more stage I-II ovarian cancer (20.92% vs 13.79%), less metastatic diseases (25.1% vs 32.13%) and had a higher probability of undergoing surgery (94.1% vs 87.9%). The overall survival of HGSOC patients with breast cancer was better than that of patients without breast cancer (HR = 0.77, 95% CI 0.65 to 0.91; P = 0.0015). Further, patients who developed ovarian cancer before breast cancer had better overall survival than those who developed breast cancer before or simultaneously with ovarian cancer (HR = 0.35, 95% CI 0.23 to 0.52; P < 0.001). CONCLUSION HGSOC combined with breast cancer is a common phenomenon. HGSOC patients with breast cancer, especially those diagnosed with ovarian cancer before breast cancer have a better prognosis. Further validation is warranted and more genetic and mechanistical study is needed.
Collapse
Affiliation(s)
- Ni Zhang
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wanfang Zhang
- Department of Oncology, Taikang Tongji (Wuhan) Hospital, Wuhan, China
| | - Yu Liu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Hui Qiu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qiuji Wu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| |
Collapse
|
22
|
Wang C, Han X, Kong S, Zhang S, Ning H, Wu F. Deciphering the mechanisms of PARP inhibitor resistance in prostate cancer: Implications for precision medicine. Biomed Pharmacother 2025; 185:117955. [PMID: 40086424 DOI: 10.1016/j.biopha.2025.117955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 02/23/2025] [Accepted: 03/04/2025] [Indexed: 03/16/2025] Open
Abstract
Prostate cancer is a leading malignancy among men. While early-stage prostate cancer can be effectively managed, metastatic prostate cancer remains incurable, with a median survival of 3-5 years. The primary treatment for advanced prostate cancer is androgen deprivation therapy (ADT), but resistance to ADT often leads to castrationresistant prostate cancer (CRPC), presenting a significant therapeutic challenge. The advent of precision medicine has introduced promising new treatments, including PARP inhibitors (PARPi), which target defects in DNA repair mechanisms in cancer cells. PARPi have shown efficacy in treating advanced prostate cancer, especially in patients with metastatic CRPC (mCRPC) harboring homologous recombination (HR)-associated gene mutations. Despite these advancements, resistance to PARPi remains a critical issue. Here, we explored the primary mechanisms of PARPi resistance in prostate cancer. Key resistance mechanisms include homologous recombination recovery through reverse mutations in BRCA genes, BRCA promoter demethylation, and non-degradation of mutated BRCA proteins. The tumor microenvironment and overactivation of the base excision repair pathway also play significant roles in bypassing PARPi-induced synthetic lethality. In addition, we explored the clinical implications and therapeutic strategies to overcome resistance,emphasizing the need for precision medicine approaches. Our findings highlight the need for comprehensive strategies to improve PARPi sensitivity and effectiveness,ultimately aiming to extend patient survival and improve the quality of life for those with advanced prostate cancer. As our understanding of PARPi resistance evolves, more diverse and effective individualized treatment regimens will emerge.
Collapse
Affiliation(s)
- Cheng Wang
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, PR China
| | - Xiaoran Han
- Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong Province, PR China
| | - Shaoqiu Kong
- Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong Province, PR China
| | - Shanhua Zhang
- Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong Province, PR China
| | - Hao Ning
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, PR China; Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong Province, PR China.
| | - Fei Wu
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, PR China; Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong Province, PR China.
| |
Collapse
|
23
|
Li P, Zhang Y, Yu Y. A large-scale method to measure the absolute stoichiometries of protein Poly-ADP-Ribosylation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.27.645734. [PMID: 40196648 PMCID: PMC11974908 DOI: 10.1101/2025.03.27.645734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Poly-ADP-ribosylation (PARylation) is a reversible posttranslational modification that occurs in higher eukaryotes. While thousands of PARylated substrates have been identified, the specific biological functions of most PARylated proteins remain elusive. PARylation stoichiometry is a critical parameter to assess the potential functions of a PARylated protein. Here, we developed a large-scale strategy to measure the absolute stoichiometries of protein PARylation. By integrating mild cell lysis, boronate enrichment and carefully designed titration experiments, we were able to determine the PARylation stoichiometries for a total of 235 proteins. This approach enables the capture of all PARylation events on various amino acid acceptors. We revealed that PARylation occupancy spans over three orders of magnitude. However, most PARylation events occur at low stoichiometric values (median 0.578%). Notably, we observed that high stoichiometry PARylation (>1%) predominantly targets proteins involved in transcription regulation and chromatin remodeling. Thus, our study provides a systems-scale, quantitative view of PARylation stoichiometries under genotoxic conditions, which serves as invaluable resources for future functional studies of this important protein posttranslational modification.
Collapse
Affiliation(s)
- Peng Li
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yajie Zhang
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yonghao Yu
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| |
Collapse
|
24
|
Rodríguez-Sánchez A, Quijada-Álamo M, Pérez-Carretero C, Herrero AB, Arroyo-Barea A, Dávila-Valls J, Rubio A, García de Coca A, Benito-Sánchez R, Rodríguez-Vicente AE, Hernández-Rivas JM, Hernández-Sánchez M. SAMHD1 dysfunction impairs DNA damage response and increases sensitivity to PARP inhibition in chronic lymphocytic leukemia. Sci Rep 2025; 15:10446. [PMID: 40140468 PMCID: PMC11947222 DOI: 10.1038/s41598-025-93629-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Chronic lymphocytic leukemia (CLL) is a clinically and genetically heterogenous disease. Recent next-generation sequencing (NGS) studies have uncovered numerous low-frequency mutated genes in CLL patients, with SAMHD1 emerging as a candidate driver gene. However, the biological and clinical implications of SAMHD1 mutations remain unclear. Using CRISPR/Cas9, we generated CLL models to investigate the impact of SAMHD1 deficiency on pathogenesis and explore therapeutic strategies. Moreover, we performed NGS in treatment-naïve CLL patients to characterize SAMHD1 mutations and employed RNA-sequencing to evaluate their clinical significance. Our study shows that SAMHD1 inactivation impairs the DNA damage response by reducing homologous recombination efficiency through BRCA1 and RAD51 dysregulation. Importantly, SAMHD1 colocalizes with BRCA1 at DNA damage sites in CLL cells. This research also identifies that SAMHD1-mutated cells are more sensitive to PARP inhibition. Clinically, SAMHD1 dysfunction negatively impacts clinical outcome of CLL cases: SAMHD1 mutations reduce failure-free survival (median 46 vs 57 months, p = 0.033), while low SAMHD1 expression associates with shorter time to first treatment (median 47 vs 77 months; p = 0.00073). Overall, this study elucidates that SAMHD1 dysfunction compromises DNA damage response mechanisms, potentially contributing to unfavorable clinical outcomes in CLL, and proposes PARP-inhibitors as a potential therapeutic approach for SAMHD1-mutated CLL cells.
Collapse
MESH Headings
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- SAM Domain and HD Domain-Containing Protein 1/genetics
- SAM Domain and HD Domain-Containing Protein 1/metabolism
- DNA Damage
- Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
- Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
- Mutation
- Female
- Male
- BRCA1 Protein/metabolism
- BRCA1 Protein/genetics
- Middle Aged
- Aged
- CRISPR-Cas Systems
- Cell Line, Tumor
Collapse
Affiliation(s)
- Alberto Rodríguez-Sánchez
- Centro de Investigación del Cáncer, Universidad de Salamanca, IBSAL, IBMCC, CSIC, Salamanca, Spain
- Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain
| | - Miguel Quijada-Álamo
- Centro de Investigación del Cáncer, Universidad de Salamanca, IBSAL, IBMCC, CSIC, Salamanca, Spain
- Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Claudia Pérez-Carretero
- Centro de Investigación del Cáncer, Universidad de Salamanca, IBSAL, IBMCC, CSIC, Salamanca, Spain
- Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain
| | - Ana B Herrero
- Centro de Investigación del Cáncer, Universidad de Salamanca, IBSAL, IBMCC, CSIC, Salamanca, Spain
- Departamento de Medicina, Unidad de Medicina Molecular, Universidad de Salamanca, Salamanca, Spain
| | - Andrés Arroyo-Barea
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain
| | - Julio Dávila-Valls
- Servicio de Hematología, Hospital Nuestra Señora de Sonsoles, SACYL, Ávila, Spain
| | - Araceli Rubio
- Servicio de Hematología, Hospital Miguel Servet, SERGAS, Zaragoza, Spain
| | | | - Rocío Benito-Sánchez
- Centro de Investigación del Cáncer, Universidad de Salamanca, IBSAL, IBMCC, CSIC, Salamanca, Spain
- Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain
| | - Ana E Rodríguez-Vicente
- Centro de Investigación del Cáncer, Universidad de Salamanca, IBSAL, IBMCC, CSIC, Salamanca, Spain
- Departamento de Anatomía e Histología Humanas, Facultad de Medicina, Universidad de Salamanca, Salamanca, Spain
| | - Jesús María Hernández-Rivas
- Centro de Investigación del Cáncer, Universidad de Salamanca, IBSAL, IBMCC, CSIC, Salamanca, Spain
- Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain
| | - María Hernández-Sánchez
- Centro de Investigación del Cáncer, Universidad de Salamanca, IBSAL, IBMCC, CSIC, Salamanca, Spain.
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
| |
Collapse
|
25
|
Xu Z, Zhu M, Geng L, Zhang J, Xia J, Wang Q, An H, Xia A, Yu Y, Liu S, Tong J, Zhu WG, Jiang Y, Sun B. Targeting NAT10 attenuates homologous recombination via destabilizing DNA:RNA hybrids and overcomes PARP inhibitor resistance in cancers. Drug Resist Updat 2025; 81:101241. [PMID: 40132530 DOI: 10.1016/j.drup.2025.101241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/09/2025] [Accepted: 03/16/2025] [Indexed: 03/27/2025]
Abstract
AIMS RNA metabolism has been extensively studied in DNA double-strand break (DSB) repair. The RNA acetyltransferase N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification in DSB repair remains largely elusive. In this study, we aim to decipher the role for ac4C modification by NAT10 in DSB repair in hepatocellular carcinoma (HCC). METHODS Laser micro-irradiation and chromatin immunoprecipitation (ChIP) were used to assess the accumulation of ac4C modification and NAT10 at DSB sites. Cryo-electron microscopy (cryo-EM) was used to determine the structures of NAT10 in complex with its inhibitor, remodelin. Hepatocyte-specific deletion of NAT10 mouse models were adopted to detect the effects of NAT10 on HCC progression. Subcutaneous xenograft, human HCC organoid and patient-derived xenograft (PDX) model were exploited to determine the therapy efficiency of the combination of a poly (ADP-ribose) polymerase 1 (PARP1) inhibitor (PARPi) and remodelin. RESULTS NAT10 promptly accumulates at DSB sites, where it executes ac4C modification on RNAs at DNA:RNA hybrids dependent on PARP1. This in turn enhances the stability of DNA:RNA hybrids and promotes homologous recombination (HR) repair. The ablation of NAT10 curtails HCC progression. Furthermore, the cryo-EM yields a remarkable 2.9 angstroms resolution structure of NAT10-remodelin, showcasing a C2 symmetric architecture. Remodelin treatment significantly enhanced the sensitivity of HCC cells to a PARPi and targeting NAT10 also restored sensitivity to a PARPi in ovarian and breast cancer cells that had developed resistance. CONCLUSION Our study elucidated the mechanism of NAT10-mediated ac4C modification in DSB repair, revealing that targeting NAT10 confers synthetic lethality to PARP inhibition in HCC. Our findings suggest that co-inhibition of NAT10 and PARP1 is an effective novel therapeutic strategy for patients with HCC and have the potential to overcome PARPi resistance.
