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1
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Berney M, Ferguson S, McGouran JF. Function and inhibition of the DNA repair enzyme SNM1A. Bioorg Chem 2025; 156:108225. [PMID: 39914034 DOI: 10.1016/j.bioorg.2025.108225] [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: 09/30/2024] [Revised: 01/09/2025] [Accepted: 01/28/2025] [Indexed: 03/28/2025]
Abstract
SNM1A is an enzyme involved in several important biological pathways. To date, most investigations have focused on its role in repairing interstrand crosslinks, a highly cytotoxic form of DNA damage. SNM1A acts as a 5'-3' exonuclease, displaying an unusual capability to digest DNA past the site of a crosslink lesion. Recently, additional functions of this enzyme in the repair of DNA double-strand breaks and critically shortened telomeres have been uncovered. Furthermore, SNM1A is involved in two cell cycle checkpoints that arrest cell division in response to DNA damage. Inhibition of both DNA repair enzymes and cell cycle checkpoint proteins are effective strategies for cancer treatment, and SNM1A is therefore of significant interest as a potential therapeutic target. As a member of the metallo-β-lactamase superfamily, SNM1A is postulated to contain two metal ions in the active site that catalyse hydrolysis of the phosphodiester backbone of DNA. Substrate-mimic probes based on a nucleoside or oligonucleotide scaffold appended with a metal-binding group have proven effective in vitro. High-throughput screening campaigns have identified potent inhibitors, some of which were successful in sensitising cells to DNA-damaging cancer drugs. This review discusses the biological role, structure, and mechanism of action of SNM1A, and the development of SNM1A inhibitors for cancer therapy.
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Affiliation(s)
- Mark Berney
- National Institute for Bioprocess Research and Training, Foster Avenue, Mount Merrion, Dublin, Ireland; School of Chemical and Bioprocess Engineering, University College Dublin, Belfield, Dublin 4, Ireland
| | - Steven Ferguson
- National Institute for Bioprocess Research and Training, Foster Avenue, Mount Merrion, Dublin, Ireland; School of Chemical and Bioprocess Engineering, University College Dublin, Belfield, Dublin 4, Ireland; SSPC, The SFI Research Centre for Pharmaceuticals, Ireland
| | - Joanna F McGouran
- School of Chemistry, and Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland; SSPC, The SFI Research Centre for Pharmaceuticals, Ireland.
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2
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Yan L, Shi J, Zhu J. Cellular and molecular events in colorectal cancer: biological mechanisms, cell death pathways, drug resistance and signalling network interactions. Discov Oncol 2024; 15:294. [PMID: 39031216 PMCID: PMC11265098 DOI: 10.1007/s12672-024-01163-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 07/15/2024] [Indexed: 07/22/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, affecting millions each year. It emerges from the colon or rectum, parts of the digestive system, and is closely linked to both genetic and environmental factors. In CRC, genetic mutations such as APC, KRAS, and TP53, along with epigenetic changes like DNA methylation and histone modifications, play crucial roles in tumor development and treatment responses. This paper delves into the complex biological underpinnings of CRC, highlighting the pivotal roles of genetic alterations, cell death pathways, and the intricate network of signaling interactions that contribute to the disease's progression. It explores the dysregulation of apoptosis, autophagy, and other cell death mechanisms, underscoring the aberrant activation of these pathways in CRC. Additionally, the paper examines how mutations in key molecular pathways, including Wnt, EGFR/MAPK, and PI3K, fuel CRC development, and how these alterations can serve as both diagnostic and prognostic markers. The dual function of autophagy in CRC, acting as a tumor suppressor or promoter depending on the context, is also scrutinized. Through a comprehensive analysis of cellular and molecular events, this research aims to deepen our understanding of CRC and pave the way for more effective diagnostics, prognostics, and therapeutic strategies.
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Affiliation(s)
- Lei Yan
- Medical Department, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jia Shi
- Department of Obstetrics and Gynecology, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jiazuo Zhu
- Department of Oncology, Xuancheng City Central Hospital, No. 117 Tong Road, Xuancheng, Anhui, China.
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3
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Ozawa S, Miura T, Terashima J, Habano W. Cellular irinotecan resistance in colorectal cancer and overcoming irinotecan refractoriness through various combination trials including DNA methyltransferase inhibitors: a review. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 4:946-964. [PMID: 35582377 PMCID: PMC8992440 DOI: 10.20517/cdr.2021.82] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/27/2021] [Accepted: 10/26/2021] [Indexed: 12/28/2022]
Abstract
Treatment with pharmacological drugs for colorectal cancer (CRC) remains unsatisfactory. A major cause of failure in pharmacotherapy is the resistance of colon cancer cells to the drugs, creating an urgent issue. In this review, we summarize previous studies on the resistance of CRC cells to irinotecan and discuss possible reasons for refractoriness. Our review presents the following five major causes of irinotecan resistance in human CRC: (1) cellular irinotecan resistance is induced mainly through the increased expression of the drug efflux transporter, ABCG2; (2) cellular irinotecan resistance is also induced in association with a nuclear receptor, pregnane/steroid X receptor (PXR/SXR), which is enriched in the CYP3A4 gene enhancer region in CRC cells by exposing the cells to SN-38; (3) irinotecan-resistant cells possess either reduced DNA topoisomerase I (Top1) expression at both the mRNA and protein levels or Top1 missense mutations; (4) alterations in the tumor microenvironment lead to drug resistance through intercellular vesicle-mediated transmission of miRNAs; and (5) CRC stem cells are the most difficult targets to successfully treat CRC. In the clinical setting, CRC gradually develops resistance to initially effective irinotecan-based therapy. To solve this problem, several clinical trials, such as irinotecan plus cetuximab vs. cetuximab monotherapy, have been conducted. Another clinical trial on irinotecan plus guadecitabine, a DNA-methyltransferase inhibitor, has also been conducted.
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Affiliation(s)
- Shogo Ozawa
- Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
| | - Toshitaka Miura
- Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
| | - Jun Terashima
- Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
| | - Wataru Habano
- Division of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
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4
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Walters K, Stornetta A, Jacobs F, Villalta PW, Razzoli M, Grant M, Zordoky B, Bartolomucci A, Borgatti A, Balbo S. Identification of new candidate biomarkers to support doxorubicin treatments in canine cancer patients. BMC Vet Res 2021; 17:378. [PMID: 34876121 PMCID: PMC8650425 DOI: 10.1186/s12917-021-03062-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 10/13/2021] [Indexed: 11/10/2022] Open
Abstract
Background Both human and veterinary cancer chemotherapy are undergoing a paradigm shift from a “one size fits all” approach to more personalized, patient-oriented treatment strategies. Personalized chemotherapy is dependent on the identification and validation of biomarkers that can predict treatment outcome and/or risk of toxicity. Many cytotoxic chemotherapy agents, including doxorubicin, base their mechanism of action by interaction with DNA and disruption of normal cellular processes. We developed a high-resolution/accurate-mass liquid chromatography-mass spectrometry DNA screening approach for monitoring doxorubicin-induced DNA modifications (adducts) in vitro and in vivo. We used, for the first time, a new strategy involving the use of isotope-labeled DNA, which greatly facilitates adduct discovery. The overall goal of this work was to identify doxorubicin-DNA adducts to be used as biomarkers to predict drug efficacy for use in veterinary oncology. Results We used our novel mass spectrometry approach to screen for adducts in purified DNA exposed to doxorubicin. This initial in vitro screening identified nine potential doxorubicin-DNA adduct masses, as well as an intense signal corresponding to DNA-intercalated doxorubicin. Two of the adduct masses, together with doxorubicin and its metabolite doxorubicinol, were subsequently detected in vivo in liver DNA extracted from mice exposed to doxorubicin. Finally, the presence of these adducts and analytes was explored in the DNA isolated from dogs undergoing treatment with doxorubicin. The previously identified nine DOX-DNA adducts were not detected in these preliminary three samples collected seven days post-treatment, however intercalated doxorubicin and doxorubicinol were detected. Conclusions This work sets the stage for future evaluation of doxorubicin-DNA adducts and doxorubicin-related molecules as candidate biomarkers to personalize chemotherapy protocols for canine cancer patients. It demonstrates our ability to combine in one method the analysis of DNA adducts and DNA-intercalated doxorubicin and doxorubicinol. The last two analytes interestingly, were persistent in samples from canine patients undergoing doxorubicin chemotherapy seven days after treatment. The presence of doxorubicin in all samples suggests a role for it as a promising biomarker for use in veterinary chemotherapy. Future studies will involve the analysis of more samples from canine cancer patients to elucidate optimal timepoints for monitoring intercalated doxorubicin and doxorubicin-DNA adducts and the correlation of these markers with therapy outcome. Supplementary Information The online version contains supplementary material available at 10.1186/s12917-021-03062-x.
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Affiliation(s)
- Kristine Walters
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, 1365 Gortner Avenue, St Paul, MN, 55108, USA.,WestVet 24/7 Animal Emergency & Specialty Center, 5024 W Chinden Boulevard, Garden City, ID, 83714, USA
| | - Alessia Stornetta
- Masonic Cancer Center, University of Minnesota, 2231 6th Street Southeast, Minneapolis, MN, 55455, USA
| | - Foster Jacobs
- Masonic Cancer Center, University of Minnesota, 2231 6th Street Southeast, Minneapolis, MN, 55455, USA.,Division of Environmental Health Sciences, School of Public Health, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN, 55455, USA
| | - Peter W Villalta
- Masonic Cancer Center, University of Minnesota, 2231 6th Street Southeast, Minneapolis, MN, 55455, USA
| | - Maria Razzoli
- Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th Street SE, Minneapolis, MN, 55455, USA
| | - Marianne Grant
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 308 Harvard Street S.E, Minneapolis, MN, 55455, USA
| | - Beshay Zordoky
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 308 Harvard Street S.E, Minneapolis, MN, 55455, USA
| | - Alessandro Bartolomucci
- Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th Street SE, Minneapolis, MN, 55455, USA
| | - Antonella Borgatti
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, 1365 Gortner Avenue, St Paul, MN, 55108, USA.,Masonic Cancer Center, University of Minnesota, 2231 6th Street Southeast, Minneapolis, MN, 55455, USA.,Clinical Investigation Center, College of Veterinary Medicine, St. Paul, MN, 55108, USA
| | - Silvia Balbo
- Masonic Cancer Center, University of Minnesota, 2231 6th Street Southeast, Minneapolis, MN, 55455, USA. .,Division of Environmental Health Sciences, School of Public Health, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN, 55455, USA.
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5
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Küçükköse E, Wensink GE, Roelse CM, van Schelven SJ, Raats DAE, Boj SF, Koopman M, Laoukili J, Roodhart JML, Kranenburg O. Mismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy. Cancers (Basel) 2021; 13:5434. [PMID: 34771595 PMCID: PMC8582471 DOI: 10.3390/cancers13215434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/18/2021] [Accepted: 10/26/2021] [Indexed: 12/31/2022] Open
Abstract
DNA mismatch repair deficiency (dMMR) in metastatic colorectal cancer (mCRC) is associated with poor survival and a poor response to systemic treatment. However, it is unclear whether dMMR results in a tumor cell-intrinsic state of treatment resistance, or whether alternative mechanisms play a role. To address this, we generated a cohort of MMR-proficient and -deficient Patient-Derived Organoids (PDOs) and tested their response to commonly used drugs in the treatment of mCRC, including 5-fluorouracil (5-FU), oxaliplatin, SN-38, binimetinib, encorafenib, and cetuximab. MMR status did not correlate with the response of PDOs to any of the drugs tested. In contrast, the presence of activating mutations in the KRAS and BRAF oncogenes was significantly associated with resistance to chemotherapy and sensitivity to drugs targeting oncogene-activated pathways. We conclude that mutant KRAS and BRAF impact the intrinsic sensitivity of tumor cells to chemotherapy and targeted therapy. By contrast, tumor cell-extrinsic mechanisms-for instance signals derived from the microenvironment-must underlie the association of MMR status with therapy response. Future drug screens on rationally chosen cohorts of PDOs have great potential in developing tailored therapies for specific CRC subtypes including, but not restricted to, those defined by BRAF/KRAS and MMR status.
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Affiliation(s)
- Emre Küçükköse
- Laboratory Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (E.K.); (C.M.R.); (S.J.v.S.); (D.A.E.R.); (J.L.)
| | - G. Emerens Wensink
- Division of Imaging and Cancer, Department of Medical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (G.E.W.); (M.K.)
| | - Celine M. Roelse
- Laboratory Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (E.K.); (C.M.R.); (S.J.v.S.); (D.A.E.R.); (J.L.)
| | - Susanne J. van Schelven
- Laboratory Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (E.K.); (C.M.R.); (S.J.v.S.); (D.A.E.R.); (J.L.)
| | - Daniëlle A. E. Raats
- Laboratory Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (E.K.); (C.M.R.); (S.J.v.S.); (D.A.E.R.); (J.L.)
| | - Sylvia F. Boj
- Foundation Hubrecht Organoid Technology, 3584 CM Utrecht, The Netherlands;
| | - Miriam Koopman
- Division of Imaging and Cancer, Department of Medical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (G.E.W.); (M.K.)
| | - Jamila Laoukili
- Laboratory Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (E.K.); (C.M.R.); (S.J.v.S.); (D.A.E.R.); (J.L.)
| | - Jeanine M. L. Roodhart
- Laboratory Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (E.K.); (C.M.R.); (S.J.v.S.); (D.A.E.R.); (J.L.)
- Division of Imaging and Cancer, Department of Medical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (G.E.W.); (M.K.)
| | - Onno Kranenburg
- Laboratory Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (E.K.); (C.M.R.); (S.J.v.S.); (D.A.E.R.); (J.L.)
- Utrecht Platform for Organoid Technology, Utrecht University, 3584 CX Utrecht, The Netherlands
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6
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Pierobon M, Robert NJ, Northfelt DW, Jahanzeb M, Wong S, Hodge KA, Baldelli E, Aldrich J, Craig DW, Liotta LA, Avramovic S, Wojtusiak J, Alemi F, Wulfkuhle JD, Bellos A, Gallagher RI, Arguello D, Conrad A, Kemkes A, Loesch DM, Vocila L, Dunetz B, Carpten JD, Petricoin EF, Anthony SP. Multi-omic molecular profiling guide's efficacious treatment selection in refractory metastatic breast cancer: a prospective phase II clinical trial. Mol Oncol 2021; 16:104-115. [PMID: 34437759 PMCID: PMC8732340 DOI: 10.1002/1878-0261.13091] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 07/30/2021] [Accepted: 08/25/2021] [Indexed: 11/22/2022] Open
Abstract
This prospective phase II clinical trial (Side Out 2) explored the clinical benefits of treatment selection informed by multi‐omic molecular profiling (MoMP) in refractory metastatic breast cancers (MBCs). Core needle biopsies were collected from 32 patients with MBC at trial enrollment. Patients had received an average of 3.94 previous lines of treatment in the metastatic setting before enrollment in this study. Samples underwent MoMP, including exome sequencing, RNA sequencing (RNA‐Seq), immunohistochemistry, and quantitative protein pathway activation mapping by Reverse Phase Protein Microarray (RPPA). Clinical benefit was assessed using the previously published growth modulation index (GMI) under the hypothesis that MoMP‐selected therapy would warrant further investigation for GMI ≥ 1.3 in ≥ 35% of the patients. Of the 32 patients enrolled, 29 received treatment based on their MoMP and 25 met the follow‐up criteria established by the trial protocol. Molecular information was delivered to the tumor board in a median time frame of 14 days (11–22 days), and targetable alterations for commercially available agents were found in 23/25 patients (92%). Of the 25 patients, 14 (56%) reached GMI ≥ 1.3. A high level of DNA topoisomerase I (TOPO1) led to the selection of irinotecan‐based treatments in 48% (12/25) of the patients. A pooled analysis suggested clinical benefit in patients with high TOPO1 expression receiving irinotecan‐based regimens (GMI ≥ 1.3 in 66.7% of cases). These results confirmed previous observations that MoMP increases the frequency of identifiable actionable alterations (92% of patients). The MoMP proposed allows the identification of biomarkers that are frequently expressed in MBCs and the evaluation of their role as predictors of response to commercially available agents. Lastly, this study confirmed the role of MoMP for informing treatment selection in refractory MBC patients: more than half of the enrolled patients reached a GMI ≥ 1.3 even after multiple lines of previous therapies for metastatic disease.
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Affiliation(s)
| | | | | | - Mohammad Jahanzeb
- A Division of 21st Century Oncology, Florida Precision Oncology, Raton, FL, USA
| | - Shukmei Wong
- Translational Genomics Research Institute, Phoenix, AZ, USA
| | | | | | | | - David W Craig
- Translational Genomics Research Institute, Phoenix, AZ, USA
| | | | - Sanja Avramovic
- Department of Health Administration and Policy, George Mason University, Fairfax, VA, USA
| | - Janusz Wojtusiak
- Department of Health Administration and Policy, George Mason University, Fairfax, VA, USA
| | - Farrokh Alemi
- Department of Health Administration and Policy, George Mason University, Fairfax, VA, USA
| | | | | | | | | | | | | | | | - Linda Vocila
- Translational Drug Development (TD2), Scottsdale, AZ, USA
| | | | - John D Carpten
- Translational Genomics Research Institute, Phoenix, AZ, USA
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7
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Sreekumar R, Al-Saihati H, Emaduddin M, Moutasim K, Mellone M, Patel A, Kilic S, Cetin M, Erdemir S, Navio MS, Lopez MA, Curtis N, Yagci T, Primrose JN, Price BD, Berx G, Thomas GJ, Tulchinsky E, Mirnezami A, Sayan AE. The ZEB2-dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes ERCC1 and ERCC4 in colorectal cancer. Mol Oncol 2021; 15:2065-2083. [PMID: 33931939 PMCID: PMC8333771 DOI: 10.1002/1878-0261.12965] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 02/16/2021] [Accepted: 04/12/2021] [Indexed: 12/18/2022] Open
Abstract
Resistance to adjuvant chemotherapy is a major clinical problem in the treatment of colorectal cancer (CRC). The aim of this study was to elucidate the role of an epithelial to mesenchymal transition (EMT)‐inducing protein, ZEB2, in chemoresistance of CRC, and to uncover the underlying mechanism. We performed IHC for ZEB2 and association analyses with clinical outcomes on primary CRC and matched CRC liver metastases in compliance with observational biomarker study guidelines. ZEB2 expression in primary tumours was an independent prognostic marker of reduced overall survival and disease‐free survival in patients who received adjuvant FOLFOX chemotherapy. ZEB2 expression was retained in 96% of liver metastases. The ZEB2‐dependent EMT transcriptional programme activated nucleotide excision repair (NER) pathway largely via upregulation of the ERCC1 gene and other components in NER pathway, leading to enhanced viability of CRC cells upon oxaliplatin treatment. ERCC1‐overexpressing CRC cells did not respond to oxaliplatin in vivo, as assessed using a murine orthotopic model in a randomised and blinded preclinical study. Our findings show that ZEB2 is a biomarker of tumour response to chemotherapy and risk of recurrence in CRC patients. We propose that the ZEB2‐ERCC1 axis is a key determinant of chemoresistance in CRC.
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Affiliation(s)
| | - Hajir Al-Saihati
- Cancer Sciences Division, University of Southampton, UK.,College of Applied Medical Sciences, University of Hafr Al-Batin, Saudi Arabia
| | | | | | | | - Ashish Patel
- Cancer Sciences Division, University of Southampton, UK
| | - Seval Kilic
- Cancer Sciences Division, University of Southampton, UK
| | - Metin Cetin
- Department of Molecular Biology and Genetics, Gebze Technical University, Turkey
| | - Sule Erdemir
- Department of Molecular Biology and Genetics, Gebze Technical University, Turkey
| | | | | | - Nathan Curtis
- Department of Surgery, Southampton University Hospital NHS Trust, UK
| | - Tamer Yagci
- Department of Molecular Biology and Genetics, Gebze Technical University, Turkey
| | - John N Primrose
- Cancer Sciences Division, University of Southampton, UK.,Department of Surgery, Southampton University Hospital NHS Trust, UK
| | - Brendan D Price
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Geert Berx
- Molecular Cellular Oncology Lab, Department for Biomedical Molecular Biology, Ghent University, Belgium.,Cancer Research Institute Ghent (CRIG), Belgium
| | | | - Eugene Tulchinsky
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, Kazakhstan
| | - Alex Mirnezami
- Cancer Sciences Division, University of Southampton, UK.,College of Applied Medical Sciences, University of Hafr Al-Batin, Saudi Arabia
| | - A Emre Sayan
- Cancer Sciences Division, University of Southampton, UK
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8
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Avolio M, Trusolino L. Rational Treatment of Metastatic Colorectal Cancer: A Reverse Tale of Men, Mice, and Culture Dishes. Cancer Discov 2021; 11:1644-1660. [PMID: 33820776 DOI: 10.1158/2159-8290.cd-20-1531] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/04/2021] [Accepted: 02/01/2021] [Indexed: 11/16/2022]
Abstract
Stratification of colorectal cancer into subgroups with different response to therapy was initially guided by descriptive associations between specific biomarkers and treatment outcome. Recently, preclinical models based on propagatable patient-derived tumor samples have yielded an improved understanding of disease biology, which has facilitated the functional validation of correlative information and the discovery of novel response determinants, therapeutic targets, and mechanisms of tumor adaptation and drug resistance. We review the contribution of patient-derived models to advancing colorectal cancer characterization, discuss their influence on clinical decision-making, and highlight emerging challenges in the interpretation and clinical transferability of results obtainable with such approaches. SIGNIFICANCE: Association studies in patients with colorectal cancer have led to the identification of response biomarkers, some of which have been implemented as companion diagnostics for therapeutic decisions. By enabling biological investigation in a clinically relevant experimental context, patient-derived colorectal cancer models have proved useful to examine the causal role of such biomarkers in dictating drug sensitivity and are providing fresh knowledge on new actionable targets, dynamics of tumor evolution and adaptation, and mechanisms of drug resistance.
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Affiliation(s)
- Marco Avolio
- Department of Oncology, University of Torino, Candiolo, Torino, Italy.,Candiolo Cancer Institute - FPO IRCCS, Candiolo, Torino, Italy
| | - Livio Trusolino
- Department of Oncology, University of Torino, Candiolo, Torino, Italy. .,Candiolo Cancer Institute - FPO IRCCS, Candiolo, Torino, Italy
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9
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Ruiz-Bañobre J, Goel A. Genomic and epigenomic biomarkers in colorectal cancer: From diagnosis to therapy. Adv Cancer Res 2021; 151:231-304. [PMID: 34148615 PMCID: PMC10338180 DOI: 10.1016/bs.acr.2021.02.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Despite ongoing efforts aimed at increasing screening for CRC and early detection, and development of more effective therapeutic regimens, the overall morbidity and mortality from this malignancy remains a clinical challenge. Therefore, identifying and developing genomic and epigenomic biomarkers that can improve CRC diagnosis and help predict response to current therapies are of paramount importance for improving survival outcomes in CRC patients, sparing patients from toxicity associated with current regimens, and reducing the economic burden associated with these treatments. Although efforts to develop biomarkers over the past decades have achieved some success, the recent availability of high-throughput analytical tools, together with the use of machine learning algorithms, will likely hasten the development of more robust diagnostic biomarkers and improved guidance for clinical decision-making in the coming years. In this chapter, we provide a systematic and comprehensive overview on the current status of genomic and epigenomic biomarkers in CRC, and comment on their potential clinical significance in the management of patients with this fatal malignancy, including in the context of precision medicine.
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Affiliation(s)
- Juan Ruiz-Bañobre
- Medical Oncology Department, University Clinical Hospital of Santiago de Compostela, University of Santiago de Compostela (USC), CIBERONC, Santiago de Compostela, Spain; Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago de Compostela, University of Santiago de Compostela (USC), CIBERONC, Santiago de Compostela, Spain
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, United States.
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10
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Wensink E, Bond M, Kucukkose E, May A, Vink G, Koopman M, Kranenburg O, Roodhart J. A review of the sensitivity of metastatic colorectal cancer patients with deficient mismatch repair to standard-of-care chemotherapy and monoclonal antibodies, with recommendations for future research. Cancer Treat Rev 2021; 95:102174. [PMID: 33721596 DOI: 10.1016/j.ctrv.2021.102174] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 02/17/2021] [Accepted: 02/19/2021] [Indexed: 12/29/2022]
Abstract
In 5% of metastatic colorectal cancer (mCRC) patients, tumours display a deficient mismatch repair (dMMR) system. Immunotherapy is beneficial in dMMR mCRC patients and has recently been approved by the Food and Drug Administration for patients with unresectable or metastatic dMMR CRC. Although dMMR and proficient MMR (pMMR) CRC tumours are biologically distinct, they are commonly treated with the same chemotherapy and monoclonal antibodies. This includes dMMR mCRC patients who did not respond to immunotherapy (20-30%). However, it is unclear if these treatments are equally beneficial in dMMR mCRC. Of note, dMMR mCRC patients have a worse prognosis compared to pMMR, which may in part be caused by a lower response to treatment. To avoid unnecessary exposure to ineffective treatments and their associated toxicity, it is important to identify which systemic treatments are most beneficial in dMMR mCRC patients, thus improving their outcome. Indeed, future treatment strategies are likely to involve combinations of immunotherapy, chemotherapy and monoclonal antibodies. In this evidence-based review, we summarize clinical trials reporting treatment efficacy of different types of chemotherapy and monoclonal antibodies in dMMR mCRC patients. We also review the biological rationale behind a potential differential benefit of chemotherapy with or without monoclonal antibodies in dMMR mCRC patients. A barrier in the interpretation of preclinical results is the choice of model systems. They largely comprise traditional models, including cell lines and xenografts, rather than more representative models, such as patient-derived organoids. We provide concrete recommendations for clinical investigators and fundamental researchers to accelerate research regarding which systemic therapy is most effective in dMMR mCRC patients.
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Affiliation(s)
- Emerens Wensink
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
| | - Marinde Bond
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584CX Utrecht, the Netherlands
| | - Emre Kucukkose
- Department of Surgical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
| | - Anne May
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584CX Utrecht, the Netherlands
| | - Geraldine Vink
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands; Department of Research and Development, Netherlands Comprehensive Cancer Organisation, Godebaldkwartier 419, 3511DT Utrecht, the Netherlands
| | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
| | - Onno Kranenburg
- Department of Surgical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands; Utrecht Platform for Organoid Technology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
| | - Jeanine Roodhart
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands.
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11
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Vranić S, Bešlija S, Gatalica Z. Targeting HER2 expression in cancer: New drugs and new indications. Bosn J Basic Med Sci 2021; 21:1-4. [PMID: 32530388 PMCID: PMC7861626 DOI: 10.17305/bjbms.2020.4908] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 06/07/2020] [Indexed: 12/13/2022] Open
Abstract
Functional activation of human epidermal growth factor receptor 2 (HER2) has been shown to strongly promote carcinogenesis, leading to the investigation of HER2-directed agents in cancers with HER2 genomic alterations. This has been best documented in the context of HER2 gene amplification in breast and gastric/gastroesophageal junction carcinomas for which several HER2-directed agents are available and have become a part of standard treatment regimens. Somatic HER2 gene mutations have been recently described at low frequency in a variety of human cancers and have emerged as a novel predictive biomarker for HER2-directed therapies. Preclinical data also indicate that activating HER2 mutations are potent oncogenic drivers in a manner that is analogous to HER2 amplification. HER2 mutations may clinically confer sensitivity to HER2-directed agents as recently shown in a phase II clinical trial with antibody-drug conjugate against HER2 trastuzumab deruxtecan in patients with non-squamous non-small cell lung carcinoma.
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Affiliation(s)
- Semir Vranić
- College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Semir Bešlija
- Department of Oncology, Clinical Center of the University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Zoran Gatalica
- Creighton University School of Medicine, Phoenix, Arizona, United States and Oklahoma University College of Medicine, Oklahoma City, Oklahoma, United States
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12
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Ando K, Ozonoff A, Lee SY, Voisine M, Parker JT, Nakanishi R, Nishimura S, Yang J, Grace Z, Tran B, Diefenbach TJ, Maehara Y, Yasui H, Irino T, Salgia R, Terashima M, Gibbs P, Ramanathan RK, Oki E, Mori M, Kulke M, Hartshorn K, Bharti A. Multicohort Retrospective Validation of a Predictive Biomarker for Topoisomerase I Inhibitors. Clin Colorectal Cancer 2020; 20:e129-e138. [PMID: 33731288 DOI: 10.1016/j.clcc.2020.11.005] [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: 09/17/2020] [Revised: 11/24/2020] [Accepted: 11/29/2020] [Indexed: 12/01/2022]
Abstract
PURPOSE The camptothecin (CPT) analogs topotecan and irinotecan specifically target topoisomerase I (topoI) and are used to treat colorectal, gastric, and pancreatic cancer. Response rate for this class of drug varies from 10% to 30%, and there is no predictive biomarker for patient stratification by response. On the basis of our understanding of CPT drug resistance mechanisms, we developed an immunohistochemistry-based predictive test, P-topoI-Dx, to stratify the patient population into those who did and did not experience a response. PATIENTS AND METHODS The retrospective validation studies included a training set (n = 79) and a validation cohort (n = 27) of gastric cancer (GC) patients, and 8 cohorts of colorectal cancer (CRC) patient tissue (n = 176). Progression-free survival for 6 months was considered a positive response to CPT-based therapy. Formalin-fixed, paraffin-embedded slides were immunohistochemically stained with anti-phospho-specific topoI-Serine10 (topoI-pS10), quantitated, and analyzed statistically. RESULTS We determined a threshold of 35% positive staining to offer optimal test characteristics in GC. The GC (n = 79) training set demonstrated 76.6% (95% confidence interval, 64-86) sensitivity; 68.8% (41-88) specificity; positive predictive value (PPV) 92.5% (81-98); and negative predictive value (NPV) 42.3% (24-62). The GC validation set (n = 27) demonstrated 82.4% (56-95) sensitivity and 70.0% (35-92) specificity. Estimated PPV and NPV were 82.4% (56-95) and 70.0% (35-92) respectively. In the CRC validation set (n = 176), the 40% threshold demonstrated 87.5% (78-94) sensitivity; 70.0% (59-79) specificity; PPV 70.7% (61-79); and NPV 87.0 % (77-93). CONCLUSION The analysis of retrospective data from patients (n = 282) provides clinical validity to our P-topoI-Dx immunohistochemical test to identify patients with disease that is most likely to respond to topoI inhibitors.