Collapse
Affiliation(s)
- Zhu Xu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China; Department of Cell Biology, School of Life Science, Anhui Medical University, Hefei, Anhui, China
| | - Mingming Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China
| | - Longpo Geng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China
| | - Jun Zhang
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, Guangdong, China
| | - Jing Xia
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China
| | - Qiang Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China
| | - Hongda An
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China
| | - Anliang Xia
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China
| | - Yuanyuan Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China
| | - Shihan Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China
| | - Junjie Tong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China; Department of Cell Biology, School of Life Science, Anhui Medical University, Hefei, Anhui, China
| | - Wei-Guo Zhu
- International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, Guangdong, China
| | - Yiyang Jiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China; Department of Cell Biology, School of Life Science, Anhui Medical University, Hefei, Anhui, China.
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; MOE Innovation Center for Basic Research in Tumor Immunotherapy, Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China.
| |
Collapse
|
26
|
Lin X, Qiu Y, Soni A, Stuschke M, Iliakis G. Reversing regulatory safeguards: Targeting the ATR pathway to overcome PARP inhibitor resistance. MOLECULAR THERAPY. ONCOLOGY 2025; 33:200934. [PMID: 39968096 PMCID: PMC11834088 DOI: 10.1016/j.omton.2025.200934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
Abstract
The development of poly (ADP-ribose) polymerase inhibitors (PARPis) is widely considered a therapeutic milestone in the management of BRCA1/2-deficient malignancies. Since a growing number of cancer treatment guidelines include PARPis, the inevitably emerging PARPi resistance becomes a serious limitation that must be addressed. Targeting the DNA damage response signaling kinase, ATR (ataxia telangiectasia and rad3-related serine/threonine kinase), activated in response to PARPi-induced replication stress, represents a promising approach in fighting PARPi-resistant cancers. The success of this combination therapy in preclinical models has inspired efforts to translate its potential through extensive clinical research and clinical trials. However, the available clinical evidence suggests that PARPi/ATRi combinations have yet to reach their anticipated therapeutic potential. In this review, we summarize work elucidating mechanisms underpinning the effectiveness of ATRi in fighting PARPi resistance and review translational studies reporting efficacy in different types of cancer. Finally, we discuss potential biomarkers of patient selection for customized combinations of PARPi/ATRi treatments.
Collapse
Affiliation(s)
- Xixi Lin
- Department of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
- Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Ye Qiu
- Department of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
- Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Aashish Soni
- Department of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
- Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Martin Stuschke
- Department of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, German Cancer Research Center (DKFZ), 45147 Essen, Germany
| | - George Iliakis
- Department of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
- Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
| |
Collapse
|
27
|
Cottrell TR, Lotze MT, Ali A, Bifulco CB, Capitini CM, Chow LQM, Cillo AR, Collyar D, Cope L, Deutsch JS, Dubrovsky G, Gnjatic S, Goh D, Halabi S, Kohanbash G, Maecker HT, Maleki Vareki S, Mullin S, Seliger B, Taube J, Vos W, Yeong J, Anderson KG, Bruno TC, Chiuzan C, Diaz-Padilla I, Garrett-Mayer E, Glitza Oliva IC, Grandi P, Hill EG, Hobbs BP, Najjar YG, Pettit Nassi P, Simons VH, Subudhi SK, Sullivan RJ, Takimoto CH. Society for Immunotherapy of Cancer (SITC) consensus statement on essential biomarkers for immunotherapy clinical protocols. J Immunother Cancer 2025; 13:e010928. [PMID: 40054999 PMCID: PMC11891540 DOI: 10.1136/jitc-2024-010928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 02/05/2025] [Indexed: 03/12/2025] Open
Abstract
Immunotherapy of cancer is now an essential pillar of treatment for patients with many individual tumor types. Novel immune targets and technical advances are driving a rapid exploration of new treatment strategies incorporating immune agents in cancer clinical practice. Immunotherapies perturb a complex system of interactions among genomically unstable tumor cells, diverse cells within the tumor microenvironment including the systemic adaptive and innate immune cells. The drive to develop increasingly effective immunotherapy regimens is tempered by the risk of immune-related adverse events. Evidence-based biomarkers that measure the potential for therapeutic response and/or toxicity are critical to guide optimal patient care and contextualize the results of immunotherapy clinical trials. Responding to the lack of guidance on biomarker testing in early-phase immunotherapy clinical trials, we propose a definition and listing of essential biomarkers recommended for inclusion in all such protocols. These recommendations are based on consensus provided by the Society for Immunotherapy of Cancer (SITC) Clinical Immuno-Oncology Network (SCION) faculty with input from the SITC Pathology and Biomarker Committees and the Journal for ImmunoTherapy of Cancer readership. A consensus-based selection of essential biomarkers was conducted using a Delphi survey of SCION faculty. Regular updates to these recommendations are planned. The inaugural list of essential biomarkers includes complete blood count with differential to generate a neutrophil-to-lymphocyte ratio or systemic immune-inflammation index, serum lactate dehydrogenase and albumin, programmed death-ligand 1 immunohistochemistry, microsatellite stability assessment, and tumor mutational burden. Inclusion of these biomarkers across early-phase immunotherapy clinical trials will capture variation among trials, provide deeper insight into the novel and established therapies, and support improved patient selection and stratification for later-phase clinical trials.
Collapse
Affiliation(s)
- Tricia R Cottrell
- Queen's University Sinclair Cancer Research Institute, Kingston, Ontario, Canada
| | | | - Alaa Ali
- Stem Cell Transplant and Cellular Immunotherapy Program, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, Washington, DC, USA
| | - Carlo B Bifulco
- Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA
| | - Christian M Capitini
- University of Wisconsin School of Medicine and Public Health and Carbone Cancer Center, Madison, Wisconsin, USA
| | | | - Anthony R Cillo
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Deborah Collyar
- Patient Advocates In Research (PAIR), Danville, California, USA
| | - Leslie Cope
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | | | | | - Sacha Gnjatic
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Denise Goh
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Susan Halabi
- Duke School of Medicine and Duke Cancer Institute, Durham, North Carolina, USA
| | - Gary Kohanbash
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Holden T Maecker
- Stanford University School of Medicine, Stanford, California, USA
| | - Saman Maleki Vareki
- Department of Oncology and Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Sarah Mullin
- Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Barbara Seliger
- Campus Brandenburg an der Havel, Brandenburg Medical School, Halle, Germany
| | - Janis Taube
- Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Wim Vos
- Radiomics.bio, Liège, Belgium
| | - Joe Yeong
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore
- Department of Anatomical Pathology, Singapore General Hospital, Singapore
| | - Kristin G Anderson
- Department of Microbiology, Immunology and Cancer Biology, Department of Obstetrics and Gynecology, Beirne B. Carter Center for Immunology Research and the University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, Virginia, USA
| | - Tullia C Bruno
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Tumor Microenvironment Center, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Codruta Chiuzan
- Institute of Health System Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA
| | | | | | | | | | - Elizabeth G Hill
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Brian P Hobbs
- Dell Medical School, The University of Texas, Austin, Texas, USA
| | - Yana G Najjar
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | | | | | - Sumit K Subudhi
- The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ryan J Sullivan
- Massachusetts General Hospital, Harvard Medical School, Needham, Massachusetts, USA
| | | |
Collapse
|
28
|
Balewski Ł, Inkielewicz-Stępniak I, Gdaniec M, Turecka K, Hering A, Ordyszewska A, Kornicka A. Synthesis, Structure, and Stability of Copper(II) Complexes Containing Imidazoline-Phthalazine Ligands with Potential Anticancer Activity. Pharmaceuticals (Basel) 2025; 18:375. [PMID: 40143151 PMCID: PMC11946467 DOI: 10.3390/ph18030375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 02/27/2025] [Accepted: 03/02/2025] [Indexed: 03/28/2025] Open
Abstract
Background/Objectives: Recently, there has been great interest in metallopharmaceuticals as potential anticancer agents. In this context, presented studies aim to synthesize and evaluate of two copper(II) complexes derived from phthalazine- and imidazoline-based ligands against on three human cancer cell lines: cervix epithelial cell line (HeLa), breast epithelial-like adenocarcinoma (MCF-7), and triple-negative breast epithelial cancer cell line (MDA-MB-231), as well as non-tumorigenic cell line (HDFa). Moreover their antimicrobial, and antioxidant properties were assessed. Methods: The synthetized compounds-both free ligands L1, L2, L3 and copper(II) complexes C1 and C2-were characterized by elemental analysis, infrared spectroscopy. Additionally, a single-crystal X-ray diffraction studies we performed for free ligand L3 and its copper(II) complex C2. The stability of Cu(II)-complexes C1 and C2 was evaluated by UV-Vis spectroscopy. The cytotoxic potency of free ligands and their copper(II) complexes was estimated on HeLa, MCF-7, MDA-MB-231, as well as non-cancerous HDFa by use of an MTT assay after 48 h of incubation. Moreover, the antimicrobial activity of ligands L1 and L3 and their copper(II) complexes C1 and C2 was evaluated using reference strains of the following bacteria and yeasts: Staphylococcus aureus, Escherichia coli, and Candida albicans. The free radical scavenging properties of free ligands L1, L3 and the corresponding copper(II) complexes C1, C2 was tested with two colorimetric methods-ABTS, DPPH, and reduction ability assay (FRAP). Additionally, the ADME webtool was used to assess the drug-likeness of the synthesized compounds, as well as their physicochemical and pharmacokinetic properties. Results: Copper(II) complex C2 exhibited antitumor properties towards MDA-MB-231 compared with Cisplatin (cancer cell viability rate of 23.6% vs. 22.5%). At a concentration of 200 μg/mL, complexes C1 and C2 were less cytotoxic than the reference Cisplatin against a normal, non-cancerous skin fibroblast cell line (HDFa). According to in vitro tests, C2 reduced the viability of HeLa, MCF-7, and MDA-MB-231 cells by about 57.5-81.2%. It was evident that all compounds were devoid of antibacterial or antifungal activity. In vitro assays revealed that a moderate antiradical effect was observed for free ligand L1 containing phthalazin-1(2H)-imine in the ABTS radical scavenging assay (IC50 = 23.63 µg/mL). Conclusions: The anticancer studies revealed that the most potent compound was copper(II) complex C2 bearing a phthalazin-1(2H)-one scaffold. None of the tested compounds showed antimicrobial or antifungal activity. This feature seems to be beneficial in terms of their potential uses as anticancer agents in the future. In vitro antiradical assays revealed that a moderate antioxidant effect was observed only for free ligand L1 containing phthalazin-1(2H)-imine.