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Affiliation(s)
- Koji Ando
- Division of Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA; Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Al Ozonoff
- Division of Infectious Diseases, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Shin-Yin Lee
- Division of Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA
| | - Michael Voisine
- Division of Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA
| | - Julian-Taylor Parker
- Division of Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA
| | - Ryota Nakanishi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Sho Nishimura
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jing Yang
- Department of Pathology, Boston University School of Medicine, Boston, MA
| | - Zhao Grace
- Department of Pathology, Boston University School of Medicine, Boston, MA
| | - Ben Tran
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
| | | | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroshi Yasui
- Division of Gastric Surgery and Division of Gastrointestinal Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Tomoyuki Irino
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Ravi Salgia
- Department of Medical Oncology and Therapeutic Research, City of Hope, Duarte, CA
| | - Masanori Terashima
- Division of Gastric Surgery and Division of Gastrointestinal Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Peter Gibbs
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
| | | | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Matthew Kulke
- Division of Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA
| | - Kevan Hartshorn
- Division of Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA
| | - Ajit Bharti
- Division of Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA.
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13
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Neumeyer S, Hua X, Seibold P, Jansen L, Benner A, Burwinkel B, Halama N, Berndt SI, Phipps AI, Sakoda LC, Schoen RE, Slattery ML, Chan AT, Gala M, Joshi AD, Ogino S, Song M, Herpel E, Bläker H, Kloor M, Scherer D, Ulrich A, Ulrich CM, Win AK, Figueiredo JC, Hopper JL, Macrae F, Milne RL, Giles GG, Buchanan DD, Peters U, Hoffmeister M, Brenner H, Newcomb PA, Chang-Claude J. Genetic Variants in the Regulatory T cell-Related Pathway and Colorectal Cancer Prognosis. Cancer Epidemiol Biomarkers Prev 2020; 29:2719-2728. [PMID: 33008876 PMCID: PMC7976673 DOI: 10.1158/1055-9965.epi-20-0714] [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: 05/11/2020] [Revised: 07/29/2020] [Accepted: 09/28/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis. METHODS In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer-specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated because tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2,047 colorectal cancer patients of the International Survival Analysis in Colorectal Cancer Consortium (ISACC). RESULTS A significant association of the TGFBR3 SNP rs7524066 with more favorable colorectal cancer-specific survival [hazard ratio (HR) per minor allele: 0.83; 95% confidence interval (CI), 0.74-0.94; P value: 0.0033] was replicated in ISACC (HR: 0.82; 95% CI, 0.68-0.98; P value: 0.03). Suggestive evidence for association was found with two IL7 SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed. CONCLUSIONS Common genetic variation in the Treg pathway implicating genes such as TGFBR3 and IL7 was shown to be associated with prognosis of colorectal cancer patients. IMPACT The implicated genes warrant further investigation.
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Affiliation(s)
- Sonja Neumeyer
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Xinwei Hua
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- School of Public Health, University of Washington, Seattle, Washington
| | - Petra Seibold
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Lina Jansen
- Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany
| | - Axel Benner
- Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Barbara Burwinkel
- Division of Molecular Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Gynecology and Obstetrics, Molecular Biology of Breast Cancer, University of Heidelberg, Heidelberg, Germany
| | - Niels Halama
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
- Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, Heidelberg, Germany
- Institute for Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Epidemiology Department, University of Washington, Seattle, Washington
| | - Lori C Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Robert E Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Manish Gala
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Amit D Joshi
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Shuji Ogino
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Mingyang Song
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Esther Herpel
- NCT Tissue Bank, National Center for Tumor Diseases (NCT), Heidelberg, Germany
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Hendrik Bläker
- Institute of Pathology, Charité University Medicine, Berlin, Germany
| | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Dominique Scherer
- Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany
| | - Alexis Ulrich
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University of Heidelberg, Germany
| | - Cornelia M Ulrich
- Huntsman Cancer Institute, Population Sciences, Salt Lake City, Utah
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
| | - Aung K Win
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, Australia
| | - Jane C Figueiredo
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles California
| | - John L Hopper
- Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Victoria, Australia
| | - Finlay Macrae
- Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Victoria, Australia
| | - Roger L Milne
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Graham G Giles
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Epidemiology, University of Washington, Seattle, Washington
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Polly A Newcomb
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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14
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Fleten KG, Lund-Andersen C, Waagene S, Abrahamsen TW, Mørch Y, Boye K, Torgunrud A, Flatmark K. Experimental Treatment of Mucinous Peritoneal Metastases Using Patient-Derived Xenograft Models. Transl Oncol 2020; 13:100793. [PMID: 32447231 PMCID: PMC7243185 DOI: 10.1016/j.tranon.2020.100793] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/23/2020] [Accepted: 04/24/2020] [Indexed: 01/05/2023] Open
Abstract
Mucinous peritoneal metastases (PM) generally respond poorly to systemic treatment, and there is a clear unmet need for new treatment strategies to improve survival and quality of life for patients with PM. In this work, the growth inhibitory effect of five drugs (oxaliplatin (OXA; 5 mg/kg), irinotecan (IRI; 60 mg/kg), cabazitaxel (CBZ; 15 or 30 mg/kg), regorafenib (REG; 10, 30 or 60 mg/kg), and capecitabine (CAP; 359 or 755 mg/kg) was investigated in three orthotopic patient-derived xenograft models that mimic mucinous PM. Drugs were administered intraperitoneally (i.p.) as monotherapy weekly for 4 weeks (OXA, IRI), as one single i.p. injection (CBZ), or orally (REG, CAP) daily 5 of 7 days per week for four weeks, and i.p. tumor growth and survival were monitored and compared between treatment groups. The i.p. administered drugs (OXA, IRI, CBZ) had the strongest growth inhibitory effect, with OXA being most efficacious, completely inhibiting tumor growth in the majority of the animals. CBZ and IRI also strongly inhibited tumor growth, but with more variation in efficacy between the models. A moderate reduction in tumor growth was observed in all models treated with REG, while CAP had little to no growth inhibitory effect. Targeted next-generation-sequencing has identified mutational profiles typically associated with PM (mutations in KRAS, GNAS, and BRAF oncogenes), supporting the representativeness of the models. The results presented in this work support the continued exploration of i.p. treatment protocols for PM, with OXA remaining and CBZ emerging as particularly interesting candidates for further studies.
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Affiliation(s)
- Karianne Giller Fleten
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Christin Lund-Andersen
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Stein Waagene
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Torveig Weum Abrahamsen
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Yrr Mørch
- Department of Biotechnology and Nanomedicine, SINTEF, AS, Trondheim, Norway
| | - Kjetil Boye
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Annette Torgunrud
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Kjersti Flatmark
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
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15
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Irinotecan-Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview. Int J Mol Sci 2020; 21:ijms21144919. [PMID: 32664667 PMCID: PMC7404108 DOI: 10.3390/ijms21144919] [Citation(s) in RCA: 139] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/09/2020] [Accepted: 07/11/2020] [Indexed: 02/06/2023] Open
Abstract
Irinotecan has been used in the treatment of various malignancies for many years. Still, the knowledge regarding this drug is expanding. The pharmacogenetics of the drug is the crucial component of response to irinotecan. Furthermore, new formulations of the drug are introduced in order to better deliver the drug and avoid potentially life-threatening side effects. Here, we give a comprehensive overview on irinotecan’s molecular mode of action, metabolism, pharmacogenetics, and toxicity. Moreover, this article features clinically used combinations of the drug with other anticancer agents and introduces novel formulations of drugs (e.g., liposomal formulations, dendrimers, and nanoparticles). It also outlines crucial mechanisms of tumor cells’ resistance to the active metabolite, ethyl-10-hydroxy-camptothecin (SN-38). We are sure that the article will constitute an important source of information for both new researchers in the field of irinotecan chemotherapy and professionals or clinicians who are interested in the topic.
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16
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Nikanjam M, Riviere P, Goodman A, Barkauskas DA, Frampton G, Kurzrock R. Tumor mutational burden is not predictive of cytotoxic chemotherapy response. Oncoimmunology 2020; 9:1781997. [PMID: 32923144 PMCID: PMC7458654 DOI: 10.1080/2162402x.2020.1781997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background High tumor mutational burden (TMB) predicts checkpoint blockade responsiveness, although the association with outcomes may be nuanced in certain tissue contexts. The correlation between TMB and cytotoxic chemotherapy sensitivity is unknown. This study evaluated the relationship between TMB and outcome in patients with solid tumors receiving cytotoxic chemotherapy. Methods University of California San Diego patients who received cytotoxic chemotherapy within one year after biopsy for TMB evaluation were included in a retrospective analysis. Physician notes and imaging reports in the electronic medical record were reviewed to determine clinical benefit and progression-free survival (PFS). Results Among 1526 patients with TMB availability, there were 294 eligible patients who received chemotherapy. There were no significant differences in TMB between those with stable disease ≥6 months/partial response/complete response versus others (t-test, p = .22). There were no significant differences in PFS for patients with TMB <10 vs. TMB ≥10 mutations/Mb (log-rank test, median and 95% CI: 6.0 (4.8–7.4) vs. 5.4 (4.3–6.6) months; p = .21). Nor were there significant differences in PFS for patients with a TMB <10 vs. TMB ≥10 mutations/mb for breast (p = .07), lung (p = .47), or gastrointestinal cancer (p = .53). Conclusions In summary, TMB was not predictive of stable disease ≥6 months/partial response/complete response or PFS in patients receiving cytotoxic chemotherapy. Trials Registration NCT02478931
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Affiliation(s)
- Mina Nikanjam
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UC San Diego Moores Cancer Center, San Diego, CA, USA
| | - Paul Riviere
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UC San Diego Moores Cancer Center, San Diego, CA, USA
| | - Aaron Goodman
- Division of Blood and Marrow Transplantation, UC San Diego Moores Cancer Center, San Diego, CA, USA
| | - Donald A Barkauskas
- Department of Preventive Medicine, Biostatistics Division, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Garrett Frampton
- Department of Cancer Genomics Research, Foundation Medicine, Cambridge, MA, USA
| | - Razelle Kurzrock
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UC San Diego Moores Cancer Center, San Diego, CA, USA
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Different Camptothecin Sensitivities in Subpopulations of Colon Cancer Cells Correlate with Expression of Different Phospho-Isoforms of Topoisomerase I with Different Activities. Cancers (Basel) 2020; 12:cancers12051240. [PMID: 32423158 PMCID: PMC7281652 DOI: 10.3390/cancers12051240] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 05/08/2020] [Accepted: 05/13/2020] [Indexed: 12/25/2022] Open
Abstract
The heterogeneity of tumor cells and the potential existence of rare cells with reduced chemotherapeutic response is expected to play a pivotal role in the development of drug resistant cancers. Herein, we utilized the colon cancer cell lines, Caco2 and DLD1, to investigate heterogeneity of topoisomerase 1 (TOP1) activity in different cell subpopulations, and the consequences for the chemotherapeutic response towards the TOP1 targeting drug, camptothecin. The cell lines consisted of two subpopulations: one (the stem-cell-like cells) divided asymmetrically, was camptothecin resistant, had a differently phosphorylated TOP1 and a lower Casein Kinase II (CKII) activity than the camptothecin sensitive non-stem-cell-like cells. The tumor suppressor p14ARF had a different effect in the two cell subpopulations. In the stem-cell-like cells, p14ARF suppressed TOP1 activity and downregulation of this factor increased the sensitivity towards camptothecin. It had the opposite effect in non-stem-cell-like cells. Since it is only the stem-cell-like cells that have tumorigenic activity our results point towards new considerations for future cancer therapy. Moreover, the data underscore the importance of considering cell-to-cell variations in the analysis of molecular processes in cell lines.
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18
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Comprehensive tumor profiling-guided therapy in rare or refractory solid cancer: A feasibility study in daily clinical practice. Bull Cancer 2020; 107:410-416. [DOI: 10.1016/j.bulcan.2019.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 12/03/2019] [Accepted: 12/22/2019] [Indexed: 11/22/2022]
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19
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Current and New Predictors for Treatment Response in Metastatic Colorectal Cancer. The Role of Circulating miRNAs as Biomarkers. Int J Mol Sci 2020; 21:ijms21062089. [PMID: 32197436 PMCID: PMC7139554 DOI: 10.3390/ijms21062089] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/12/2020] [Accepted: 03/16/2020] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most frequently diagnosed cancer in the world. More than half of all CRC patients will eventually develop metastases and require treatment accordingly, but few validated predictive factors for response to systemic treatments exist. In order to ascertain which patients benefit from specific treatments, there is a strong need for new and reliable biomarkers. We conducted a comprehensive search using the PUBMED database, up to December 2019, in order to identify relevant studies on predictive biomarkers for treatment response in metastatic CRC. We will herein present the currently used and potential biomarkers for treatment response and bring up-to-date knowledge on the role of circulating microRNAs, associated with chemotherapy and targeted therapy regimens used in metastatic CRC treatment. Molecular, tumor-related, disease-related, clinical, and laboratory predictive markers for treatment response were identified, mostly proposed, with few validated. Several circulating microRNAs have already proven their role of prediction for treatment response in CRC, but future clinical studies are needed to confirm their role as biomarkers across large cohorts of patients.