Collapse
Affiliation(s)
- Łukasz Balewski
- Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of Gdansk, Gen. J. Hallera 107, 80-416 Gdańsk, Poland
| | - Iwona Inkielewicz-Stępniak
- Department of Pharmaceutical Pathophysiology, Faculty of Pharmacy, Medical University of Gdansk, Gen. Dębinki 7, 80-211 Gdańsk, Poland
| | - Maria Gdaniec
- Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland
| | - Katarzyna Turecka
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Medical University of Gdansk, Gen. J. Hallera 107, 80-416 Gdańsk, Poland
| | - Anna Hering
- Department of Biology and Pharmaceutical Botany, Faculty of Pharmacy, Medical University of Gdansk, Gen. J. Hallera 107, 80-416 Gdańsk, Poland
| | - Anna Ordyszewska
- Department of Inorganic Chemistry, Faculty of Chemistry and Advanced Materials Centers, Gdańsk University of Technology, Narutowicza 11/12, 80-233 Gdansk, Poland
| | - Anita Kornicka
- Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of Gdansk, Gen. J. Hallera 107, 80-416 Gdańsk, Poland
| |
Collapse
|
29
|
Rouault CD, Bansard L, Martínez-Balsalobre E, Bonnet C, Wicinski J, Lin S, Colombeau L, Debieu S, Pinna G, Vandamme M, Machu M, Rosnet O, Chevrier V, Popovici C, Sobol H, Castellano R, Pasquier E, Guasch G, Rodriguez R, Pannequin J, Pascussi JM, Lachaud C, Charafe-Jauffret E, Ginestier C. Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibition in breast cancer. Nat Commun 2025; 16:2159. [PMID: 40038300 PMCID: PMC11880418 DOI: 10.1038/s41467-025-57476-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 02/19/2025] [Indexed: 03/06/2025] Open
Abstract
The targeting of cancer stem cells (CSCs) has proven to be an effective approach for limiting tumor progression, thus necessitating the identification of new drugs with anti-CSC activity. Through a high-throughput drug repositioning screen, we identify the antibiotic Nifuroxazide (NIF) as a potent anti-CSC compound. Utilizing a click chemistry strategy, we demonstrate that NIF is a prodrug that is specifically bioactivated in breast CSCs. Mechanistically, NIF-induced CSC death is a result of a synergistic action that combines the generation of DNA interstrand crosslinks with the inhibition of the Fanconi anemia (FA) pathway activity. NIF treatment mimics FA-deficiency through the inhibition of STAT3, which we identify as a non-canonical transcription factor of FA-related genes. NIF induces a chemical HRDness (Homologous Recombination Deficiency) in CSCs that (re)sensitizes breast cancers with innate or acquired resistance to PARP inhibitor (PARPi) in patient-derived xenograft models. Our results suggest that NIF may be useful in combination with PARPi for the treatment of breast tumors, regardless of their HRD status.
Collapse
Affiliation(s)
- Celia D Rouault
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer, Marseille, France
| | - Lucile Bansard
- IGF, University Montpellier, CNRS INSERM, Montpellier, France
| | - Elena Martínez-Balsalobre
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, DNA Interstrand Crosslink Lesions and Blood Disorder Team, Marseille, France
| | - Caroline Bonnet
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer, Marseille, France
| | - Julien Wicinski
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer, Marseille, France
| | - Shuheng Lin
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer, Marseille, France
| | - Ludovic Colombeau
- Institut Curie, CNRS, INSERM, Biomedicine Laboratory PSL Research University, Paris, France
| | - Sylvain Debieu
- Institut Curie, CNRS, INSERM, Biomedicine Laboratory PSL Research University, Paris, France
| | - Guillaume Pinna
- Plateforme ARN Interférence (PARI), Université Paris Cité, Inserm, CEA Stabilité Génétique Cellules Souches et Radiations, Fontenay-aux-Roses, France
| | - Marie Vandamme
- Plateforme ARN Interférence (PARI), Université Paris Cité, Inserm, CEA Stabilité Génétique Cellules Souches et Radiations, Fontenay-aux-Roses, France
| | - Margot Machu
- IGF, University Montpellier, CNRS INSERM, Montpellier, France
| | - Olivier Rosnet
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer, Marseille, France
| | - Véronique Chevrier
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer, Marseille, France
| | - Cornel Popovici
- Aix-Marseille University, Cancer Genetic Laboratory, Cancer Biology Department Institut Paoli-Calmettes, Marseille, France
| | - Hagay Sobol
- Aix-Marseille University, Cancer Genetic Laboratory, Cancer Biology Department Institut Paoli-Calmettes, Marseille, France
| | - Rémy Castellano
- CRCM, Aix-Marseille University, INSERM, CNRS, Institut Paoli-Calmettes, TrGET Plateform, Marseille, France
| | - Eddy Pasquier
- CRCM, INSERM, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Reverse Molecular Pharmacology in Pediatric Oncology, Marseille, France
| | - Geraldine Guasch
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer, Marseille, France
| | - Raphaël Rodriguez
- Institut Curie, CNRS, INSERM, Biomedicine Laboratory PSL Research University, Paris, France
| | - Julie Pannequin
- IGF, University Montpellier, CNRS INSERM, Montpellier, France
| | | | - Christophe Lachaud
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, DNA Interstrand Crosslink Lesions and Blood Disorder Team, Marseille, France
| | - Emmanuelle Charafe-Jauffret
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer, Marseille, France.
| | - Christophe Ginestier
- CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer, Marseille, France.
| |
Collapse
|
30
|
Carpani M, Smussi D, Esposito A, Consoli F, Berruti A, Alberti A. Amoxicillin-Induced Atypical Exanthema in a Patient with EBV-Related Nasopharyngeal Carcinoma: A Case Report. Viruses 2025; 17:368. [PMID: 40143296 PMCID: PMC11946185 DOI: 10.3390/v17030368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 02/26/2025] [Accepted: 02/28/2025] [Indexed: 03/28/2025] Open
Abstract
INTRODUCTION The concomitant use of antibiotics, especially beta lactams, during acute EBV infection is widely associated with an increased risk of skin manifestations; the actual pathophysiology and prevalence of this phenomenon are still debated. CASE REPORT We present the first reported case of atypical exanthema associated with amoxicillin intake in a patient with EBV-related nasopharyngeal carcinoma. We recorded a pattern in the plasma EBV-DNA load consisting of a significant increase at the onset of the rash with a sudden remission after its resolution. The patient recovered without sequelae. DISCUSSION/CONCLUSIONS The temporal relationship and the reported data on rash morphology, clinical findings and triggering factors support a possible correlation between the intake of beta-lactam antibiotics, particularly amoxicillin, and the onset of cutaneous manifestations in a patient with nasopharyngeal carcinoma. Such reactions can be a challenging differential diagnosis and may warrant increased provider consideration when choosing to prescribe beta lactams in patients affected by nasopharyngeal cancer.
Collapse
Affiliation(s)
| | | | | | | | - Alfredo Berruti
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, ASST Spedali Civili, 25123 Brescia, Italy; (M.C.); (D.S.); (A.A.)
| | | |
Collapse
|
31
|
Cui L, Liu R, Han S, Zhang C, Wang B, Ruan Y, Yu X, Li Y, Yao Y, Guan X, Liao Y, Su D, Ma Y, Li S, Liu C, Zhang Y. Targeting Arachidonic Acid Metabolism Enhances Immunotherapy Efficacy in ARID1A-Deficient Colorectal Cancer. Cancer Res 2025; 85:925-941. [PMID: 39652583 PMCID: PMC11873721 DOI: 10.1158/0008-5472.can-24-1611] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 09/15/2024] [Accepted: 12/04/2024] [Indexed: 03/04/2025]
Abstract
AT-rich interactive domain-containing protein 1A (ARID1A), a core constituent of the switch/sucrose nonfermentable (SWI/SNF) complex, is mutated in approximately 10% of colorectal cancers. Whereas ARID1A deficiency corresponds to heightened immune activity in colorectal cancer, immune checkpoint inhibitors (ICI) have shown limited efficacy in these tumors. The discovery of targetable vulnerabilities associated with ARID1A deficiency in colorectal cancer could expand treatment options for patients. In this study, we demonstrated that arachidonic acid (AA) metabolism inhibitors synergize with ICIs in ARID1A-deficient colorectal cancer by enhancing the activity of CD8+ T cells and inhibiting vasculogenic mimicry. Epigenetic analysis using ATAC-seq and ChIP-qPCR revealed that the lack of ARID1A results in reduced levels of PTGS1 and PTGS2, the key enzymes that control the AA pathway. Low PTGS1 and PTGS2 expression generated a reliance on the remaining functionality of the AA pathway in ARID1A-deficient cells. The AA pathway inhibitor aspirin selectively inhibited the growth of ARID1A-deficient colorectal cancer, and aspirin sensitized tumors lacking ARID1A to immunotherapy. Together, these findings suggest that blocking AA metabolism can enhance immune responses against tumors by activating CD8+ T cells and inhibiting vasculogenic mimicry, which synergizes with ICIs to improve treatment of ARID1A-deficient colorectal cancer. Significance: The arachidonic acid pathway is a metabolic vulnerability in ARID1A-deficient colorectal cancer that can be targeted with aspirin to suppress tumor growth and enhance sensitivity to immunotherapy, providing a promising therapeutic strategy.
Collapse
Affiliation(s)
- Luying Cui
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Ruiqi Liu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shuling Han
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Chunhui Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Bojun Wang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Yuli Ruan
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Xuefan Yu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Yien Li
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yuanfei Yao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Xin Guan
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Yuanyu Liao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Dan Su
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Yue Ma
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Shuijie Li
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, China
- Heilongjiang Province Key Laboratory of Research on Molecular Targeted Anti-Tumor Drugs, Harbin, China
| | - Chao Liu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| |
Collapse
|
32
|
Espín R, Medina-Jover F, Sigüenza-Andrade J, Farran-Matas S, Mateo F, Figueras A, Sanz R, Vicent G, Shabbir A, Ruiz-Auladell L, Racionero-Andrés E, García I, Baiges A, Franco-Luzón L, Martínez-Tebar A, Pardo-Cea M, Martínez-Iniesta M, Wang X, Cuyàs E, Menendez J, Lopez-Cerda M, Muñoz P, Richaud I, Raya A, Fabregat I, Villanueva A, Serrat X, Cerón J, Alemany M, Guix I, Herencia-Ropero A, Serra V, Krishnan R, Mekhail K, Hakem R, Bruna J, Barcellos-Hoff M, Viñals F, Aytes Á, Pujana M. Harnessing transcriptional regulation of alternative end-joining to predict cancer treatment. NAR Cancer 2025; 7:zcaf007. [PMID: 40061566 PMCID: PMC11886861 DOI: 10.1093/narcan/zcaf007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 02/13/2025] [Accepted: 03/04/2025] [Indexed: 04/15/2025] Open
Abstract
Alternative end-joining (alt-EJ) is an error-prone DNA repair pathway that cancer cells deficient in homologous recombination rely on, making them vulnerable to synthetic lethality via inhibition of poly(ADP-ribose) polymerase (PARP). Targeting alt-EJ effector DNA polymerase theta (POLθ), which synergizes with PARP inhibitors and can overcome resistance, is of significant preclinical and clinical interest. However, the transcriptional regulation of alt-EJ and its interactions with processes driving cancer progression remain poorly understood. Here, we show that alt-EJ is suppressed by hypoxia while positively associated with MYC (myelocytomatosis oncogene) transcriptional activity. Hypoxia reduces PARP1 and POLQ expression, decreases MYC binding at their promoters, and lowers PARylation and alt-EJ-mediated DNA repair in cancer cells. Tumors with HIF1A mutations overexpress the alt-EJ gene signature. Inhibition of hypoxia-inducible factor 1α or HIF1A expression depletion, combined with PARP or POLθ inhibition, synergistically reduces the colony-forming capacity of cancer cells. Deep learning reveals the anticorrelation between alt-EJ and hypoxia across regions in tumor images, and the predictions for these and MYC activity achieve area under the curve values between 0.70 and 0.86. These findings further highlight the critical role of hypoxia in modulating DNA repair and present a strategy for predicting and improving outcomes centered on targeting alt-EJ.
Collapse
Affiliation(s)
- Roderic Espín
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Ferran Medina-Jover
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Department of Physiological Sciences, University of Barcelona, L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Javier Sigüenza-Andrade
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Sònia Farran-Matas
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Francesca Mateo
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Agnes Figueras
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Rosario T Sanz
- Molecular Biology Institute of Barcelona, Spanish National Research Council (IBMB-CSIC), Barcelona 08028, Spain
| | - Guillermo Pablo Vicent
- Molecular Biology Institute of Barcelona, Spanish National Research Council (IBMB-CSIC), Barcelona 08028, Spain
| | - Arzoo Shabbir
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Lara Ruiz-Auladell
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | | | - Irene García
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Alexandra Baiges
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Lídia Franco-Luzón
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Adrián Martínez-Tebar
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Miguel Angel Pardo-Cea
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - María Martínez-Iniesta
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Xieng Chen Wang
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Elisabet Cuyàs
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Girona Biomedical Research Institute (IDIBGI), Salt, Girona 17190, Spain
| | - Javier A Menendez
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Girona Biomedical Research Institute (IDIBGI), Salt, Girona 17190, Spain
| | - Marta Lopez-Cerda
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Purificacion Muñoz
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Ivonne Richaud
- Regenerative Medicine Program and Program for Clinical Translation of Regenerative Medicine in Catalonia—P-CMR[C], Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Biomedical Research Network Centre in Bioengineering, Nanomaterials, and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Angel Raya
- Regenerative Medicine Program and Program for Clinical Translation of Regenerative Medicine in Catalonia—P-CMR[C], Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Biomedical Research Network Centre in Bioengineering, Nanomaterials, and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Madrid 28029, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona 08010, Spain
| | - Isabel Fabregat
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Biomedical Research Networking Centre in Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Alberto Villanueva
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Xènia Serrat
- Modeling Human Diseases in C. elegans Group, Genes, Diseases, and Therapies Program, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Julián Cerón
- Modeling Human Diseases in C. elegans Group, Genes, Diseases, and Therapies Program, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Montserrat Alemany
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Neuro-Oncology Unit, University Hospital of Bellvitge, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Inés Guix
- Department of Radiation Oncology and Helen Diller Family Comprehensive Cancer Centre, University of California San Francisco, San Francisco, CA 94115, United States
| | - Andrea Herencia-Ropero
- Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona 08193, Spain
- Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
| | - Violeta Serra
- Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
| | - Rehna Krishnan
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada
| | - Karim Mekhail
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Razqallah Hakem
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Jordi Bruna
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Neuro-Oncology Unit, University Hospital of Bellvitge, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Mary Helen Barcellos-Hoff
- Department of Radiation Oncology and Helen Diller Family Comprehensive Cancer Centre, University of California San Francisco, San Francisco, CA 94115, United States
| | - Francesc Viñals
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Department of Physiological Sciences, University of Barcelona, L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Álvaro Aytes
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
| | - Miquel Angel Pujana
- ProCURE, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona 08908, Spain
- Girona Biomedical Research Institute (IDIBGI), Salt, Girona 17190, Spain
| |
Collapse
|
33
|
Merkuryev AV, Egorov VV. Role of PARP-1 structural and functional features in PARP-1 inhibitors development. Bioorg Chem 2025; 156:108188. [PMID: 39855113 DOI: 10.1016/j.bioorg.2025.108188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 12/18/2024] [Accepted: 01/17/2025] [Indexed: 01/27/2025]
Abstract
Poly(ADP-ribose) polymerase-1 (PARP-1) is the key enzyme among other PARPs for post-translational modification of DNA repair proteins. It has four functional domains for DNA-binding, automodification and enzymatic activity. PARP-1 participates in poly-ADP-ribosylation of itself or other proteins during DNA damage response. It recruits reparation machinery proteins that restore native DNA sequence. PARP-1 participates in chromatin structure organization and gene expression regulation. It was shown that PARP-1-dependent regulation mechanisms affect on possible risk of carcinogenesis. Therefore, PARP-1 was proposed as a novel target for cancer treatment. Three generations of PARP-1 inhibitors had been developed depending on pharmacophore structure. To date, four PARP-1 inhibitors have been approved for cancer treatment as a chemotherapy potentiators or as a stand-alone therapy. However, different cytotoxicity effects of specific PARP-1 inhibitors were observed due to diverse PARP-1 activity in cellular processes. Moreover, cancer cells can develop resistance to PARP-1 inhibitors and decrease chemotherapy efficacy. There are promising strategies how to avoid these disadvantages including dual-targeted inhibitors and combination therapy.
Collapse
|
34
|
Lerksuthirat T, Prasopporn S, Wikiniyadhanee R, Chitphuk S, Stitchantrakul W, Owneium P, Jirawatnotai S, Dejsuphong D. DNA damage response mutations enhance the antitumor efficacy of ATR and PARP inhibitors in cholangiocarcinoma cell lines. Oncol Lett 2025; 29:128. [PMID: 39822940 PMCID: PMC11736248 DOI: 10.3892/ol.2025.14874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 11/28/2024] [Indexed: 01/19/2025] Open
Abstract
Cholangiocarcinoma (CCA) is a biliary tract carcinoma that is challenging to treat due to its heterogeneity and limited treatment options. Genetic alterations in DNA damage response (DDR) pathways and homologous recombination (HR) defects are common in CCA. This has prompted interest in the use of ataxia telangiectasia and Rad3-related protein (ATR) and poly(ADP-ribose) polymerase (PARP) inhibitors to treat CCA. The present study investigated the impact of an ATR inhibitor and various PARP inhibitors, individually and in combination, on CCA cell lines with different DDR mutation profiles. DDR gene alterations in these cell lines were analyzed, and the responses of the cells to treatment with the PARP inhibitors olaparib, veliparib and talazoparib and/or the ATR inhibitor AZD6738 were evaluated. Assessments focused on cellular viability, clonogenic survival and the combination index, alongside changes in DNA damage assessed via the formation of micronuclei and γ-H2A histone family member X foci. The results revealed that the CCA cell lines with more DDR mutations exhibited greater sensitivity to single and combination treatments. Talazoparib was found to be the most potent PARP inhibitor in the CCA cell lines. The combination of AZD6738 and talazoparib demonstrated varying synergistic effects depending on the genetic background of the CCA cells, with greater efficacy in the cell lines less sensitive to single drug treatments. Mechanistically, this combination promoted the accumulation of DNA damage, including DNA double-strand breaks. Overall, the study underscores the importance of HR in CCA. It reveals an association between the extent of DDR mutations and the response to AZD6738 and PARP inhibitors in CCA, both as single agents and in combination. These findings highlight that the number of mutated genes influences variability in the drug response.
Collapse
Affiliation(s)
- Tassanee Lerksuthirat
- Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Sunisa Prasopporn
- Siriraj Center of Research for Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Rakkreat Wikiniyadhanee
- Program in Translational Medicine, Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samutprakarn 10540, Thailand
| | - Sermsiri Chitphuk
- Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Wasana Stitchantrakul
- Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Paravee Owneium
- Program in Translational Medicine, Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samutprakarn 10540, Thailand
| | - Siwanon Jirawatnotai
- Siriraj Center of Research for Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Donniphat Dejsuphong
- Program in Translational Medicine, Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samutprakarn 10540, Thailand
| |
Collapse
|
35
|
Tanegashima T, Shiota M, Terada N, Saito T, Yokomizo A, Kohei N, Goto T, Kawamura S, Hashimoto Y, Takahashi A, Kimura T, Tabata KI, Tomida R, Hashimoto K, Sakurai T, Shimazui T, Sakamoto S, Kamiyama M, Tanaka N, Mitsuzuka K, Kato T, Narita S, Yasumoto H, Teraoka S, Kato M, Osawa T, Nagumo Y, Matsumoto H, Enokida H, Sugiyama T, Kuroiwa K, Kitamura H, Kamoto T, Eto M. Improved prognosis of de novo metastatic prostate cancer after an introduction of life-prolonging agents for castration-resistant prostate cancer. Int J Clin Oncol 2025; 30:551-558. [PMID: 39688742 DOI: 10.1007/s10147-024-02681-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 12/05/2024] [Indexed: 12/18/2024]
Abstract
BACKGROUND In Japan, since 2014, new treatments such as androgen receptor signaling inhibitors and cabazitaxel have become applicable for metastatic castration-resistant prostate cancer (mCRPC), leading to dramatic changes in treatment options. OBJECTIVE This study aims to evaluate the impact of recent advancements in treatment options on the overall survival (OS) of patients diagnosed with de novo metastatic castration-sensitive prostate cancer (mCSPC) in Japan. METHODS A retrospective analysis was conducted on 2450 Japanese men diagnosed with de novo mCSPC between 2008 and 2018. Patients were stratified into two groups based on the period of diagnosis: an earlier period (2008-2013) and a later period (2014-2018). OS was compared between earlier and later periods using Kaplan-Meier analysis in total and propensity score matched subpopulation as well as risk-stratified subgroups. RESULTS Patients diagnosed in the later period exhibited significantly improved OS compared to those diagnosed in the earlier period. The risk score, calculated based on ISUP grade group, LDH levels, and ALP levels, was a poor prognostic factor. In the later period, compared to the earlier period, there was no improvement in OS in the favorable-risk group, but a significant improvement was observed in the poor-risk group. CONCLUSION It was suggested that the introduction of novel androgen receptor signaling inhibitors and chemotherapy treatment regimens since 2014 has led to improved survival outcomes for patients with de novo mCSPC, particularly those with poor-risk profiles. The findings highlight the impact of recent advancements in treatment on the prognosis of patients with metastatic prostate cancer in Japan.