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Stein MK, Williard FW, Xiu J, Tsao MW, Martin MG, Deschner BW, Dickson PV, Glazer ES, Yakoub D, Shibata D, Grothey AF, Philip PA, Hwang JJ, Shields AF, Marshall JL, Korn WM, Lenz HJ, Deneve JL. Comprehensive tumor profiling reveals unique molecular differences between peritoneal metastases and primary colorectal adenocarcinoma. J Surg Oncol 2020; 121:1320-1328. [PMID: 32166754 DOI: 10.1002/jso.25899] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Accepted: 02/20/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND OBJECTIVES Peritoneal metastases (PM) from primary colorectal cancer (pCRC) are associated with poor outcomes; however, molecular differences are not well defined. METHODS We compared unpaired tumor profiles of patients with pCRC and PM from Caris Life Sciences. Testing included next-generation sequencing of 592 genes, microsatellite instability (MSI) and tumor mutational burden (TMB). Mutations were test-defined as pathogenic (PATH). RESULTS Six hundred seventeen pCRC and 348 PM patients had similar gender (55% male) and age (median 59). PATHs were similar between PM and pCRC in KRAS, BRAF, SMAD2, SMAD4, and PTEN. pCRC PATHs were increased in APC (76% vs 48%, P < .01), ARID1A (29% vs 12%, P < .05), TP53 (72% vs 53%, P < .01), PIK3CA (22% vs 15%, P < .05), and FBXW7 (13% vs 7%, P < .01) compared with PM. Mucinous PM had more PATHs in GNAS (19% vs 8%, P = .032) while nonmucinous PM had more PATHs in BRAF (13% vs 8%, P = .027). Right-sided PM had decreased PATHs in APC (39% vs 68%, P < .0001), ARID1A (7% vs 38%, P < .004), and TP53 (48% vs 65%, P = .033) while there were no difference for left-sided PM. Nine percent of pCRC and 6% of PM were MSI-high (P = NS). There was no difference in TMB-high, TMB-intermediate, or TMB-low between PM and pCRC. CONCLUSIONS PM have similar rates of KRAS mutation with increased PATHs in GNAS (mucinous) and BRAF (nonmucinous) compared to pCRC. No differences in MSI or TMB were identified between PM and pCRC tumors. These findings inform future study into the molecular profile of PM.
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Affiliation(s)
- Matthew K Stein
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Forrest W Williard
- College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
| | | | - Miriam W Tsao
- Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Michael G Martin
- Deparment of Hematology/Oncology, West Cancer Center, Memphis, Tennessee
| | - Benjamin W Deschner
- Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Paxton V Dickson
- Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Evan S Glazer
- Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Danny Yakoub
- Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee
| | - David Shibata
- Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Axel F Grothey
- Deparment of Hematology/Oncology, West Cancer Center, Memphis, Tennessee
| | - Philip A Philip
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Jimmy J Hwang
- Division of Hematology/Oncology, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina
| | - Anthony F Shields
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - John L Marshall
- Division of Hematology/Oncology, Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | | | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Jeremiah L Deneve
- Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee
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21
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Shao WH, Wang CY, Wang LY, Xiao F, Xiao DS, Yang H, Long XY, Zhang L, Luo HG, Yin JY, Wu W. A Hereditable Mutation of MSH2 Gene Associated with Lynch Syndrome in a Five Generation Chinese Family. Cancer Manag Res 2020; 12:1469-1482. [PMID: 32161499 PMCID: PMC7051253 DOI: 10.2147/cmar.s222572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 12/24/2019] [Indexed: 12/12/2022] Open
Abstract
Purpose In order to clarify which variants of the MMR gene could provide current "healthy" members in affected families a more accurate risk assessment or predictive testing. Patients and Methods One family, which meets the criteria according to both Amsterdam I/II and Bethesda guidelines, is reported in this study. The proband and some relatives of the patient have been investigated for whole genome sequencing, microsatellite instability, immunohistochemical MMR protein staining and verified by Sanger sequencing. Results A heterozygous insertion of uncertain significance (c.420dup, p.Met141Tyrfs) in MSH2 gene was found in proband (III-16) and part of His relatives. The variant was associated with a lack of expression of MSH2 protein (MMR deficient) and high microsatellite instability analysis (MSI) status in tumor tissues of LS patients. In addition, we found that the variant could affect the expression of MSH2 and the response to chemotherapy drugs in vitro. Conclusion We identified an insertion mutation (rs1114167810, c.420dup, p.Met141Tyrfs) in MSH2 in LS using whole genome-wide sequencing (WGS). We further confirmed that this mutation plays an important role in LS patients of this pedigree based on in vivo and vitro study.
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Affiliation(s)
- Wei-Hua Shao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410078, People's Republic of China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, People's Republic of China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, People's Republic of China.,Department of Geratic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China
| | - Cheng-Yu Wang
- Department of Geratic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.,National Clinical Research Center for Geriatric Disorders, Changsha, Hunan 410008, People's Republic of China
| | - Lei-Yun Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410078, People's Republic of China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, People's Republic of China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, People's Republic of China.,Department of Geratic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China
| | - Fan Xiao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410078, People's Republic of China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, People's Republic of China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, People's Republic of China.,Department of Geratic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China
| | - De-Sheng Xiao
- Department of Pathology, Xiangya Hospital/School of Basic Medicine, Central South University, Changsha 410078, Hunan, People's Republic of China
| | - Hao Yang
- Department of Geratic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.,National Clinical Research Center for Geriatric Disorders, Changsha, Hunan 410008, People's Republic of China
| | - Xue-Ying Long
- Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China
| | - Le Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Heng-Gui Luo
- Department of General Surgery, The Central Hospital of Xiangtan City, Xiangtan, Hunan, People's Republic of China
| | - Ji-Ye Yin
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410078, People's Republic of China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, People's Republic of China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, People's Republic of China.,Department of Geratic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China
| | - Wei Wu
- Department of Geratic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.,National Clinical Research Center for Geriatric Disorders, Changsha, Hunan 410008, People's Republic of China
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22
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El Otmani I, El Agy F, El Baradai S, Bouguenouch L, Lahmidani N, El Abkari M, Benajah DA, Toughrai I, El Bouhaddouti H, Mouaqit O, Ibn Majdoub Hassani K, Mazaz K, Benjelloun EB, Ousadden A, El Rhazi K, Bouhafa T, Benbrahim Z, Ouldim K, Ibrahimi SA, Ait Taleb K, Chbani L. Analysis of Molecular Pretreated Tumor Profiles as Predictive Biomarkers of Therapeutic Response and Survival Outcomes after Neoadjuvant Therapy for Rectal Cancer in Moroccan Population. DISEASE MARKERS 2020; 2020:8459303. [PMID: 31998419 PMCID: PMC6977322 DOI: 10.1155/2020/8459303] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 10/30/2019] [Accepted: 12/24/2019] [Indexed: 02/06/2023]
Abstract
Pathologic features depending on tumor response to preoperative chemoradiotherapy are important to determine the outcomes in patients with rectal cancer. Evaluating the potential predictive roles of biomarker expression and their prognostic impact is a promising challenge. We reported here the immunohistochemical staining of a panel marker of mismatch repair protein (MMR), Ki67, HER-2, and p53. Additionally, identification of somatic mutations of KRAS, NRAS, and BRAF genes were performed by direct sequencing and pyrosequencing in pretreated biopsy tissues from 57 patients diagnosed for rectal cancer. Clinical features and pathological criteria for postneoadjuvant treatment surgical resection specimen's data were collected. Immunohistochemical expression and mutational status were correlated with therapeutic response, overall survival, and disease progression. The mean age of patients was 56 years. Seven (12.3%) out of 57 patients had a complete therapeutic response. Our analysis showed that when using complete therapeutic response (Dworak 4) and incomplete therapeutic response (Dworak 3, 2, and 1) as grouping factor, high p53 expression at the pretreatment biopsy was significantly associated to an incomplete response (p = 0.002). For 20 and 2 out of 57, KRAS and NRAS mutations were detected, respectively. The majority of these mutations affected codon 12. KRAS mutations detected at codon 146 (A146T, A146V) was associated with the appearance of recurrence and distant metastasis (p = 0.019). A high expression of HER-2 corresponding to score 3+ was observed in 3 pretreatment biopsy specimens. This class was significantly associated with a short relapse-free survival (p = 0.002). Furthermore, the high expression of Ki67 was moderately correlated with an older age (p = 0.016, r = 0.319). In addition, this shows that high p53 expression in the pretreatment biopsy was associated with an incomplete response in surgical resection specimens after neoadjuvant treatment, and a HER-2 score 3+ can be a predictive factor of distant metastasis and local recurrence. Larger, prospective, and more studies are needed.
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Affiliation(s)
- Ihsane El Otmani
- Laboratory of Biomedical and Translational Research, University of Medicine and Pharmacy of Fez, Morocco
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, 30070 Fes, Morocco
- Unit of Medical Genetics and Oncogenetics, University Hospital Hassan II, 30070 Fes, Morocco
| | - Fatima El Agy
- Laboratory of Biomedical and Translational Research, University of Medicine and Pharmacy of Fez, Morocco
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, 30070 Fes, Morocco
| | - Sanae El Baradai
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, 30070 Fes, Morocco
| | - Laila Bouguenouch
- Unit of Medical Genetics and Oncogenetics, University Hospital Hassan II, 30070 Fes, Morocco
| | - Nada Lahmidani
- Department of Gastroenterology, University Hospital Hassan II, 30070 Fes, Morocco
| | - Mohammed El Abkari
- Department of Gastroenterology, University Hospital Hassan II, 30070 Fes, Morocco
| | - Dafr Allah Benajah
- Department of Gastroenterology, University Hospital Hassan II, 30070 Fes, Morocco
| | - Imane Toughrai
- Department of General surgery, University Hospital Hassan II, 30070 Fes, Morocco
| | | | - Ouadii Mouaqit
- Department of General surgery, University Hospital Hassan II, 30070 Fes, Morocco
| | | | - Khalid Mazaz
- Department of General surgery, University Hospital Hassan II, 30070 Fes, Morocco
| | - El Bachir Benjelloun
- Department of General surgery, University Hospital Hassan II, 30070 Fes, Morocco
| | - Abdelmalek Ousadden
- Department of General surgery, University Hospital Hassan II, 30070 Fes, Morocco
| | - Karima El Rhazi
- Department of Epidemiology, University of Medicine and Pharmacy, 30070 Fes, Morocco
| | - Touria Bouhafa
- Department of Radiotherapy, University Hospital Hassan II, 30070 Fes, Morocco
| | - Zineb Benbrahim
- Department of Oncology, University Hospital Hassan II, 30070 Fes, Morocco
| | - Karim Ouldim
- Unit of Medical Genetics and Oncogenetics, University Hospital Hassan II, 30070 Fes, Morocco
| | - Sidi Adil Ibrahimi
- Department of General surgery, University Hospital Hassan II, 30070 Fes, Morocco
| | - Khalid Ait Taleb
- Department of General surgery, University Hospital Hassan II, 30070 Fes, Morocco
| | - Laila Chbani
- Laboratory of Biomedical and Translational Research, University of Medicine and Pharmacy of Fez, Morocco
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, 30070 Fes, Morocco
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23
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Reynolds IS, O’Connell E, Fichtner M, McNamara DA, Kay EW, Prehn JHM, Furney SJ, Burke JP. Mucinous adenocarcinoma is a pharmacogenomically distinct subtype of colorectal cancer. THE PHARMACOGENOMICS JOURNAL 2019; 20:524-532. [DOI: 10.1038/s41397-019-0137-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 11/22/2019] [Accepted: 11/26/2019] [Indexed: 02/07/2023]
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24
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Tesauro C, Simonsen AK, Andersen MB, Petersen KW, Kristoffersen EL, Algreen L, Hansen NY, Andersen AB, Jakobsen AK, Stougaard M, Gromov P, Knudsen BR, Gromova I. Topoisomerase I activity and sensitivity to camptothecin in breast cancer-derived cells: a comparative study. BMC Cancer 2019; 19:1158. [PMID: 31783818 PMCID: PMC6884793 DOI: 10.1186/s12885-019-6371-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 11/18/2019] [Indexed: 12/30/2022] Open
Abstract
Background Camptothecin (CPT) and its derivatives are currently used as second- or third-line treatment for patients with endocrine-resistant breast cancer (BC). These drugs convert nuclear enzyme DNA topoisomerase I (TOP1) to a cell poison with the potential to damage DNA by increasing the half-life of TOP1-DNA cleavage complexes (TOP1cc), ultimately resulting in cell death. In small and non-randomized trials for BC, researchers have observed extensive variation in CPT response rates, ranging from 14 to 64%. This variability may be due to the absence of reliable selective parameters for patient stratification. BC cell lines may serve as feasible models for generation of functional criteria that may be used to predict drug sensitivity for patient stratification and, thus, lead to more appropriate applications of CPT in clinical trials. However, no study published to date has included a comparison of multiple relevant parameters and CPT response across cell lines corresponding to specific BC subtypes. Method We evaluated the levels and possible associations of seven parameters including the status of the TOP1 gene (i.e. amplification), TOP1 protein expression level, TOP1 activity and CPT susceptibility, activity of the tyrosyl-DNA phosphodiesterase 1 (TDP1), the cellular CPT response and the cellular growth rate across a representative panel of BC cell lines, which exemplifies three major BC subtypes: Luminal, HER2 and TNBC. Results In all BC cell lines analyzed (without regard to subtype classification), we observed a significant overall correlation between growth rate and CPT response. In cell lines derived from Luminal and HER2 subtypes, we observed a correlation between TOP1 gene copy number, TOP1 activity, and CPT response, although the data were too limited for statistical analyses. In cell lines representing Luminal and TNBC subtypes, we observed a direct correlation between TOP1 protein abundancy and levels of enzymatic activity. In all three subtypes (Luminal, HER2, and TNBC), TOP1 exhibits approximately the same susceptibility to CPT. Of the three subtypes examined, the TNBC-like cell lines exhibited the highest CPT sensitivity and were characterized by the fastest growth rate. This indicates that breast tumors belonging to the TNBC subtype, may benefit from treatment with CPT derivatives. Conclusion TOP1 activity is not a marker for CPT sensitivity in breast cancer.
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Affiliation(s)
- Cinzia Tesauro
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Anne Katrine Simonsen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.,Present Address: Department of Biology, Copenhagen University, Copenhagen, Denmark
| | - Marie Bech Andersen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | | | - Emil Laust Kristoffersen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.,Present Address: MRC Laboratory of Molecular Biology, Cambridge, UK
| | - Line Algreen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | | | - Anne Bech Andersen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | | | - Magnus Stougaard
- Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - Pavel Gromov
- Genome Integrity Unit, Breast Cancer Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Birgitta R Knudsen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
| | - Irina Gromova
- Genome Integrity Unit, Breast Cancer Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark.
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25
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Dehshahri A, Ashrafizadeh M, Ghasemipour Afshar E, Pardakhty A, Mandegary A, Mohammadinejad R, Sethi G. Topoisomerase inhibitors: Pharmacology and emerging nanoscale delivery systems. Pharmacol Res 2019; 151:104551. [PMID: 31743776 DOI: 10.1016/j.phrs.2019.104551] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 11/11/2019] [Accepted: 11/16/2019] [Indexed: 02/07/2023]
Abstract
Topoisomerase enzymes have shown unique roles in replication and transcription. These enzymes which were initially found in Escherichia coli have attracted considerable attention as target molecules for cancer therapy. Nowadays, there are several topoisomerase inhibitors in the market to treat or at least control the progression of cancer. However, significant toxicity, low solubility and poor pharmacokinetic properties have limited their wide application and these characteristics need to be improved. Nano-delivery systems have provided an opportunity to modify the intrinsic properties of molecules and also to transfer the toxic agent to the target tissues. These delivery systems leads to the re-introduction of existing molecules present in the market as novel therapeutic agents with different physicochemical and pharmacokinetic properties. This review focusses on a variety of nano-delivery vehicles used for the improvement of pharmacological properties of topoisomerase inhibitors and thus enabling their potential application as novel drugs in the market.
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Affiliation(s)
- Ali Dehshahri
- Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Elham Ghasemipour Afshar
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Abbas Pardakhty
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Ali Mandegary
- Physiology Research Center, Institute of Neuropharmacology, and Department of Toxicology & Pharmacology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Reza Mohammadinejad
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
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26
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Nikanjam M, Arguello D, Gatalica Z, Swensen J, Barkauskas DA, Kurzrock R. Relationship between protein biomarkers of chemotherapy response and microsatellite status, tumor mutational burden and PD-L1 expression in cancer patients. Int J Cancer 2019; 146:3087-3097. [PMID: 31479512 PMCID: PMC7051881 DOI: 10.1002/ijc.32661] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 07/30/2019] [Accepted: 08/01/2019] [Indexed: 12/12/2022]
Abstract
Chemotherapy and checkpoint inhibitor immunotherapies are increasingly used in combinations. We determined associations between the presence of anti‐PD‐1/PD‐L1 therapeutic biomarkers and protein markers of potential chemotherapy response. Data were extracted from a clinical‐grade testing database (Caris Life Sciences; February 2015 through November 2017): immunotherapy response markers (microsatellite instability‐high [MSI‐H], tumor mutational burden‐high [TMB‐H], and PD‐L1 protein expression) and protein chemotherapy response markers (excision repair complementation group 1 [ERCC1], topoisomerase 1 [TOPO1], topoisomerase 2 [TOP2A], thymidylate synthase [TS], tubulin beta 3 [TUBB3], ribonucleotide reductase regulatory subunit M1 [RRM1] and O‐6‐methyl guanine DNA methyltransferase [MGMT]). Relationships were determined by the Mantel‐Haenszel chi‐squared test or Fischer's exact tests. Overall, 28,034 patients representing a total of 40 tumor types were assessed. MSI‐H was found in 3.3% of patients (73% were also TMB‐H), TMB‐H, 8.4% (28.3% were also MSI‐H) and PD‐L1 expression in 11.0% of patients (5.1% were also MSI‐H; 16.4% were also TMB‐H). Based on concurrent biomarker expression, combinations of immunotherapy with platinum (ERCC1 negativity) or with doxorubicin, epirubicin or etoposide (TOP2A positivity) have a higher probability of response, whereas combinations with irinotecan or topotecan (TOPO1 positivity), with gemcitabine (RRM1 negativity), and fluorouracil, pemetrexed or capecitabine (TS negativity) may be of less benefit. The potential for immunotherapy and taxane (TUBB3 negativity) combinations is present for MSI‐H but not TMB‐H or PD‐L1‐expressing tumors; for temozolomide and dacarbazine (MGMT negative), PD‐L1 is frequently coexpressed, but MSI‐H and TMB‐H are not associated. Protein markers of potential chemotherapy response along with next‐generation sequencing for immunotherapy response markers can help support rational combinations as part of an individualized, precision oncology approach. What's new? With the emerging success of immunotherapy of cancers, combinations with conventional chemotherapies are increasingly being tested in clinical trials. Here the authors examined concurrent biomarker expression of checkpoint (PD‐1/PD‐L1) blockade immunotherapy and various cytotoxic chemotherapies to determine which chemotherapeutic agents will best synergize with immunotherapy. They predict that combining platinum or doxorubicin, epirubicin, or etoposide treatments with PD‐1/PD‐L1 inhibitors would have a higher probability of response than other treatments, supporting a rational combination strategy in a possibly individualized treatment approach.
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Affiliation(s)
- Mina Nikanjam
- Center for Personalized Cancer Therapy, Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, CA
| | | | | | | | - Donald A Barkauskas
- Department of Preventive Medicine, Biostatistics Division, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Razelle Kurzrock
- Center for Personalized Cancer Therapy, Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, San Diego, CA
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27
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Abstract
DNA topoisomerases are enzymes that catalyze changes in the torsional and flexural strain of DNA molecules. Earlier studies implicated these enzymes in a variety of processes in both prokaryotes and eukaryotes, including DNA replication, transcription, recombination, and chromosome segregation. Studies performed over the past 3 years have provided new insight into the roles of various topoisomerases in maintaining eukaryotic chromosome structure and facilitating the decatenation of daughter chromosomes at cell division. In addition, recent studies have demonstrated that the incorporation of ribonucleotides into DNA results in trapping of topoisomerase I (TOP1)–DNA covalent complexes during aborted ribonucleotide removal. Importantly, such trapped TOP1–DNA covalent complexes, formed either during ribonucleotide removal or as a consequence of drug action, activate several repair processes, including processes involving the recently described nuclear proteases SPARTAN and GCNA-1. A variety of new TOP1 inhibitors and formulations, including antibody–drug conjugates and PEGylated complexes, exert their anticancer effects by also trapping these TOP1–DNA covalent complexes. Here we review recent developments and identify further questions raised by these new findings.
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Affiliation(s)
- Mary-Ann Bjornsti
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, 35294-0019, USA
| | - Scott H Kaufmann
- Departments of Oncology and Molecular Pharmacolgy & Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA
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28
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Lohinai Z, Megyesfalvi Z, Dome B, Weiss GJ. Next-Generation Sequencing May Discriminate Extreme Long-term versus Short-term Survival in Patients with Metastatic Small Cell Lung Cancer (SCLC). Transl Oncol 2019; 12:1539-1548. [PMID: 31476386 PMCID: PMC6727016 DOI: 10.1016/j.tranon.2019.08.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 07/31/2019] [Accepted: 08/02/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND: Molecular underpinnings that may prognosticate survival could increase understanding of small cell lung cancer (SCLC) tumor behavior. Here, we report the clinicopathological characteristics and biomarker profiles of short-term (ST) versus long-term (LT) survival in patients with metastatic SCLC. METHODS: Of the 876 consecutive metastatic SCLC patients receiving standard of care therapy, 44 met the definition of LT and 91 for ST, respectively. Available FFPE tumor tissue blocks were analyzed by next-generation sequencing (NGS). Analysis included gene mutations, copy number variations, mRNA expression, and protein expression by immunohistochemistry, followed by correlation with clinicopathological characteristics. RESULTS: There were no statistically significant and clinically relevant differences in cases with or without FFPE according to major clinicopathological variables in ST and LT. However, according to NGS, five mutually exclusive gene mutations were identified (E1A binding protein P300 [EP300] p.N217S; p.E152K; human epidermal growth factor receptor 4 [ERBB4] p.E317K; BRCA1, DNA repair associated [BRCA1] p.E1661N, and epidermal growth factor receptor [EGFR] p.V742A). Comparing LT vs. ST survivals, a twofold increase was found in the average predicted number of drugs per patient off compendium. We found high SSTR2 mRNA expressions in all LT patients (vs. two [20%] ST patients), which may reflect more benign neuroendocrine tumor characteristics. CONCLUSIONS: Consolidation radiation therapy and higher predicted drug sensitivity for off compendium were associated with LT compared to ST patients in SCLC. NGS profiling of extreme survivals may improve classification of SCLC and possibly identify clinically relevant new targets.
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Affiliation(s)
- Zoltan Lohinai
- National Koranyi Institute of Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary; Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria.
| | - Zsolt Megyesfalvi
- National Koranyi Institute of Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary
| | - Balazs Dome
- National Koranyi Institute of Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary; Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria.
| | - Glen J Weiss
- MiRanostics Consulting, Oro Valley, AZ, United States
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Multi-omic molecular comparison of primary versus metastatic pancreatic tumours. Br J Cancer 2019; 121:264-270. [PMID: 31292535 PMCID: PMC6738081 DOI: 10.1038/s41416-019-0507-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 05/22/2019] [Accepted: 06/05/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Molecular profiling is increasingly used to match patients with metastatic cancer to targeted therapies, but obtaining a high-quality biopsy specimen from metastatic sites can be difficult. METHODS Patient samples were received by Perthera to coordinate genomic, proteomic and/or phosphoproteomic testing, using a specimen from either the primary tumour or a metastatic site. The relative frequencies were compared across specimen sites to assess the potential limitations of using a primary tumour sample for clinical decision support. RESULTS No significant differences were identified at the gene or pathway level when comparing genomic alterations between primary and metastatic lesions. Site-specific trends towards enrichment of MYC amplification in liver lesions, STK11 mutations in lung lesions and ATM and ARID2 mutations in abdominal lesions were seen, but were not statistically significant after false-discovery rate correction. Comparative analyses of proteomic results revealed significantly elevated expression of ERCC1 and TOP1 in metastatic lesions. CONCLUSIONS Tumour tissue limitations remain a barrier to precision oncology efforts, and these real-world data suggest that performing molecular testing on a primary tumour specimen could be considered in patients with pancreatic adenocarcinoma who do not have adequate tissue readily available from a metastatic site.
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Kümler I, Balslev E, Stenvang J, Brünner N, Ejlertsen B, Jakobsen EH, Nielsen DL. Two open-label, single arm, non-randomized phase II studies of irinotecan for the treatment of metastatic breast cancer in patients with increased copy number of the topoisomerase I gene. BMC Cancer 2019; 19:573. [PMID: 31196001 PMCID: PMC6567440 DOI: 10.1186/s12885-019-5788-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 05/31/2019] [Indexed: 11/15/2022] Open
Abstract
Background Treatment options in metastatic breast cancer are limited. New therapies preferable with predictive biomarkers are needed. The aim of these trials was to investigate if gene copy number of the topoisomerase 1 gene was predictive of response to the topoisomerase inhibitor irinotecan. Methods Two open-label, single-arm phase II studies including HER2 positive and negative patients were conducted. Patients were eligible for inclusion if the primary tumor or a metastatic lesion had increased expression of the topoisomerase 1 gene defined as a TOP1 gene copy number of ≥4 or a TOP1/CEN20 ratio of ≥2. Patients were treated with irinotecan +/− trastuzumab weekly for 4 weeks following 2 weeks break, until progression or unacceptable toxicities. Evaluation scans were performed every 6 weeks. Primary endpoint was clinical benefit rate defined as the fraction of patients with stable disease for ≥4 months. Results The pre-planned number of 18 patients in each trial was not reached, thus no formal statistical analysis could be performed. Nine patients with HER2 negative disease and three patients with HER2 positive disease were included. Three patients obtained a partial remission and two patients had SD. Conclusions The trials did not include the planned number of patients. No association between gene copy number of the topoisomerase 1 gene and response to irinotecan could be proved, however a clinical benefit was found in 5/12 patients and in 2/3 patients with HER2 positive disease. This could call for further investigation of the drug in the metastatic setting, especially in HER2 positive BC. Trial registration Eudract registration numbers 2012–002348-26 and 2012–002347-23. Registration date August 20th 2012.
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Affiliation(s)
- Iben Kümler
- Department of Oncology, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730, Herlev, Denmark.
| | - Eva Balslev
- Department of Pathology, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730, Herlev, Denmark
| | - Jan Stenvang
- Institut for Lægemiddeldesign og Farmakologi, Jagtvej 160, 2100, København Ø, Denmark
| | - Nils Brünner
- Institut for Lægemiddeldesign og Farmakologi, Jagtvej 160, 2100, København Ø, Denmark
| | - Bent Ejlertsen
- Department of Oncology, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark
| | | | - Dorte Lisbet Nielsen
- Department of Oncology, Herlev and Gentofte Hospital, Herlev Ringvej 75, DK-2730, Herlev, Denmark
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Tokunaga R, Xiu J, Johnston C, Goldberg RM, Philip PA, Seeber A, Naseem M, Lo JH, Arai H, Battaglin F, Puccini A, Berger MD, Soni S, Zhang W, Hwang JJ, Shields AF, Marshall JL, Baba H, Korn WM, Lenz HJ. Molecular Profiling of Appendiceal Adenocarcinoma and Comparison with Right-sided and Left-sided Colorectal Cancer. Clin Cancer Res 2019; 25:3096-3103. [PMID: 30692096 PMCID: PMC6886223 DOI: 10.1158/1078-0432.ccr-18-3388] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/18/2018] [Accepted: 01/18/2019] [Indexed: 01/27/2023]
Abstract
PURPOSE The natural history and prognosis of appendiceal adenocarcinomas differ from those of adenocarcinomas arising in other large bowel sites. We aimed to compare the molecular profiles exhibited by appendiceal adenocarcinomas and colorectal cancers, or between the histopathologic subtypes of appendiceal adenocarcinoma. EXPERIMENTAL DESIGN A total of 183 samples from appendiceal adenocarcinoma [46 adenocarcinoma, not otherwise specified (NOS), 66 pseudomyxoma peritonei (PMP), 44 mucinous adenocarcinoma (MU), and 27 signet ring cell carcinoma (SR)], 994 from right-sided colorectal cancer (R-CRC), and 1,080 from left-sided CRC (L-CRC) were analyzed by next-generation sequencing (NGS) and IHC markers. Microsatellite instability (MSI) and tumor mutational burden (TMB) were tested by NGS, and programmed death ligand 1 (PD-L1) by IHC. RESULTS We observed high mutation rates in appendiceal adenocarcinoma samples for KRAS (55%), TP53 (40%), GNAS (31%), SMAD4 (16%), and APC (10%). Appendiceal adenocarcinoma exhibited higher mutation rates in KRAS and GNAS, and lower mutation rates in TP53, APC, and PIK3CA (6%) than colorectal cancers. PMP exhibited much higher mutation rates in KRAS (74%) and GNAS (63%), and much lower mutation rates in TP53 (23%), APC (2%), and PIK3CA (2%) than NOS. Alterations associated with immune checkpoint inhibitor response (MSI-high, TMB-high, PD-L1 expression) showed similar frequency in appendiceal adenocarcinoma compared with L-CRC, but not R-CRC, and those of NOS were higher than other subtypes of appendiceal adenocarcinoma and L-CRC. CONCLUSIONS Molecular profiling of appendiceal adenocarcinoma revealed different molecular characteristics than noted in R-CRC and L-CRC, and molecular heterogeneity among the histopathologic subtypes of appendiceal adenocarcinoma. Our findings may be critical to developing an individualized approach to appendiceal adenocarcinoma treatment.