Collapse
Affiliation(s)
- Tokiyoshi Tanegashima
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Masaki Shiota
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
| | - Naoki Terada
- Department of Urology, Miyazaki University, Miyazaki, Japan
| | - Toshihiro Saito
- Department of Urology, Niigata Cancer Center Hospital, Niigata, Japan
| | - Akira Yokomizo
- Department of Urology, Harasanshin Hospital, Fukuoka, Japan
| | - Naoki Kohei
- Department of Urology, Shizuoka General Hospital, Shizuoka, Japan
| | - Takayuki Goto
- Department of Urology, Kyoto University, Kyoto, Japan
| | | | | | - Atsushi Takahashi
- Department of Urology, Hakodate Goryoukaku Hospital, Hakodate, Japan
| | | | - Ken-Ichi Tabata
- Department of Urology, Kitasato University, Sagamihara, Japan
| | - Ryotaro Tomida
- Department of Urology, Shikoku Cancer Center, Matsuyama, Japan
| | - Kohei Hashimoto
- Department of Urology, Sapporo Medical University, Sapporo, Japan
| | | | - Toru Shimazui
- Department of Urology, Ibaraki Prefectural Central Hospital, Ibaraki Cancer Center, Kasama, Japan
| | | | - Manabu Kamiyama
- Department of Urology, University of Yamanashi Hospital, Chuo, Japan
| | - Nobumichi Tanaka
- Department of Urology, and Department of Prostate Brachytherapy, Nara Medical University, Kashihara, Japan
| | | | - Takuma Kato
- Department of Urology, Kagawa University, Kagawa, Japan
| | | | | | - Shogo Teraoka
- Department of Urology, Tottori University, Yonago, Japan
| | - Masashi Kato
- Department of Urology, Nagoya University, Nagoya, Japan
| | - Takahiro Osawa
- Department of Renal and Genitourinary Surgery, Hokkaido University, Sapporo, Japan
| | - Yoshiyuki Nagumo
- Department of Urology, University of Tsukuba Hospital, Tsukuba, Japan
| | | | - Hideki Enokida
- Department of Urology, Kagoshima University, Kagoshima, Japan
| | - Takayuki Sugiyama
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kentaro Kuroiwa
- Department of Urology, Miyazaki Prefectural Miyazaki Hospital, Miyazaki, Japan
| | - Hiroshi Kitamura
- Department of Urology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan
| | | | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| |
Collapse
|
36
|
Piffoux M, Leary A, Follana P, Abdeddaim C, Joly F, Bin S, Bonjour M, Boulai A, Callens C, Villeneuve L, Alexandre M, Schwiertz V, Freyer G, Rodrigues M, You B. Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial. Nat Commun 2025; 16:1821. [PMID: 39979249 PMCID: PMC11842746 DOI: 10.1038/s41467-025-56914-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 02/05/2025] [Indexed: 02/22/2025] Open
Abstract
Endometrial cancers are characterized by frequent alterations in the PI3K-AKT-mTor, IGF1 and DNA repair signaling pathways. Concomitant inhibition of these pathways was warranted. ENDOLA phase I/II trial (NCT02755844) was designed to assess the safety/efficacy of the triplet combination of the PARP inhibitor olaparib, metronomic cyclophosphamide (50 mg daily), and PI3K-AKT-mTor inhibitor metformin (1500 mg daily) in women with recurrent endometrial carcinomas. Olaparib dose-escalation (100-300 mg twice-a-day (bid)) was used to determine the recommended-phase II-trial-dose (RP2D, primary endpoint), followed by an expansion cohort to determine the non-progression rate at 10 weeks (NPR-10w, secondary endpoint). 31 patients were treated. Olaparib RP2D was defined as 300 mg bid. The tolerability was acceptable, and grade 3-4 adverse events (51% patients) were mainly hematological. The NPR-10w was 61.5%, and the median progression-free survival (mPFS) was 5.2 months. In a post-hoc analysis, when explored by molecular subtypes/alterations, longer PFS were observed in patients with tumors characterized by a non-specific-molecular-profile (NSMP, n = 4; mPFS, 9.1 months), and by both TP53 altered & high number of large genomic alterations (LGA ≥ 8)(n = 10, mPFS, 8.6 months)). The analyses about kinetics of circulating biomarkers and pharmacodynamic effects are not reported here. In total, the benefit/toxicity ratio of the all-oral olaparib/cyclophosphamide/metformin regimen was favorable in heavily pretreated patients with recurrent endometrial cancer.
Collapse
Affiliation(s)
- Max Piffoux
- Medical Oncology, Hospices Civils de Lyon, EPSILYON, Lyon, France; GINECO, Paris, France
| | - Alexandra Leary
- Medical Oncology, Institut Gustave Roussy, Villejuif, France; GINECO, Paris, France
| | | | | | - Florence Joly
- Centre Francois Baclesse, Caen, France; GINECO, Paris, France
| | - Sylvie Bin
- Pôle Santé Publique, Hospices Civils de Lyon, Lyon, France
| | - Maxime Bonjour
- Pôle Santé Publique, Hospices Civils de Lyon, Lyon, France
| | - Anais Boulai
- Genetics Department, Institut Curie and Paris Sciences Lettres University, Paris, France
| | - Celine Callens
- Genetics Department, Institut Curie and Paris Sciences Lettres University, Paris, France
| | | | | | | | - Gilles Freyer
- Medical Oncology, Hospices Civils de Lyon, EPSILYON, Lyon, France; GINECO, Paris, France
| | - Manuel Rodrigues
- Medical Oncology, Institut Curie, Paris, France
- INSERM U830, Institut Curie, Paris, France; GINECO, Paris, France
| | - Benoit You
- Medical Oncology, Hospices Civils de Lyon, EPSILYON, Lyon, France; GINECO, Paris, France.
| |
Collapse
|
37
|
Pasaol JC, Śmieszek A, Pawlak A. Exploring the Therapeutic Potential of BRCA1 and BRCA2 as Targets in Canine Oncology: A Comprehensive Review of Their Role in Cancer Development and Treatment. Int J Mol Sci 2025; 26:1768. [PMID: 40004231 PMCID: PMC11855874 DOI: 10.3390/ijms26041768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 02/12/2025] [Accepted: 02/17/2025] [Indexed: 02/27/2025] Open
Abstract
Tumor diseases represent a significant global health challenge, impacting both humans and companion animals, notably dogs. The parallels observed in the pathophysiology of cancer between humans and dogs underscore the importance of advancing comparative oncology and translational research methodologies. Furthermore, dogs serve as valuable models for human cancer research due to shared environments, genetics, and treatment responses. In particular, breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2), which are critical in human cancer, also influence the development and progression of canine tumors. The role of BRCA1 and BRCA2 in canine cancers remains underexplored, but its potential significance as therapeutic targets is strongly considered. This systematic review aims to broaden the discussion of BRCA1 and BRCA2 beyond mammary tumors, exploring their implications in various canine cancers. By emphasizing the shared genetic underpinnings between species and advocating for a comparative approach, the review indicates the potential of BRCA genes as targets for innovative cancer therapies in dogs, contributing to advances in human and veterinary oncology.
Collapse
Affiliation(s)
| | | | - Aleksandra Pawlak
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences, Norwida 31, 50-375 Wrocław, Poland; (J.C.P.); (A.Ś.)
| |
Collapse
|
38
|
DeJongh J, Cadogan E, Davies M, Ramos-Montoya A, Smith A, van Steeg T, Richards R. Defining preclinical efficacy with the DNAPK inhibitor AZD7648 in combination with olaparib: a minimal systems pharmacokinetic-pharmacodynamic model. J Pharmacokinet Pharmacodyn 2025; 52:17. [PMID: 39961902 PMCID: PMC11832700 DOI: 10.1007/s10928-025-09962-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 01/14/2025] [Indexed: 02/20/2025]
Abstract
AZD7648 is a potent inhibitor of DNA-dependent protein kinase (DNA-PK), which is part of the non-homologous end-joining DNA repair pathway. When combined with the PARP inhibitor olaparib, AZD7648 shows robust combination activity in pre-clinical ATM-knockout mouse xenograft models. To understand the combination activity of AZD7648 and olaparib, we developed a semi-mechanistic pharmacokinetic/pharmacodynamic (PK-PD) model that incorporates the mechanism of action for each drug which links to proliferating, quiescent, and dying cell states with an additional Allee effect-like term to account for the non-linear growth and regression observed at low cell densities. Model parameters were fitted to training data sets that contained continuous treatment of either monotherapy or the combination. The observed interaction of AZD7648 on olaparib PK was incorporated in the PK-PD model by an effect function specific for each of the drug's MoA and was found essential to quantify drug effects at high dose levels of combination treatments. The model was able to adequately describe the observed efficacy for both monotherapy and sustained regressions in combination groups, mainly driven by maintaining a > 2:1 AUC ratio of apoptotic:proliferating cell fractions. We found that this model was suitable for forecasting intermittent dosing schedules a priori and resulted in accurate predictions when compared to xenograft efficacy data, without the need for extra, descriptive terms to describe supra-additive effects under combined dose regimes. This model provides quantitative understanding on the combination effect of AZD7648 and olaparib and allows for the exploration of the full exposure landscape without the need to experimentally test all scenarios. Furthermore, the model can be utilized to assess what exposures would be necessary in the clinic by linking it to observed or predicted human PK exposures. The model suggests 64.9 uM olaparib is sufficient to achieve tumor stasis in the absence of AZD7648, while the combination of AZD7648 and olaparib only requires plasma concentrations of 20.2 uM AZD7648 and 19.9 uM olaparib at steady-state to achieve the same effect.
Collapse
Affiliation(s)
| | - Elaine Cadogan
- Bioscience, Early Oncology R&D, AstraZeneca, Cambridge, UK
| | | | | | - Aaron Smith
- DMPK, Early Oncology R&D, AstraZeneca, Cambridge, UK
| | | | - Ryan Richards
- DMPK, Early Oncology R&D, AstraZeneca, Waltham, MA, USA.
| |
Collapse
|
39
|
Conte M, Tomaciello M, De Feo MS, Frantellizzi V, Marampon F, De Cristofaro F, De Vincentis G, Filippi L. The Tight Relationship Between the Tumoral Microenvironment and Radium-223. Biomedicines 2025; 13:456. [PMID: 40002869 PMCID: PMC11853176 DOI: 10.3390/biomedicines13020456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 02/04/2025] [Accepted: 02/09/2025] [Indexed: 02/27/2025] Open
Abstract
Radium-223 (223Ra) was the first radioactive isotope approved for treating castration-resistant prostate cancer (CRPC) with symptomatic bone metastases without visceral metastatic disease. To better understand the action of 223Ra, its role in the tumor microenvironment represents a crucial aspect. A literature search was conducted using the PubMed/MEDLINE database and studies regarding the relationship between 223Ra and the tumoral microenvironment were considered. The tumoral microenvironment is a complex setting in which complex interactions between cells and molecules occur. Radium-223, as an alpha-emitter, induces double-stranded DNA breaks; to potentiate this effect, it could be used in patients with genetic instability but also in combination with therapies which inhibit DNA repair, modulate the immune response, or control tumor growth. In conclusion, a few studies have taken into consideration the tumoral microenvironment in association with 223Ra. However, its understanding is a priority to better comprehend how to effectively exploit 223Ra and its action mechanism.