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Affiliation(s)
- Ryuma Tokunaga
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
| | | | | | | | - Philip A Philip
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Andreas Seeber
- Department of Haematology and Oncology, Innsbruck Medical University, Innsbruck, Austria
| | - Madiha Naseem
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Jae Ho Lo
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Hiroyuki Arai
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Alberto Puccini
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Martin D Berger
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Jimmy J Hwang
- Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina
| | - Anthony F Shields
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - John L Marshall
- Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | | | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
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Ruiz-Bañobre J, Kandimalla R, Goel A. Predictive Biomarkers in Metastatic Colorectal Cancer: A Systematic Review. JCO Precis Oncol 2019; 3:PO.18.00260. [PMID: 32914007 PMCID: PMC7446314 DOI: 10.1200/po.18.00260] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2018] [Indexed: 12/13/2022] Open
Abstract
PURPOSE The development and use of predictive biomarkers to guide treatment decisions are paramount not only for improving survival in patients with metastatic colorectal cancer (mCRC), but also for sparing them from unnecessary toxicity and reducing the economic burden of expensive treatments. We conducted a systematic review of published studies and evaluated the predictive biomarker landscape in the mCRC setting from a molecular and clinical viewpoint. METHODS Studies analyzing predictive biomarkers for approved therapies in patients with mCRC were identified systematically using electronic databases. Preclinical studies and those providing no relevant information were excluded. RESULTS A total of 173 studies comprising 148 biomarkers were selected for final analysis. Of all the biomarkers analyzed, 1.4% (two of 148) were explored in a prospective manner, whereas 98.6% (146 of 148) were evaluated in retrospective studies. Of the latter group, 78.8% (115 of 146) were not tested in subsequent phases, 9.6% (14 of 146) were tested in other retrospective cohorts, 8.9% (13 of 146) were retrospectively tested in at least one or more randomized cohorts, and only 2.7% (four of 146) were prospectively tested in a clinical trial. Finally, only 1.4% (two of 148) were validated sufficiently and are recognized as biomarkers for guiding treatment decision making in patients with mCRC. These markers were RAS mutational status for anti-EGFR antibodies and microsatellite instability status for anti-programmed cell death-1 drugs. CONCLUSION Despite notable efforts to identify predictive biomarkers for various therapies used in the mCRC setting, because of a lack of data beyond retrospective studies and successful biomarker-driven approaches, only two molecular biomarkers have thus far found their translation into the clinic, highlighting the imperative need for implementing novel strategies and additional research in this clinically important field.
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Affiliation(s)
- Juan Ruiz-Bañobre
- Arquitecto Marcide University Hospital, Ferrol, Spain
- Baylor University Medical Center, Dallas, TX
- ONCOMET, University Clinical Hospital of Santiago de Compostela, CIBERONC, Santiago de Compostela, Spain
| | | | - Ajay Goel
- Baylor University Medical Center, Dallas, TX
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Fountzilas E, Kotoula V, Pentheroudakis G, Manousou K, Polychronidou G, Vrettou E, Poulios C, Papadopoulou E, Raptou G, Pectasides E, Karayannopoulou G, Chrisafi S, Papakostas P, Makatsoris T, Varthalitis I, Psyrri A, Samantas E, Bobos M, Christodoulou C, Papadimitriou C, Nasioulas G, Pectasides D, Fountzilas G. Prognostic implications of mismatch repair deficiency in patients with nonmetastatic colorectal and endometrial cancer. ESMO Open 2019; 4:e000474. [PMID: 31231557 PMCID: PMC6555870 DOI: 10.1136/esmoopen-2018-000474] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 01/31/2019] [Accepted: 02/01/2019] [Indexed: 01/13/2023] Open
Abstract
Background The clinical relevance of mismatch repair (MMR) status in patients with nonmetastatic cancer across tumour types remains unclear. Our goal was to investigate the prognostic role of MMR deficiency in patients with stage I-III colorectal and endometrial cancer. Methods Patients with nonmetastatic colorectal and endometrial cancer with tumour tissue available for analysis were identified through the Hellenic Cooperative Oncology Group (HeCOG)'s tumour repository. Patients had been referred to Departments of Medical Oncology affiliated with HeCOG. MMR protein expression was evaluated by immunohistochemistry. The primary outcome measure was overall survival (OS). Results From May 1990 to September 2012, 1158 patients with nonmetastatic colorectal (N = 991) and endometrial cancer (N = 167) were identified (median age: 64 years, men: 544). All patients with colorectal and 109 (65%) with endometrial cancer had received adjuvant treatment. MMR deficiency was observed in 114 (11.5%) of colorectal and 80 (47.9%) of endometrial tumours. More commonly deficient proteins were PMS2 (69 patients, 7%) and MLH1 (63 patients, 6.5%) in colorectal cancer and MSH2 (58 patients, 34.7%) in endometrial cancer. Colorectal MMR-deficient (dMMR) tumours were more likely to be right sided (65 % dMMR vs 27 % proficient MMR, pMMR; p < 0.001), high grade (31% vs 15%, χ2, p < 0.001) and with a mucinous component (64% vs 42%, p < 0.001). Endometrial dMMR tumours were more often of endometrioid histology (51.4 % endometrioid vs 20 % serous/clear cell, p = 0.020). Compared with MMR proficiency, MMR deficiency was associated with improved OS in patients with endometrial cancer (HR = 0.38, 95% CI 0.20 to 0.76, p = 0.006), but not in patients with colorectal cancer (HR = 0.73, 95% CI 0.49 to 1.09, p = 0.130). After adjusting for age, stage and grade, MMR deficiency maintained its favourable prognostic significance in patients with endometrial cancer (HR = 0.42, 95% CI 0.20 to 0.88, p = 0.021). Conclusions DMMR was associated with improved outcomes in patients with nonmetastatic endometrial cancer, but not in patients with nonmetastatic colorectal cancer who received adjuvant chemotherapy.
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Affiliation(s)
- Elena Fountzilas
- Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
| | - Vassiliki Kotoula
- Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece.,Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Kyriaki Manousou
- Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece, Athens, Greece
| | - Genovefa Polychronidou
- Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece
| | - Eleni Vrettou
- Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece
| | - Christos Poulios
- Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece
| | | | - Georgia Raptou
- Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece
| | - Eirini Pectasides
- Department of Medicine, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.,Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Georgia Karayannopoulou
- Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece
| | - Sofia Chrisafi
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Thomas Makatsoris
- Department of Medicine, Division of Oncology, University Hospital, University of Patras Medical School, Patras, Greece
| | | | - Amanda Psyrri
- Section of Medical Oncology, Department of Internal Medicine, Attikon University Hospital, Faculty of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece
| | - Epaminontas Samantas
- Third Department of Medical Oncology, AgiiAnargiri Cancer Hospital, Athens, Greece
| | - Mattheos Bobos
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Christos Papadimitriou
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece
| | | | - Dimitrios Pectasides
- Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece
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Abstract
Immunohistochemistry (IHC) can be applied to diagnostic aspects of pathologic examination to provide aid in assignment of lineage and histologic type of cancer. Increasingly, however, IHC is widely used to provide prognostic and predictive (theranostic) information about the neoplastic disease. A refinement of theranostic application of IHC can be seen in the use of "genomic probing" where antibody staining results are directly correlated with an underlying genetic alteration in the tumor (somatic mutations) and/or the patient (germline constitution). All these aspects of IHC find their best use in guiding the oncologists in the optimal use of therapy for the patients.
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Affiliation(s)
| | | | - Semir Vranić
- College of Medicine, Qatar University, Doha, Qatar
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Cinelli MA. Topoisomerase 1B poisons: Over a half-century of drug leads, clinical candidates, and serendipitous discoveries. Med Res Rev 2018; 39:1294-1337. [PMID: 30456874 DOI: 10.1002/med.21546] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Revised: 10/08/2018] [Accepted: 10/09/2018] [Indexed: 12/17/2022]
Abstract
Topoisomerases are DNA processing enzymes that relieve supercoiling (torsional strain) in DNA, are necessary for normal cellular division, and act by nicking (and then religating) DNA strands. Type 1B topoisomerase (Top1) is overexpressed in certain tumors, and the enzyme has been extensively investigated as a target for cancer chemotherapy. Various chemical agents can act as "poisons" of the enzyme's religation step, leading to Top1-DNA lesions, DNA breakage, and eventual cellular death. In this review, agents that poison Top1 (and have thus been investigated for their anticancer properties) are surveyed, including natural products (such as camptothecins and indolocarbazoles), semisynthetic camptothecin and luotonin derivatives, and synthetic compounds (such as benzonaphthyridines, aromathecins, and indenoisoquinolines), as well as targeted therapies and conjugates. Top1 has also been investigated as a therapeutic target in certain viral and parasitic infections, as well as autoimmune, inflammatory, and neurological disorders, and a summary of literature describing alternative indications is also provided. This review should provide both a reference for the medicinal chemist and potentially offer clues to aid in the development of new Top1 poisons.
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Affiliation(s)
- Maris A Cinelli
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan
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Salem ME, Yin J, Weinberg BA, Renfro LA, Pederson LD, Maughan TS, Adams RA, Van Cutsem E, Falcone A, Tebbutt NC, Seymour MT, Díaz-Rubio E, Aranda E, Bokemeyer C, Heinemann V, Wasan H, de Gramont A, Grothey A, Shi Q, Sargent DJ, Marshall JL. Clinicopathological differences and survival outcomes with first-line therapy in patients with left-sided colon cancer and rectal cancer: Pooled analysis of 2879 patients from AGITG (MAX), COIN, FOCUS2, OPUS, CRYSTAL and COIN-B trials in the ARCAD database. Eur J Cancer 2018; 103:205-213. [PMID: 30268921 DOI: 10.1016/j.ejca.2018.08.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 08/22/2018] [Indexed: 01/09/2023]
Abstract
PURPOSE Patients with left-sided colon tumours have better survival and respond differently to biologics compared with patients with right-sided tumours. Left-sided colon tumours and rectal cancers are often grouped together. Herein, we examined the clinicopathological differences and outcomes between left-sided colon and rectal cancers. PATIENTS AND METHODS Data from 2879 metastatic colorectal cancer patients enrolled on six first-line clinical trials during 2004-2010 were pooled. Patients were included if the primary tumour origin was clearly defined. Progression-free survival (PFS) and overall survival (OS) were compared in the two groups after adjusting for patient and tumour characteristics, metastatic sites and the first-line regimen. RESULTS In total, 1374 patients with metastatic left-sided colon cancer and 1505 patients with metastatic rectal cancers were evaluated. Left-sided colon cancer patients were more likely to be female (40.1% versus 32.6%; P < 0.0001) and older (31.0% ≥ 70 years versus 25.8%; P = 0.0033) compared with rectal cancers patients. Patients with left-sided colon cancer had higher rates of liver metastases (80.9% versus 72.3%, P < 0.0001) but lower rates of lung metastases (34.2% versus 53.8%, P < 0.0001). KRAS mutations were slightly less frequent among left-sided tumours (34.8% versus 40.5%; P = 0.0103). Patients with left-sided tumours had approximately similar PFS (median 7.4 versus 6.9 months; hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.87-1.03; P = 0.1998) and OS (median 17.4 versus 16.6 months; HR 0.99, 95% CI 0.91-1.07; P = 0.7597) compared with rectal cancer patients. CONCLUSION The site of tumour origin within the left side was not prognostic of outcomes. Moreover, neither bevacizumab nor cetuximab impacted, differently, the findings of the comparisons in outcomes between patients with left-sided colon tumours or rectal cancers.
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Affiliation(s)
- Mohamed E Salem
- Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA.
| | - Jun Yin
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Benjamin A Weinberg
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Lindsay A Renfro
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Levi D Pederson
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | | | | | - Eric Van Cutsem
- Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium
| | | | | | - Matthew T Seymour
- Gastrointestinal Cancer Research Unit, Cookridge Hospital, Leeds, UK
| | - Eduardo Díaz-Rubio
- Department Oncology, Hospital Clínico San Carlos, CIBERONC, Madrid, Spain
| | - Enrique Aranda
- Reina Sofia Hospital, University of Cordoba, Maimonides Institute of Biomedical Research, CIBERONC, Avenida de Menendez Pidal, Cordoba, Spain
| | - Carsten Bokemeyer
- Department of Oncology, Haematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Volker Heinemann
- Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany
| | | | - Aimery de Gramont
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | - Axel Grothey
- Medical Oncology, West Cancer Center, Germantown, TN, USA
| | - Qian Shi
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Daniel J Sargent
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - John L Marshall
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
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Madi A, Fisher D, Maughan TS, Colley JP, Meade AM, Maynard J, Humphreys V, Wasan H, Adams RA, Idziaszczyk S, Harris R, Kaplan RS, Cheadle JP. Pharmacogenetic analyses of 2183 patients with advanced colorectal cancer; potential role for common dihydropyrimidine dehydrogenase variants in toxicity to chemotherapy. Eur J Cancer 2018; 102:31-39. [PMID: 30114658 DOI: 10.1016/j.ejca.2018.07.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 06/29/2018] [Accepted: 07/08/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Inherited genetic variants may influence response to, and side-effects from, chemotherapy. We sought to generate a comprehensive inherited pharmacogenetic profile for oxaliplatin and 5FU/capecitabine therapy in advanced colorectal cancer (aCRC). METHODS We analysed more than 200 potentially functional, common, inherited variants in genes within the 5FU, capecitabine, oxaliplatin and DNA repair pathways, together with four rare dihydropyrimidine dehydrogenase (DPYD) variants, in 2183 aCRC patients treated with oxaliplatin-fluoropyrimidine chemotherapy with, or without, cetuximab (from MRC COIN and COIN-B trials). Primary end-points were response, any toxicity and peripheral neuropathy. We had >85% power to detect odds ratios (ORs) = 1.3 for variants with minor allele frequencies >20%. RESULTS Variants in DNA repair genes (Asn279Ser in EXO1 and Arg399Gln in XRCC1) were most associated with response (OR 1.9, 95% confidence interval [CI] 1.2-2.9, P = 0.004, and OR 0.7, 95% CI 0.5-0.9, P = 0.003, respectively). Common variants in DPYD (Cys29Arg and Val732Ile) were most associated with toxicity (OR 0.8, 95% CI 0.7-1.0, P = 0.008, and OR 1.6, 95% CI 1.1-2.1, P = 0.006, respectively). Two rare DPYD variants were associated with increased toxicity (Asp949Val with neutropenia, nausea and vomiting, diarrhoea and infection; IVS14+1G>A with lethargy, diarrhoea, stomatitis, hand-foot syndrome and infection; all ORs > 3). Asp317His in DCLRE1A was most associated with peripheral neuropathy (OR 1.3, 95% CI 1.1-1.6, P = 0.003). No common variant associations remained significant after Bonferroni correction. CONCLUSIONS DNA repair genes may play a significant role in the pharmacogenetics of aCRC. Our data suggest that both common and rare DPYD variants may be associated with toxicity to fluoropyrimidine-based chemotherapy.