Collapse
Affiliation(s)
- Miriam Conte
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Miriam Tomaciello
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Maria Silvia De Feo
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Viviana Frantellizzi
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Francesco Marampon
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Flaminia De Cristofaro
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Giuseppe De Vincentis
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Luca Filippi
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
| |
Collapse
|
40
|
Addy BS, Firempong CK, Komlaga G, Addo-Fordjour P, Domfeh SA, Afolayan OD, Yaw Nyarko EN, Emikpe BO. A bioactive fraction from the leaves of Ceiba pentandra (L.) Gaertn. exhibits antiproliferative activity via cell cycle arrest at the G1/S checkpoint and initiation of apoptosis via poly [ADP-ribose] polymerase 1 (PARP1) cleavage in HeLa cells. JOURNAL OF ETHNOPHARMACOLOGY 2025; 341:119363. [PMID: 39814326 DOI: 10.1016/j.jep.2025.119363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 01/02/2025] [Accepted: 01/11/2025] [Indexed: 01/18/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ceibapentandra (L.) Gaertn. (Malvaceae) has been used in Africa traditionally to manage a variety of illnesses, including cancer. The hydroethanolic extract of the leaves of C. pentandra has been shown to possess antiproliferative activity. However, the fractionation of antiproliferative bioactive constituents from the leaves of C. pentandra and the determination of the mechanisms of action of such bioactive constituents remain unexplored. AIM OF THE STUDY This work sought to fractionate the extract of C. pentandra leaves, establish the antiproliferative activity of the fractionated constituents, and determine the active constituents' possible mechanisms of action. MATERIAL AND METHODS Chromatographic techniques were used to fractionate bioactive constituents from C. pentandra leaves. The fractionated constituents were evaluated for their antiproliferative activity against four cancer cell lines (viz hepatocellular carcinoma, colorectal adenocarcinoma, cervical carcinoma, and mammary adenocarcinoma) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT)-based assay. The possible mechanisms of action of the active constituent, Fraction A (IsoA), were also determined via western blot analysis. RESULTS Six constituents were fractionated from the leaves of C. pentandra. Among the six constituents, IsoA stood out for its remarkable antiproliferative activity across the four cancer cell lines, with hepatocellular carcinoma (HepG2) cells being the most affected. With half-maximal inhibitory concentration (IC50) values ranging from 6.4±1.2 μg/mL to 19.2±3.4 μg/mL, IsoA demonstrated great potential in inhibiting cancer cell proliferation. Notably, IsoA's mechanisms of action involve critical molecular targets associated with cell cycle regulation and apoptosis. It significantly increased the levels of phosphorylated cyclin-dependent kinase 2 (Cdk2 pTyr15), a key regulator of cell cycle arrest, and cleaved poly [ADP-ribose] polymerase 1 (PARP1), a hallmark of apoptosis initiation. These findings underscore the therapeutic potential of IsoA in cancer treatment. CONCLUSIONS IsoA demonstrated highly promising in vitro antiproliferative activity by effectively arresting the cell cycle at the G1/S checkpoint, halting cancer cell proliferation. Additionally, IsoA induced programmed cell death (apoptosis) through mechanisms such as PARP1 cleavage, highlighting its potential as a candidate for cancer therapy.
Collapse
Affiliation(s)
- Bright Selorm Addy
- Department of Biochemistry and Biotechnology, College of Sciences, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana; Department of Pharmaceutical Sciences, School of Pharmacy, Central University, Accra, Ghana.
| | - Caleb Kesse Firempong
- Department of Biochemistry and Biotechnology, College of Sciences, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana
| | - Gustav Komlaga
- Department of Pharmacognosy, College of Health Sciences, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana
| | - Patrick Addo-Fordjour
- Department of Theoretical and Applied Biology, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana
| | - Seth Agyei Domfeh
- Department of Biochemistry and Biotechnology, College of Sciences, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana
| | - Oluwatomisin Deborah Afolayan
- Department of Biochemistry and Biotechnology, College of Sciences, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana
| | - Eric Nana Yaw Nyarko
- Department of Chemical Pathology, University of Ghana Medical School, University of Ghana, Accra, Ghana
| | - Benjamin Obukowho Emikpe
- Department of Veterinary Pathology, School of Veterinary Medicine, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana
| |
Collapse
|
41
|
Buckley-Benbow L, Agnarelli A, Bellelli R. 'Where is my gap': mechanisms underpinning PARP inhibitor sensitivity in cancer. Biochem Soc Trans 2025; 53:BST20241633. [PMID: 39927794 DOI: 10.1042/bst20241633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/20/2025] [Accepted: 01/23/2025] [Indexed: 02/11/2025]
Abstract
The introduction of poly-ADP ribose polymerase (PARP) inhibitors (PARPi) has completely changed the treatment landscape of breast cancer susceptibility 1-2 (BRCA1-BRCA2)-mutant cancers and generated a new avenue of research in the fields of DNA damage response and cancer therapy. Despite this, primary and secondary resistances to PARPi have become a challenge in the clinic, and novel therapies are urgently needed to address this problem. After two decades of research, a unifying model explaining sensitivity of cancer cells to PARPi is still missing. Here, we review the current knowledge in the field and the increasing evidence pointing to a crucial role for replicative gaps in mediating sensitization to PARPi in BRCA-mutant and 'wild-type' cancer cells. Finally, we discuss the challenges to be addressed to further improve the utilization of PARPi and tackle the emergence of resistance in the clinical context.
Collapse
Affiliation(s)
- Lauryn Buckley-Benbow
- Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, Barbican, London EC1M 6BQ, U.K
| | - Alessandro Agnarelli
- Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, Barbican, London EC1M 6BQ, U.K
| | - Roberto Bellelli
- Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, Barbican, London EC1M 6BQ, U.K
| |
Collapse
|
42
|
Erdogan MK, Usca AB. Gallic Acid Enhances Olaparib-Induced Cell Death and Attenuates Olaparib Resistance in Human Osteosarcoma U2OS Cell Line. Curr Issues Mol Biol 2025; 47:104. [PMID: 39996825 PMCID: PMC11854715 DOI: 10.3390/cimb47020104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/28/2024] [Accepted: 01/07/2025] [Indexed: 02/26/2025] Open
Abstract
Cancer remains one of the most formidable diseases globally and continues to be a leading cause of mortality. While chemotherapeutic agents are crucial in cancer treatment, they often come with severe side effects. Furthermore, the development of acquired drug resistance poses a significant challenge in the ongoing battle against cancer. Combining these chemotherapeutic agents with plant-derived phenolic compounds offers a promising approach, potentially reducing side effects and counteracting drug resistance. Phytochemicals, the bioactive compounds found in plants, exhibit a range of health-promoting properties, including anticarcinogenic, antimutagenic, antiproliferative, antioxidant, antimicrobial, neuroprotective, and cardioprotective effects. Their ability to enhance treatment, coupled with their non-toxic, multi-targeted nature and synergistic potential when used alongside conventional drugs, underscores the growing importance of natural therapeutics. In this study, we investigated the anticancer effects of olaparib (OL), a small-molecule PARP inhibitor that has shown promising results in both preclinical and clinical trials, and gallic acid (GA), a phenolic compound, in olaparib-resistant human osteosarcoma U2OS cells (U2OS-PIR). Both parental U2OS and U2OS-PIR cell lines were treated with increasing concentrations of olaparib and gallic acid, and their cytotoxic effects were assessed using the WST-1 cell viability assay. The synergistic potential of OL and GA, based on their determined IC50 values, was further explored in combination treatment. A colony survival assay revealed the combination's ability to significantly reduce the colony-forming capacity of cancer cells. Additionally, the apoptotic effects of OL and GA, both individually and in combination, were examined in U2OS-PIR cells using acridine orange/ethidium bromide dual staining. The anti-angiogenic properties were assessed through a VEGF ELISA, while the expression of proteins involved in DNA damage and apoptotic signaling pathways was analyzed via Western blot. The results of this study demonstrate that gallic acid effectively suppresses cell viability and colony formation, particularly when used in combination therapy to combat OL resistance. Additionally, GA inhibits angiogenesis and induces DNA damage and apoptosis by modulating key apoptosis-related proteins, including cPARP, Bcl-2, and Bax. These findings highlight gallic acid as a potential compound for enhancing therapeutic efficacy in overcoming acquired drug resistance.
Collapse
Affiliation(s)
- Mehmet Kadir Erdogan
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Bingol University, Bingol 12000, Türkiye
| | - Ayse Busra Usca
- Department of Biology, Science Institute, Bingol University, Bingol 12000, Türkiye
| |
Collapse
|
43
|
Karami Fath M, Najafiyan B, Morovatshoar R, Khorsandi M, Dashtizadeh A, Kiani A, Farzam F, Kazemi KS, Nabi Afjadi M. Potential promising of synthetic lethality in cancer research and treatment. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:1403-1431. [PMID: 39305329 DOI: 10.1007/s00210-024-03444-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 09/08/2024] [Indexed: 02/14/2025]
Abstract
Cancer is a complex disease driven by multiple genetic changes, including mutations in oncogenes, tumor suppressor genes, DNA repair genes, and genes involved in cancer metabolism. Synthetic lethality (SL) is a promising approach in cancer research and treatment, where the simultaneous dysfunction of specific genes or pathways causes cell death. By targeting vulnerabilities created by these dysfunctions, SL therapies selectively kill cancer cells while sparing normal cells. SL therapies, such as PARP inhibitors, WEE1 inhibitors, ATR and ATM inhibitors, and DNA-PK inhibitors, offer a distinct approach to cancer treatment compared to conventional targeted therapies. Instead of directly inhibiting specific molecules or pathways, SL therapies exploit genetic or molecular vulnerabilities in cancer cells to induce selective cell death, offering benefits such as targeted therapy, enhanced treatment efficacy, and minimized harm to healthy tissues. SL therapies can be personalized based on each patient's unique genetic profile and combined with other treatment modalities to potentially achieve synergistic effects. They also broaden the effectiveness of treatment across different cancer types, potentially overcoming drug resistance and improving patient outcomes. This review offers an overview of the current understanding of SL mechanisms, advancements, and challenges, as well as the preclinical and clinical development of SL. It also discusses new directions and opportunities for utilizing SL in targeted therapy for anticancer treatment.