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Affiliation(s)
- Ayman Madi
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - David Fisher
- MRC Clinical Trials Unit, Aviation House, 125 Kingsway, London, WC2B 6NH, UK
| | - Timothy S Maughan
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - James P Colley
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Angela M Meade
- MRC Clinical Trials Unit, Aviation House, 125 Kingsway, London, WC2B 6NH, UK
| | - Julie Maynard
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Vikki Humphreys
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Harpreet Wasan
- Imperial College Healthcare NHS Trust, Hammersmith Hospital, Du Cane Road, London, W12 0HS, UK
| | - Richard A Adams
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Shelley Idziaszczyk
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Rebecca Harris
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Richard S Kaplan
- MRC Clinical Trials Unit, Aviation House, 125 Kingsway, London, WC2B 6NH, UK
| | - Jeremy P Cheadle
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
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Rao S, Beckman RA, Riazi S, Yabar CS, Boca SM, Marshall JL, Pishvaian MJ, Brody JR, Madhavan S. Quantification and expert evaluation of evidence for chemopredictive biomarkers to personalize cancer treatment. Oncotarget 2018; 8:37923-37934. [PMID: 27888622 PMCID: PMC5514962 DOI: 10.18632/oncotarget.13544] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 11/12/2016] [Indexed: 02/06/2023] Open
Abstract
Predictive biomarkers have the potential to facilitate cancer precision medicine by guiding the optimal choice of therapies for patients. However, clinicians are faced with an enormous volume of often-contradictory evidence regarding the therapeutic context of chemopredictive biomarkers. We extensively surveyed public literature to systematically review the predictive effect of 7 biomarkers claimed to predict response to various chemotherapy drugs: ERCC1-platinums, RRM1-gemcitabine, TYMS-5-fluorouracil/Capecitabine, TUBB3-taxanes, MGMT-temozolomide, TOP1-irinotecan/topotecan, and TOP2A-anthracyclines. We focused on studies that investigated changes in gene or protein expression as predictors of drug sensitivity or resistance. We considered an evidence framework that ranked studies from high level I evidence for randomized controlled trials to low level IV evidence for pre-clinical studies and patient case studies. We found that further in-depth analysis will be required to explore methodological issues, inconsistencies between studies, and tumor specific effects present even within high evidence level studies. Some of these nuances will lend themselves to automation, others will require manual curation. However, the comprehensive cataloging and analysis of dispersed public data utilizing an evidence framework provides a high level perspective on clinical actionability of these protein biomarkers. This framework and perspective will ultimately facilitate clinical trial design as well as therapeutic decision-making for individual patients.
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Affiliation(s)
- Shruti Rao
- Innovation Center for Biomedical Informatics, Georgetown University, Washington, DC, USA
| | - Robert A Beckman
- Innovation Center for Biomedical Informatics, Georgetown University, Washington, DC, USA.,Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.,Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, DC, USA
| | - Shahla Riazi
- Innovation Center for Biomedical Informatics, Georgetown University, Washington, DC, USA
| | - Cinthya S Yabar
- Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA.,Department of Surgery, Albert Einstein Medical Center, Philadelphia, PA, USA
| | - Simina M Boca
- Innovation Center for Biomedical Informatics, Georgetown University, Washington, DC, USA.,Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.,Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, DC, USA
| | - John L Marshall
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.,Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Michael J Pishvaian
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.,Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Jonathan R Brody
- Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA
| | - Subha Madhavan
- Innovation Center for Biomedical Informatics, Georgetown University, Washington, DC, USA.,Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
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Rugo HS, Cortes J, Awada A, O'Shaughnessy J, Twelves C, Im SA, Hannah A, Lu L, Sy S, Caygill K, Zajchowski DA, Davis DW, Tagliaferri M, Hoch U, Perez EA. Change in Topoisomerase 1-Positive Circulating Tumor Cells Affects Overall Survival in Patients with Advanced Breast Cancer after Treatment with Etirinotecan Pegol. Clin Cancer Res 2018; 24:3348-3357. [PMID: 29618616 DOI: 10.1158/1078-0432.ccr-17-3059] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 01/10/2018] [Accepted: 03/26/2018] [Indexed: 11/16/2022]
Abstract
Purpose: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTC) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP).Experimental Design: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician's choice (TPC). Blood from 656 of 852 patients (77%) was processed with ApoStream to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers [topoisomerase 1 (Top1), topoisomerase 2 (Top2), Ki67, RAD51, ABCG2, γH2AX, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)] in CTCs. Patients were classified as Top1 low (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 with overall survival (OS) was investigated using Cox regression and Kaplan-Meier analyses.Results: Overall, 98% of samples were successfully processed, of which 97% had detectable CTCs (median, 47-63 CTCs/mL; range, 0-2,020 CTCs/mL). Top1, Top2, and TUNEL expression was detected in 52% to 90% of samples; no significant associations with OS were observed in pretreatment samples for either group. EP-treated patients with low C2D1Top1+ CTCs had improved OS compared with those with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P = 0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P = 0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR, 0.57; P = 0.01).Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit. Clin Cancer Res; 24(14); 3348-57. ©2018 AACR.
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Affiliation(s)
- Hope S Rugo
- University of California, San Francisco, San Francisco, California
| | - Javier Cortes
- Ramon y Cajal University Hospital, Madrid, and Vall D'Hebron Institute of Oncology, Barcelona, Spain
| | - Ahmad Awada
- Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium
| | - Joyce O'Shaughnessy
- Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, Texas
| | - Chris Twelves
- University of Leeds and Leeds Teaching Hospital Trust, Leeds, United Kingdom
| | - Seock-Ah Im
- Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | | | - Lin Lu
- Nektar Therapeutics, San Francisco, California
| | - Sherwin Sy
- Nektar Therapeutics, San Francisco, California
| | | | | | | | | | - Ute Hoch
- Nektar Therapeutics, San Francisco, California.
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40
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Shaojun C, Li H, Haixin H, Guisheng L. Expression of Topoisomerase 1 and carboxylesterase 2 correlates with irinotecan treatment response in metastatic colorectal cancer. Cancer Biol Ther 2018; 19:153-159. [PMID: 29261002 PMCID: PMC5790385 DOI: 10.1080/15384047.2017.1414754] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 11/06/2017] [Accepted: 12/05/2017] [Indexed: 12/11/2022] Open
Abstract
Topoisomerase 1 (TOPO-1) and carboxylesterase 2 (CES-2) are found to play crucial roles in the pathogenesis of various cancers. The prognostic role of TOPO-1 and CES-2 in patients with metastatic colorectal cancer (mCRC) who underwent irinotecan chemotherapy was largely unknown. In the current study, we assessed the expression of TOPO-1 and CES-2 in mCRC and analyzed its potential relevance to irinotecan based therapy. A total of 98 patients with mCRC were included in this study. The expression of TOPO-1 and CES-2 in mCRC tissues was evaluated by immunohistochemistry. For TOPO-1, 46 patients showed high expression and 52 patients showed low expression. For CES-2, 53 patients showed high expression and 45 patients showed low expression. The correlation between TOPO-1 or CES-2 expression and clinicopathological characteristics of mCRC patients was analyzed. Neither TOPO-1 nor CES-2 had significant correlation with age, gender, tumor site, tumor grade and metastatic sites in mCRC patients. However, high expression of CES-2 but not TOP-1 was positively correlated with better curative effect. Kaplan-Meier and log-rank test were applied to assess the correlation between progression-free survival (PFS)/overall survival (OS) and TOPO-1 or CES-2 expression in mCRC patients. High expression of TOPO-1 and CES-2 are correlated with longer PFS and OS. In summary, our findings suggest that TOPO-1 and CES-2 may play important roles irinotecan sensitivity in mCRC patients. Evaluation of expression of TOPO-1 and CES-2 may provide preliminary clinical evidence for the management of irinotecan-based therapy in mCRC patients.
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Affiliation(s)
- Chen Shaojun
- Department of Medical Oncology, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Hua Li
- Department of Medical Oncology, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Huang Haixin
- Department of Medical Oncology, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Li Guisheng
- Department of Medical Oncology, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
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41
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Shalaby SM, El-Shal AS, Abdelaziz LA, Abd-Elbary E, Khairy MM. Promoter methylation and expression of DNA repair genes MGMT and ERCC1 in tissue and blood of rectal cancer patients. Gene 2018; 644:66-73. [DOI: 10.1016/j.gene.2017.10.056] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Revised: 09/30/2017] [Accepted: 10/18/2017] [Indexed: 01/26/2023]
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Perkins AL, Peterson KL, Beito TG, Flatten KS, Kaufmann SH, Harki DA. Synthesis of a peptide-universal nucleotide antigen: towards next-generation antibodies to detect topoisomerase I-DNA covalent complexes. Org Biomol Chem 2018; 14:4103-9. [PMID: 27113574 DOI: 10.1039/c5ob02049b] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The topoisomerase (topo) I-DNA covalent complex represents an attractive target for developing diagnostic antibodies to measure responsiveness to drugs. We report a new antigen, peptide , and four murine monoclonal antibodies raised against that exhibit excellent specificity for recognition of in comparison to structurally similar peptides by enzyme-linked immunosorbent assays. Although topo I-DNA complex detection was not achieved in cellular samples by these new antibodies, a new strategy for antigen design is reported.
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Affiliation(s)
- Angela L Perkins
- Department of Medicinal Chemistry, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA.
| | - Kevin L Peterson
- Division of Oncology Research, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA
| | - Thomas G Beito
- Monoclonal Antibody Core, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA
| | - Karen S Flatten
- Division of Oncology Research, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA
| | - Scott H Kaufmann
- Division of Oncology Research, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA
| | - Daniel A Harki
- Department of Medicinal Chemistry, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA.
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43
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Topcagic J, Feldman R, Ghazalpour A, Swensen J, Gatalica Z, Vranic S. Comprehensive molecular profiling of advanced/metastatic olfactory neuroblastomas. PLoS One 2018; 13:e0191244. [PMID: 29324814 PMCID: PMC5764485 DOI: 10.1371/journal.pone.0191244] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Accepted: 01/02/2018] [Indexed: 02/06/2023] Open
Abstract
Olfactory neuroblastoma (ONB) is a rare, locally aggressive, malignant neoplasm originating in the olfactory epithelium in the nasal vault. The recurrence rate of ONB remains high and there are no specific treatment guidelines for recurrent/metastatic ONBs. This study retrospectively evaluated 23 ONB samples profiled at Caris Life Sciences (Phoenix, Arizona) using DNA sequencing (Sanger/NGS [Illumina], n = 15) and gene fusions (Archer FusionPlex, n = 6), whole genome RNA microarray (HumanHT-12 v4 beadChip, Illumina, n = 4), gene copy number assays (chromogenic and fluorescent in situ hybridization), and immunohistochemistry. Mutations were detected in 63% ONBs including TP53, CTNNB1, EGFR, APC, cKIT, cMET, PDGFRA, CDH1, FH, and SMAD4 genes. Twenty-one genes were over-expressed and 19 genes under-expressed by microarray assay. Some of the upregulated genes included CD24, SCG2, and IGFBP-2. None of the cases harbored copy number variations of EGFR, HER2 and cMET genes, and no gene fusions were identified. Multiple protein biomarkers of potential response or resistance to classic chemotherapy drugs were identified, such as low ERCC1 [cisplatin sensitivity in 10/12], high TOPO1 [irinotecan sensitivity in 12/19], high TUBB3 [vincristine resistance in 13/14], and high MRP1 [multidrug resistance in 6/6 cases]. None of the cases (0/10) were positive for PD-L1 in tumor cells. Overexpression of pNTRK was observed in 67% (4/6) of the cases without underlying genetic alterations. Molecular alterations detected in our study (e.g., Wnt and cKIT/PDGFRA pathways) are potentially treatable using novel therapeutic approaches. Identified protein biomarkers of response or resistance to classic chemotherapy could be useful in optimizing existing chemotherapy treatment(s) in ONBs.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- DNA Copy Number Variations
- DNA, Neoplasm/genetics
- Esthesioneuroblastoma, Olfactory/genetics
- Esthesioneuroblastoma, Olfactory/metabolism
- Esthesioneuroblastoma, Olfactory/secondary
- Female
- Gene Expression Profiling
- Gene Fusion
- Humans
- Immunohistochemistry
- In Situ Hybridization, Fluorescence
- Male
- Middle Aged
- Molecular Targeted Therapy
- Mutation
- Nasal Cavity
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/metabolism
- Neoplasm Recurrence, Local/therapy
- Nose Neoplasms/genetics
- Nose Neoplasms/metabolism
- Nose Neoplasms/therapy
- Retrospective Studies
- Sequence Analysis, DNA
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Affiliation(s)
- Jasmina Topcagic
- Association of Basic Medical Sciences of Federation of Bosnia and Herzegovina, Sarajevo, Bosnia and Herzegovina
| | - Rebecca Feldman
- Caris Life Sciences, Phoenix, Arizona, United States of America
| | | | - Jeffrey Swensen
- Caris Life Sciences, Phoenix, Arizona, United States of America
| | - Zoran Gatalica
- Caris Life Sciences, Phoenix, Arizona, United States of America
| | - Semir Vranic
- Association of Basic Medical Sciences of Federation of Bosnia and Herzegovina, Sarajevo, Bosnia and Herzegovina
- Department of Pathology, Clinical Center and School of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
- College of Medicine, Qatar University, Doha, Qatar
- * E-mail: ,
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44
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Ramanathan RK, Weiss GJ, Posner RG, Rajeshkumar NV, Jameson G, Aziz M, Hoering A, Bolejack V, Maitra A, Fulk M, Stites EC, Hlavacek WS, Gatalica Z, Xiu J, Hidalgo M, Von Hoff DD, Barrett MT. A phase 2 trial of personalized cytotoxic therapy based on tumor immunohistochemistry in previously treated metastatic pancreatic cancer patients. J Gastrointest Oncol 2018; 8:925-935. [PMID: 29299351 DOI: 10.21037/jgo.2017.09.05] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Background The choice of a regimen in metastatic pancreatic cancer patients following progression on 1st line therapy is empiric and outcomes are unsatisfactory. This phase II study was performed to evaluate the efficacy of therapy selected by immunohistochemistry (IHC) in these patients following progression after one or more therapies. Methods Eligible patients underwent a percutaneous biopsy of a metastatic lesion and treatment selection was determined by IHC. The study required 35 evaluable patients (power of 86%) for detecting a true 1-year survival rate of >20%. Results A tumor biopsy was performed in 48 of 49 accrued patients. Study therapy was not given (n=13) either due to insufficient tumor on biopsy (n=8) or due to worsening cancer related symptoms after biopsy (n=5). The demographics of evaluable patients (n=35) are male/female (59%/41%), with age range 34-78 years (median 63 years). Patients had 1-6 prior regimens (median of 2). The most common IHC targets were topoisomerase 1 or 2, thymidylate synthase, excision repair cross-complementation group 1 protein (ERCC1), and osteonectin secreted protein acidic and rich in cysteine (SPARC). Commercially available treatment regimens prescribed included FOLFIRI, FOLFOX, irinotecan, and doxorubicin. The response (RECIST) was 9%, the median survival was 5.6 months (94% CI, 3.8-8.2), and the 1-year survival was 20% (95% CI, 7-33%). Conclusions In all patients, IHC assays resulted in identification of at least two targets for therapy and a non-cross resistant regimen could be prescribed for therapy with evidence of some benefit. An IHC based treatment strategy is feasible and needs validation in larger studies.