Collapse
Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Behnam Najafiyan
- Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Morovatshoar
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Mahdieh Khorsandi
- Department of Biotechnology, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Arash Kiani
- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Farnoosh Farzam
- Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | - Kimia Sadat Kazemi
- Faculty of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohsen Nabi Afjadi
- Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran.
| |
Collapse
|
44
|
Kim S, Bae K, Lee JL, Lee WS, Ock C, Lee M, Bang J, Hong MJ, Roh E, Ha KS, Lim J, Kim Y. First-In-Human Dose Finding Study of Venadaparib (IDX-1197), a Potent and Selective PARP Inhibitor, in Patients With Advanced Solid Tumors. Cancer Med 2025; 14:e70576. [PMID: 39945311 PMCID: PMC11822664 DOI: 10.1002/cam4.70576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 12/16/2024] [Accepted: 12/24/2024] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND Venadaparib, a novel poly (ADP-ribose) polymerase (PARP) inhibitor, has demonstrated high PARP-1/2 selectivity over other PARP family members and exhibited strong PARP-trapping activity, effectively inhibiting tumor growth in homologous recombination deficient (HRD) cancer in vitro and in vivo. METHODS This phase 1, dose-finding study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and anticancer efficacy of venadaparib as monotherapy in patients with advanced solid tumors that progressed after standard-of-care therapy. The study employed a conventional 3+3 design, with doses ranging from 2 mg/d to 240 mg/d. RESULTS Among the 32 enrolled patients, the most common tumor types were breast (16 patients) and ovarian (12 patients) cancers. No dose-limiting toxicities (DLTs) were observed up to 240 mg/d. The most frequent grade 3 or 4 adverse events were anemia (50%), neutropenia (22%) and thrombocytopenia (6%). Tumor shrinkage by Response Evaluation Criteria in Solid Tumours (RECIST) was observed at doses ≥ 40 mg/d, regardless of BRCA mutation status.Two partial responses out of four ovarian cancer patients receiving venadaparib ≥ 40 mg/d were reported. Clinical benefit, defined as stable disease or partial response, was observed at the lowest tested dose. Venadaparib exhibited ≥ 90% PAR inhibitory effect in pharmacodynamic analysis from 10 mg/d based on tumor samples. The recommended phase 2 dose (RP2D) was defined as 160 mg once daily. CONCLUSIONS Further studies are warranted to explore efficacy and safety of venadaparib in other tumor types and in combination with various agents, as well as to explore relevant biomarkers. (ClinicalTrials.gov ID: NCT03317743).
Collapse
Affiliation(s)
- Sung‐Bae Kim
- Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Kyun‐Seop Bae
- Department of Clinical Pharmacology & Therapeutics, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | - Jae Lyun Lee
- Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| | | | | | | | | | | | | | | | - Jong‐Ha Lim
- Ildong Pharmaceutical Co. LtdGyeonggi‐doRepublic of Korea
| | - Yong‐Man Kim
- Department of Obstetrics and Gynecology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
| |
Collapse
|
45
|
Pio Maiorano MF, Loizzi V, Maiorano BA, Cormio G. Haematological toxicity of PARP inhibitors in advanced ovarian cancer: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2025; 305:232-240. [PMID: 39724774 DOI: 10.1016/j.ejogrb.2024.12.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/29/2024] [Accepted: 12/13/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND Poly (ADP-ribose) polymerase inhibitors (PARPis) are effective treatment options for patients with advanced ovarian cancer (OC). A typical adverse event (AE) of these agents is haematological toxicity, which represents the leading cause of treatment modification and discontinuation. This systematic review and meta-analysis aimed to analyse the risk of haematological AEs, including anaemia, neutropenia and thrombocytopenia due to the use of PARPis in patients with OC. METHODS This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. PubMed, EMBASE and Cochrane databases, and international meeting abstracts were searched systematically for clinical trials concerning the use of PARPis in patients with OC. The search deadline was 30 March 2024. The pooled incidence of all grades and grade 3or more (≥G3) anaemia, neutropenia and thrombocytopenia were analysed. Subsequently, risk ratios (RRs) were calculated for all grades and ≥G3 AEs of PARPis compared with non-PARPis from randomized controlled trials. RESULTS In total, 12 phase II/III trials with olaparib, niraparib and rucaparib were included in this study. Anaemia was the most common all grade (28.8 %) and ≥G3 (12.1 %) AE. The administration of PARPis increased the risk of developing all grade anaemia [risk ratio (RR) = 2.44], neutropenia (RR = 3.15) and thrombocytopenia (RR = 4.66) significantly compared with non-PARPis. Similarly, a significant increase in the risk of ≥G3 anaemia (RR = 5.73) and thrombocytopenia (RR = 5.44), and a non-significant increase in the risk of neutropenia (RR = 3.41) were detected. CONCLUSIONS In patients with advanced OC, PARPis increase the risk of haematological toxicity compared with other treatments (high-quality evidence). Clinicians should be aware of this risk and the correct management, as these drugs are highly employed in these patients.
Collapse
Affiliation(s)
| | - Vera Loizzi
- Department of Interdisciplinary Medicine, University of Bari 'Aldo Moro', Bari, Italy; Gynaecologic Oncology Unit, IRCCS Istituto Tumori 'Giovanni Paolo II', Bari, Italy
| | | | - Gennaro Cormio
- Department of Interdisciplinary Medicine, University of Bari 'Aldo Moro', Bari, Italy; Gynaecologic Oncology Unit, IRCCS Istituto Tumori 'Giovanni Paolo II', Bari, Italy
| |
Collapse
|
46
|
Ilyina V, Gatina A, Trizna E, Siniagina M, Yadykova L, Ivannikova A, Ozhegov G, Zhuravleva D, Fedorova M, Gorshkova A, Evseev P, Drucker V, Bogachev M, Validov S, Kharitonova M, Kayumov A. New Bacteriophage Pseudomonas Phage Ka2 from a Tributary Stream of Lake Baikal. Viruses 2025; 17:189. [PMID: 40006944 PMCID: PMC11861027 DOI: 10.3390/v17020189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/20/2025] [Accepted: 01/25/2025] [Indexed: 02/27/2025] Open
Abstract
Pseudomonas aeruginosa, an opportunistic pathogen, causes various biofilm-associated infections like pneumonia, infections in cystic fibrosis patients, and urinary tract and burn infections with high morbidity and mortality, as well as low treatment efficacy due to the extremely wide spread of isolates with multidrug resistance. Here, we report the new bacteriophage Pseudomonas phage Ka2 isolated from a tributary stream of Lake Baikal and belonging to the Pbunavirus genus. Transmission electron microscopy resolved that Pseudomonas phage Ka2 has a capsid of 57 ± 9 nm and a contractile and inflexible tail of 115 ± 10 nm in the non-contracted state. The genome consists of 66,310 bp with a GC content of 55% and contains 96 coding sequences. Among them, 52 encode proteins have known functions, and none of them are potentially associated with lysogeny. The bacteriophage lyses 21 of 30 P. aeruginosa clinical isolates and decreases the MIC of amikacin, gentamicin, and cefepime up to 16-fold and the MIC of colistin up to 32-fold. When treating the biofilms with Ka2, the biomass was reduced by twice, and up to a 32-fold decrease in the antibiotics MBC against biofilm-embedded cells was achieved by the combination of Ka2 with cefepime for the PAO1 strain, along with a decrease of up to 16-fold with either amikacin or colistin for clinical isolates. Taken together, these data characterize the new Pseudomonas phage Ka2 as a promising tool for the combined treatment of infections associated with P. aeruginosa biofilms.
Collapse
Affiliation(s)
- Valeriya Ilyina
- Institute of Fundamental Biology and Medicine, Kazan Federal University, 420012 Kazan, Russia; (V.I.); (A.G.); (E.T.); (M.S.); (L.Y.); (A.I.); (G.O.); (D.Z.); (M.F.); (M.K.)
| | - Alina Gatina
- Institute of Fundamental Biology and Medicine, Kazan Federal University, 420012 Kazan, Russia; (V.I.); (A.G.); (E.T.); (M.S.); (L.Y.); (A.I.); (G.O.); (D.Z.); (M.F.); (M.K.)
| | - Elena Trizna
- Institute of Fundamental Biology and Medicine, Kazan Federal University, 420012 Kazan, Russia; (V.I.); (A.G.); (E.T.); (M.S.); (L.Y.); (A.I.); (G.O.); (D.Z.); (M.F.); (M.K.)
| | - Maria Siniagina
- Institute of Fundamental Biology and Medicine, Kazan Federal University, 420012 Kazan, Russia; (V.I.); (A.G.); (E.T.); (M.S.); (L.Y.); (A.I.); (G.O.); (D.Z.); (M.F.); (M.K.)
| | - Liudmila Yadykova
- Institute of Fundamental Biology and Medicine, Kazan Federal University, 420012 Kazan, Russia; (V.I.); (A.G.); (E.T.); (M.S.); (L.Y.); (A.I.); (G.O.); (D.Z.); (M.F.); (M.K.)
| | - Anastasiya Ivannikova
- Institute of Fundamental Biology and Medicine, Kazan Federal University, 420012 Kazan, Russia; (V.I.); (A.G.); (E.T.); (M.S.); (L.Y.); (A.I.); (G.O.); (D.Z.); (M.F.); (M.K.)
| | - Georgiy Ozhegov
- Institute of Fundamental Biology and Medicine, Kazan Federal University, 420012 Kazan, Russia; (V.I.); (A.G.); (E.T.); (M.S.); (L.Y.); (A.I.); (G.O.); (D.Z.); (M.F.); (M.K.)
| | - Daria Zhuravleva
- Institute of Fundamental Biology and Medicine, Kazan Federal University, 420012 Kazan, Russia; (V.I.); (A.G.); (E.T.); (M.S.); (L.Y.); (A.I.); (G.O.); (D.Z.); (M.F.); (M.K.)
| | - Marina Fedorova
- Institute of Fundamental Biology and Medicine, Kazan Federal University, 420012 Kazan, Russia; (V.I.); (A.G.); (E.T.); (M.S.); (L.Y.); (A.I.); (G.O.); (D.Z.); (M.F.); (M.K.)
| | - Anna Gorshkova
- Limnological Institute of the Siberian Branch of the Russian Academy of Sciences, 664033 Irkutsk, Russia; (A.G.); (V.D.)
| | - Peter Evseev
- Laboratory of Molecular Microbiology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia;
| | - Valentin Drucker
- Limnological Institute of the Siberian Branch of the Russian Academy of Sciences, 664033 Irkutsk, Russia; (A.G.); (V.D.)
| | - Mikhail Bogachev
- Biomedical Engineering Research Centre, St. Petersburg Electrotechnical University, 197022 St. Petersburg, Russia;
| | - Shamil Validov
- Laboratory of Molecular Genetics and Microbiology Methods, Kazan Scientific Center of the Russian Academy of Sciences, 420111 Kazan, Russia;
| | - Maya Kharitonova
- Institute of Fundamental Biology and Medicine, Kazan Federal University, 420012 Kazan, Russia; (V.I.); (A.G.); (E.T.); (M.S.); (L.Y.); (A.I.); (G.O.); (D.Z.); (M.F.); (M.K.)
| | - Airat Kayumov
- Institute of Fundamental Biology and Medicine, Kazan Federal University, 420012 Kazan, Russia; (V.I.); (A.G.); (E.T.); (M.S.); (L.Y.); (A.I.); (G.O.); (D.Z.); (M.F.); (M.K.)
| |
Collapse
|
47
|
Guo T, Yuan Y, Zou Y, Guo Z, Yang T, Tang M, Ma Z, Fu Z, Bo W, Wang P, Bai P, Wang T, Jia T, Yang J, Chen L. Design, Synthesis, and Pharmacodynamic Evaluation of Highly Selective PARP1 Inhibitors with Brain Penetrance. J Med Chem 2025; 68:1731-1754. [PMID: 39789975 DOI: 10.1021/acs.jmedchem.4c02463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Selective poly(ADP-ribose) polymerase 1 (PARP1) inhibitors not only exhibit antitumor efficacy but also offer the potential to mitigate the toxicities typically associated with broader PARP inhibition. In this study, we designed and synthesized a series of small molecules targeting highly selective PARP1 inhibitors. Among these, T26 demonstrated excellent selectivity to PARP1 along with the capability to effectively cross the blood-brain barrier (BBB). T26 exhibited an IC50 of 0.2 nM against PARP1, with a remarkable 610-fold selectivity over PARP2 and high antiproliferative activity in BRCA mutant MDA-MB-436 cells with an IC50 of 2.6 nM. T26 also displayed excellent oral bioavailability (F = 87.74%) and long half-life (T1/2 = 76.07 h) in mice, supporting once every other day administration. Oral administration of T26 at 0.3 mg/kg and 3 mg/kg resulted in significant tumor growth inhibition in both subcutaneous and intracranial xenograft models of MDA-MB-436, suggesting T26 significant potential for the treatment of breast cancer metastases.
Collapse
Affiliation(s)
- Tao Guo
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yongting Yuan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yurong Zou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhongning Guo
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Tao Yang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Minghai Tang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ziyan Ma
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhiyuan Fu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Weichen Bo
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Peng Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Peng Bai
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Taijin Wang
- Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610041, China
| | - Tao Jia
- Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610041, China
| | - Jianhong Yang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lijuan Chen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610041, China
| |
Collapse
|
48
|
Wang Y, Zhang J, Wu X, Huang L, Xiao W, Guo C. The Potential of PARP Inhibitors as Antitumor Drugs and the Perspective of Molecular Design. J Med Chem 2025; 68:18-48. [PMID: 39723587 DOI: 10.1021/acs.jmedchem.4c02642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024]
Abstract
PARP (poly-ADP ribose polymerase) has received widespread attention in cancer treatment. Research has shown that PARP plays a crucial role in DNA damage repair and has become a popular target for drug design. Based on the mechanism of "synthetic lethality", multiple PARPis (PARP inhibitors) have been launched for the treatment of BRCA deficient tumors. For example, the approved PARPis have shown significant potential in cancer treatment, particularly in breast cancer and cancers associated with BRCA1/BRCA2 deficiencies. However, the clinical efficacy and safety of PARP inhibitors in different cancers remain issues that cannot be overlooked. The design of PARPis aims to eliminate their resistance and broaden their application scope. Designing selective PARP-1 inhibitors is also a potential strategy. PROTACs (Proteolysis Targeting Chimeras) to degrade PARP have become a potential novel cancer treatment strategy.
Collapse
Affiliation(s)
- Yinghan Wang
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
| | - Jingtao Zhang
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
| | - Xiaochen Wu
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
| | - Longjiang Huang
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
| | - Wenjing Xiao
- Department of Radiation Therapy, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Chuanlong Guo
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
| |
Collapse
|
49
|
Ursino M, Villacampa G, Rekowski J, Dimairo M, Solovyeva O, Ashby D, Berlin J, Boix O, Calvert M, Chan AW, Coschi CH, Evans TRJ, Garrett-Mayer E, Golub RM, Guo C, Hayward KS, Hopewell S, Isaacs JD, Ivy SP, Jaki T, Kholmanskikh O, Kightley A, Lee S, Liu R, Mander A, Marshall LV, Matcham J, Patel D, Peck R, Rantell KR, Richards DP, Rouhifard M, Seymour L, Tanaka Y, Weir CJ, de Bono J, Yap C. SPIRIT-DEFINE explanation and elaboration: recommendations for enhancing quality and impact of early phase dose-finding clinical trials protocols. EClinicalMedicine 2025; 79:102988. [PMID: 39877554 PMCID: PMC11773215 DOI: 10.1016/j.eclinm.2024.102988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 11/11/2024] [Accepted: 11/20/2024] [Indexed: 01/31/2025] Open
Abstract
Transparent and accurate reporting in early phase dose-finding (EPDF) clinical trials is crucial for informing subsequent larger trials. The SPIRIT statement, designed for trial protocol content, does not adequately cover the distinctive features of EPDF trials. Recent findings indicate that the protocol contents in past EPDF trials frequently lacked completeness and clarity. To address this gap, the international consensus-driven SPIRIT-DEFINE checklist was developed through a robust methodological framework for guideline development, with the aim to improve completeness and clarity in EPDF trial protocols. The checklist builds on the SPIRIT statement, adding 17 new items and modifying 15 existing ones.The SPIRIT-DEFINE explanation and elaboration (E&E) document provides comprehensive information to enhance understanding and usability of the SPIRIT-DEFINE checklist when writing an EPDF trial protocol. Each new or modified checklist item is accompanied by a detailed description, its rationale with supportive evidence, and examples of good reporting curated from EPDF trial protocols covering a range of therapeutic areas and interventions. We recommend utilising this paper alongside the SPIRIT statement, and any relevant extensions, to enhance the development and review of EPDF trial protocols.By facilitating adoption of the SPIRIT-DEFINE statement for EPDF trials, this E&E document can promote enhancement of methodological rigour, patient safety, transparency, and facilitate the generation of high-quality, reproducible evidence that will strengthen the foundation of early phase research and ultimately improve patient outcomes. Funding This work is a further extension of the SPIRIT-DEFINE study, which obtained no external funding. The principal investigator (CY) used internal staff resources, together with additional resources from external partners, to conduct this study. The SPIRIT-DEFINE study is a component of the DEFINE project, which also developed the MRC/NIHR funded CONSORT-DEFINE guidance. ICR-CTSU receives programmatic infrastructure funding from Cancer Research UK (C1491/A25351; CTUQQR-Dec22/100004), which has contributed to accelerating the advancement and successful completion of this work.
Collapse
Affiliation(s)
- Moreno Ursino
- ReCAP/F CRIN, INSERM, 5400, Nancy, France
- Unit of Clinical Epidemiology, University Hospital Centre Robert Debré, Université Paris Cité, Paris, France
- INSERM, Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Paris, France
- HeKA Team, Centre Inria, Paris, France
| | - Guillermo Villacampa
- Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, UK
- Statistics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- SOLTI Breast Cancer Research Group, Barcelona, Spain
| | - Jan Rekowski
- Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, UK
| | - Munyaradzi Dimairo
- Division of Population Health, Sheffield Centre for Health and Related Research, University of Sheffield, Sheffield, UK
| | - Olga Solovyeva
- Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, UK
| | - Deborah Ashby
- School of Public Health, Imperial College London, St Mary's Hospital, London, UK
| | | | | | - Melanie Calvert
- Centre for Patient Reported Outcomes Research, Institute of Applied Health Research, University of Birmingham, Birmingham, UK
- Birmingham Health Partners Centre for Regulatory Science and Innovation, University of Birmingham, Birmingham, UK
- National Institute for Health and Care Research Applied Research Collaboration West Midlands, University of Birmingham, Birmingham, UK
- National Institute for Health and Care Research Blood and Transplant Research Unit in Precision Transplant and Cellular Therapeutics, University of Birmingham, Birmingham, UK
- National Institute for Health and Care Research Birmingham Biomedical Research Centre, NIHR Birmingham Biomedical Research Centre, Institute of Translational Medicine, University Hospital NHS Foundation Trust, Birmingham, UK
| | - An-Wen Chan
- Department of Medicine, Women's College Research Institute, University of Toronto, Toronto, Canada
| | | | - Thomas R. Jeffry Evans
- Institute of Cancer Sciences, CR-UK Beatson Institute, University of Glasgow, Glasgow, UK
| | - Elizabeth Garrett-Mayer
- Center for Research and Analytics, American Society of Clinical Oncology, Alexandria, VA, USA
| | - Robert M. Golub
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Christina Guo
- The Institute of Cancer Research, London, UK
- Royal Marsden NHS Foundation Trust, London, UK
| | - Kathryn S. Hayward
- Departments of Physiotherapy and Medicine, University of Melbourne, VIC, Australia
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia
| | - Sally Hopewell
- Oxford Clinical Research Unit, NDORMS, University of Oxford, Oxford, UK
| | - John D. Isaacs
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - S. Percy Ivy
- Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Institute of Health, Bethesda, MD, USA
| | - Thomas Jaki
- MRC Biostatistics Unit, Cambridge University, Cambridge, UK
- Computational Statistics Group, University of Regensburg, Regensburg, Germany
| | | | - Andrew Kightley
- Patient and Public Involvement and Engagement (PPIE) Lead, Lichfield, UK
| | - Shing Lee
- Columbia University Mailman School of Public Health, New York, NY, USA
| | | | - Adrian Mander
- Centre for Trials Research, Cardiff University, Cardiff, UK
| | - Lynley V. Marshall
- The Institute of Cancer Research, London, UK
- Royal Marsden NHS Foundation Trust, London, UK
| | - James Matcham
- Strategic Consulting, Cytel (Australia), Perth, WA, Australia
| | - Dhrusti Patel
- Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, UK
| | - Richard Peck
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
- Hoffmann-La Roche, Basel, Switzerland
| | | | | | - Mahtab Rouhifard
- Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, UK
| | | | - Yoshiya Tanaka
- First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Christopher J. Weir
- Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UK
| | - Johann de Bono
- The Institute of Cancer Research, London, UK
- Royal Marsden NHS Foundation Trust, London, UK
| | - Christina Yap
- Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, UK
| |
Collapse
|
50
|
Drew Y, Zenke FT, Curtin NJ. DNA damage response inhibitors in cancer therapy: lessons from the past, current status and future implications. Nat Rev Drug Discov 2025; 24:19-39. [PMID: 39533099 DOI: 10.1038/s41573-024-01060-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2024] [Indexed: 11/16/2024]
Abstract
The DNA damage response (DDR) is a network of proteins that coordinate DNA repair and cell-cycle checkpoints to prevent damage being transmitted to daughter cells. DDR defects lead to genomic instability, which enables tumour development, but they also create vulnerabilities that can be used for cancer therapy. Historically, this vulnerability has been taken advantage of using DNA-damaging cytotoxic drugs and radiotherapy, which are more toxic to tumour cells than to normal tissues. However, the discovery of the unique sensitivity of tumours defective in the homologous recombination DNA repair pathway to PARP inhibition led to the approval of six PARP inhibitors worldwide and to a focus on making use of DDR defects through the development of other DDR-targeting drugs. Here, we analyse the lessons learnt from PARP inhibitor development and how these may be applied to new targets to maximize success. We explore why, despite so much research, no other DDR inhibitor class has been approved, and only a handful have advanced to later-stage clinical trials. We discuss why more reliable predictive biomarkers are needed, explore study design from past and current trials, and suggest alternative models for monotherapy and combination studies. Targeting multiple DDR pathways simultaneously and potential combinations with anti-angiogenic agents or immune checkpoint inhibitors are also discussed.
Collapse
Affiliation(s)
- Yvette Drew
- BC Cancer Vancouver Centre and Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Frank T Zenke
- Research Unit Oncology, EMD Serono, Billerica, MA, USA
| | - Nicola J Curtin
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
| |
Collapse
|