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Affiliation(s)
- Ramesh K Ramanathan
- Honor Health Research Institute, Scottsdale, AZ, USA.,Mayo Clinic Cancer Center, Phoenix, AZ, USA.,Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Glen J Weiss
- Honor Health Research Institute, Scottsdale, AZ, USA.,Translational Genomics Research Institute, Phoenix, AZ, USA
| | | | - N V Rajeshkumar
- Department of Oncology and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Human Therapeutics Division, Intrexon Corporation, Germantown, MD, USA
| | - Gayle Jameson
- Honor Health Research Institute, Scottsdale, AZ, USA
| | - Meraj Aziz
- Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Antje Hoering
- Human Therapeutics Division, Intrexon Corporation, Germantown, MD, USA
| | | | - Anirban Maitra
- Department of Oncology and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Sheikh Ahmed Pancreatic Cancer Research Center, UT MD Anderson Cancer Center, Houston, TX, USA
| | - Monica Fulk
- Honor Health Research Institute, Scottsdale, AZ, USA
| | | | | | | | | | - Manuel Hidalgo
- Beth Israel Deaconess Medical Center, Boston, MA, USA.,Centro Nacional de Investigaciones Oncológicas and Hospital de Madrid, Madrid, Spain
| | - Daniel D Von Hoff
- Honor Health Research Institute, Scottsdale, AZ, USA.,Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Michael T Barrett
- Mayo Clinic Cancer Center, Phoenix, AZ, USA.,Translational Genomics Research Institute, Phoenix, AZ, USA
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45
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Xiu J, Piccioni D, Juarez T, Pingle SC, Hu J, Rudnick J, Fink K, Spetzler DB, Maney T, Ghazalpour A, Bender R, Gatalica Z, Reddy S, Sanai N, Idbaih A, Glantz M, Kesari S. Multi-platform molecular profiling of a large cohort of glioblastomas reveals potential therapeutic strategies. Oncotarget 2017; 7:21556-69. [PMID: 26933808 PMCID: PMC5008305 DOI: 10.18632/oncotarget.7722] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 01/28/2016] [Indexed: 01/22/2023] Open
Abstract
Glioblastomas (GBM) are the most aggressive and prevalent form of gliomas with abysmal prognosis and limited treatment options. We analyzed clinically relevant molecular aberrations suggestive of response to therapies in 1035 GBM tumors. Our analysis revealed mutations in 39 genes of 48 tested. IHC revealed expression of PD-L1 in 19% and PD-1 in 46%. MGMT-methylation was seen in 43%, EGFRvIII in 19% and 1p19q co-deletion in 2%. TP53 mutation was associated with concurrent mutations, while IDH1 mutation was associated with MGMT-methylation and TP53 mutation and was mutually exclusive of EGFRvIII mutation. Distinct biomarker profiles were seen in GBM compared with WHO grade III astrocytoma, suggesting different biology and potentially different treatment approaches. Analysis of 17 metachronous paired tumors showed frequent biomarker changes, including MGMT-methylation and EGFR aberrations, indicating the need for a re-biopsy for tumor profiling to direct subsequent therapy. MGMT-methylation, PR and TOPO1 appeared as significant prognostic markers in sub-cohorts of GBM defined by age. The current study represents the largest biomarker study on clinical GBM tumors using multiple technologies to detect gene mutation, amplification, protein expression and promoter methylation. These data will inform planning for future personalized biomarker-based clinical trials and identifying effective treatments based on tumor biomarkers.
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Affiliation(s)
| | - David Piccioni
- Neuro-Oncology Program, Moores Cancer Center, UC San Diego, La Jolla, CA, USA
| | - Tiffany Juarez
- Neuro-Oncology Program, Moores Cancer Center, UC San Diego, La Jolla, CA, USA
| | - Sandeep C Pingle
- Neuro-Oncology Program, Moores Cancer Center, UC San Diego, La Jolla, CA, USA
| | - Jethro Hu
- Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | - Karen Fink
- Baylor University Medical Center, Dallas, TX, USA
| | | | | | | | | | | | | | - Nader Sanai
- Barrow Neurological Institute, Phoenix, AZ, USA
| | - Ahmed Idbaih
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France.,Sorbonne Universités, UPMC Univ Paris 06, UMRS 975, Institut du Cerveau et de la Moelle, Paris, France.,Inserm U 975, Paris, France.,CNRS, UMR 7225, Paris, France
| | | | - Santosh Kesari
- Neuro-Oncology Program, Moores Cancer Center, UC San Diego, La Jolla, CA, USA.,Translational Neuro-Oncology Laboratories, Department of Neurosciences UC San Diego, La Jolla, CA, USA.,Department of Translational Neuro-Oncology and Neurotherapeutics, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA
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46
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Zhang J, Zhu Y, Wang Y, Fu Q, Xie H, Liu Z, Fu H, Cao Y, Xu J, Dai B. Prognostic and Predictive Value of O 6-methylguanine Methyltransferase for Chemotherapy in Patients with Muscle-Invasive Bladder Cancer. Ann Surg Oncol 2017; 25:342-348. [PMID: 29116491 DOI: 10.1245/s10434-017-6145-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Indexed: 01/04/2023]
Abstract
PURPOSE DNA repair genes are potential biomarkers for chemotherapy in muscle-invasive bladder cancer (MIBC). O6-methylguanine methyltransferase (MGMT) is involved in DNA repair and is found to affect the efficacy of platinum-based chemotherapy. However, the prognostic or predictive value of MGMT expression in chemotherapy for MIBC is unknown. MATERIALS AND METHODS Immunohistochemical staining for MGMT was performed in paraffin-embedded tumor tissue of high-grade MIBC patients who underwent cystectomy in two independent cohorts [n = 74 for Fudan University Shanghai Cancer Center (FUSCC) cohort and n = 115 for Zhongshan Hospital (ZS) cohort]. MGMT messenger RNA (mRNA) analysis was conducted using patients' clinical and fragments per kilobase of exon model per million mapped fragments mRNA data from The Cancer Genome Atlas (TCGA) database (n = 245). RESULTS In our cohorts, high MGMT expression was significantly correlated with shorter overall survival (OS) in patients with platinum-based adjuvant chemotherapy [hazard ratio (HR) 2.386, p = 0.048; HR 2.920, p = 0.007; HR 2.324, p = 0.004, respectively, in FUSCC, ZS, and combination sets], but not in patients without chemotherapy. These findings were corroborated by the TCGA set (HR 1.952 and 0.697 for patients with and without chemotherapy, respectively). The chemotherapy-MGMT interaction for OS was significant in both the surgery set (p = 0.045) and TCGA set (p = 0.034). CONCLUSIONS We demonstrated that high MGMT expression is an independent poor prognostic factor in MIBC patients with platinum-based adjuvant chemotherapy, but not in patients without chemotherapy. MGMT expression may be a potential predictor for administration of adjuvant chemotherapy.
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Affiliation(s)
- Junyu Zhang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yu Zhu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yiwei Wang
- Department of Urology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiang Fu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Huyang Xie
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zheng Liu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hangcheng Fu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yifan Cao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jiejie Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
| | - Bo Dai
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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47
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Salem ME, Weinberg BA, Xiu J, El-Deiry WS, Hwang JJ, Gatalica Z, Philip PA, Shields AF, Lenz HJ, Marshall JL. Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers. Oncotarget 2017; 8:86356-86368. [PMID: 29156800 PMCID: PMC5689690 DOI: 10.18632/oncotarget.21169] [Citation(s) in RCA: 152] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 08/15/2017] [Indexed: 12/12/2022] Open
Abstract
Tumor sidedness has emerged as an important prognostic and predictive factor in the treatment of colorectal cancer. Recent studies demonstrate that patients with advanced right-sided colon cancers have a worse prognosis than those with left-sided colon or rectal cancers, and these patient subgroups respond differently to biological therapies. Historically, management of patients with metastatic colon and rectal cancers has been similar, and colon and rectal cancer patients have been grouped together in large clinical trials. Clearly, the differences in molecular biology among right-sided colon, left-sided colon, and rectal cancers should be further studied in order to account for disparities in clinical outcomes. We profiled 10,570 colorectal tumors (of which 2,413 were identified as arising from the left colon, right colon, or rectum) using next-generation sequencing, immunohistochemistry, chromogenic in-situ hybridization, and fragment analysis (Caris Life Sciences, Phoenix, AZ). Right-sided colon cancers had higher rates of microsatellite instability, more frequent aberrant activation of the EGFR pathway including higher BRAF and PIK3CA mutation rates, and increased mutational burden compared to left-sided colon and rectal cancers. Rectal cancers had higher rates of TOPO1 expression and Her2/neu amplification compared to both left- and right-sided colon cancers. Molecular variations among right-sided colon, left-sided colon, and rectal tumors may contribute to differences in clinical behavior. The site of tumor origin (left colon, right colon, or rectum) should certainly be considered when selecting treatment regimens and stratifying patients for future clinical trials.
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Affiliation(s)
- Mohamed E. Salem
- Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Benjamin A. Weinberg
- Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | | | | | - Jimmy J. Hwang
- Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA
| | | | - Philip A. Philip
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Anthony F. Shields
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Heinz-Josef Lenz
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - John L. Marshall
- Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
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Sloan R, Huang SYN, Pommier Y, Jinks-Robertson S. Effects of camptothecin or TOP1 overexpression on genetic stability in Saccharomyces cerevisiae. DNA Repair (Amst) 2017; 59:69-75. [PMID: 28961461 DOI: 10.1016/j.dnarep.2017.09.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 09/14/2017] [Accepted: 09/15/2017] [Indexed: 10/18/2022]
Abstract
Topoisomerase I (Top1) removes DNA torsional stress by nicking and resealing one strand of DNA, and is essential in higher eukaryotes. The enzyme is frequently overproduced in tumors and is the sole target of the chemotherapeutic drug camptothecin (CPT) and its clinical derivatives. CPT stabilizes the covalent Top1-DNA cleavage intermediate, which leads to toxic double-strand breaks (DSBs) when encountered by a replication fork. In the current study, we examined genetic instability associated with CPT treatment or with Top1 overexpression in the yeast Saccharomyces cerevisiae. Two types of instability were monitored: Top1-dependent deletions in haploid strains, which do not require processing into a DSB, and instability at the repetitive ribosomal DNA (rDNA) locus in diploid strains, which reflects DSB formation. Three 2-bp deletion hotspots were examined and mutations at each were elevated either when a wild-type strain was treated with CPT or when TOP1 was overexpressed, with the mutation frequency correlating with the level of TOP1 overexpression. Under both conditions, deletions at novel positions were enriched. rDNA stability was examined by measuring loss-of-heterozygosity and as was observed previously upon CPT treatment of a wild-type strain, Top1 overexpression destabilized rDNA. We conclude that too much, as well as too little of Top1 is detrimental to eukaryotic genomes, and that CPT has destabilizing effects that extend beyond those associated with DSB formation.
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Affiliation(s)
- Roketa Sloan
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, United States
| | - Shar-Yin Naomi Huang
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, United States
| | - Yves Pommier
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, United States
| | - Sue Jinks-Robertson
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, United States.
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Phase II Trial of Target-guided Personalized Chemotherapy in First-line Metastatic Colorectal Cancer. Am J Clin Oncol 2017; 39:236-42. [PMID: 24517959 DOI: 10.1097/coc.0000000000000045] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE The aim of this study was to investigate the feasibility and efficacy of personalizing treatment of patients with advanced untreated colorectal cancer (CRC). PATIENTS AND METHODS Patients with untreated metastatic CRC, performance status 0-1, and candidates for systemic chemotherapy were eligible. Tumor tissues were analyzed for KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), excision repair cross-complementing gene 1 (ERCC1), thymidylate synthase (TS), and thymidine phosphorylase (TP). Patients with Topo-1 expression received irinotecan, whereas patients with negative Topo-1 and ERCC1 expression received oxaliplatin. Otherwise, patients received physician's choice of treatment. If TS was positive, no fluoropyrimidine was administered and if negative, 5-flurorouracil if TP was negative, or capecitabine if TP was positive. KRAS-mutated patients were treated with bevacizumab, whereas KRAS-native received cetuximab. The primary endpoint of the study was progression-free survival (PFS). RESULTS A total of 74 patients were enrolled and 67 received personalized treatment including irinotecan (n=27), oxaliplatin (n=16), FOLFIRI (n=12), and FOLFOX (n=12). Thirty-eight patients received cetuximab and 29 bevacizumab. With a median follow-up time of 18.3 months (95% confidence interval [CI], 4-36), the overall median PFS was 8.3 months (95% CI, 6.9-9.7), representing a 12-month PFS rate of 36.5% (95% CI, 25-48). Overall clinical benefit, including response rate and disease stabilization, was 86% (95% CI, 73%-97%). The overall median survival was 21 months (95% CI, 11-40). CONCLUSIONS Real-time target-guided personalized first-line treatment of patients with advanced CRC is feasible but, with the approached used, did not result in a clear improvement in PFS to warrant phase III testing.
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50
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Heestand GM, Schwaederle M, Gatalica Z, Arguello D, Kurzrock R. Topoisomerase expression and amplification in solid tumours: Analysis of 24,262 patients. Eur J Cancer 2017; 83:80-87. [PMID: 28728050 PMCID: PMC5613945 DOI: 10.1016/j.ejca.2017.06.019] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 06/16/2017] [Indexed: 01/07/2023]
Abstract
Background Topoisomerase I (TOPO1) and topoisomerase IIα (TOP2A) are specific targets of multiple chemotherapy drugs. Increased expression of TOPO1 protein and amplification of the TOP2A gene have been associated with treatment response in colorectal and breast cancers, respectively. TOPO1 and TOP2A may be potential therapeutic targets in other malignancies as well. Summary of methods We analysed TOPO1 protein expression and TOP2A gene amplification in patients (n = 24,262 specimens) with diverse cancers. Since HER2 and TOP2A co-amplification have been investigated for predictive value regarding anthracycline benefit, we analysed specimens for HER2 amplification as well. Results Overexpressed TOPO1 protein was present in 51% of the tumours. Four percent of the tumours had TOP2A amplification, with gallbladder tumours and gastroesophageal/oesophageal tumours having rates over 10%. Overall, 4903 specimens were assessed for both TOP2A and HER2 amplification; 129 (2.6%) had co-amplification. High rates (>40%) of HER2 amplification were seen in patients with TOP2A amplification in breast, ovarian, gastroesophageal/oesophageal and pancreatic cancer. Conclusion Our data indicate that increased TOPO1 expression and TOP2A amplification, as well as HER2 co-alterations, are present in multiple malignancies. The implications of these observations regarding sensitivity to chemotherapy not traditionally administered to these tumour types merits investigation.
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Affiliation(s)
- Gregory M Heestand
- Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.
| | - Maria Schwaederle
- Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.
| | - Zoran Gatalica
- Caris Life Sciences, 4750 South 44th Place, Phoenix, AZ 85040, USA.
| | - David Arguello
- Caris Life Sciences, 4750 South 44th Place, Phoenix, AZ 85040, USA.
| | - Razelle Kurzrock
- Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.
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