1
|
Hoeijmakers LL, Rozeman EA, Lopez-Yurda M, Grijpink-Ongering LG, Heeres BC, van de Wiel BA, Flohil C, Sari A, Heijmink SWTPJ, van den Broek D, Broeks A, de Groot JWB, Vollebergh MA, Wilgenhof S, van Thienen JV, Haanen JBAG, Blank CU. Durable responses upon short-term addition of targeted therapy to anti-PD1 in advanced melanoma patients: 5-year progression-free and overall survival update of the IMPemBra trial. Eur J Cancer 2025; 222:115431. [PMID: 40279684 DOI: 10.1016/j.ejca.2025.115431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 04/03/2025] [Accepted: 04/09/2025] [Indexed: 04/27/2025]
Abstract
BACKGROUND The addition of targeted therapy (TT) to immune checkpoint inhibitors has been shown to transiently increase immune infiltration in melanoma. This formed the rationale for the IMPemBra trial, which showed a numerical increase in progression-free survival (PFS) in patients treated with short-term/intermittent TT and anti-PD1 compared to anti-PD1 alone. In this report, the final toxicity-analysis, 5-year PFS and exploratory analysis of overall survival (OS) will be reported, together with an analysis of subsequent therapies. PATIENTS AND METHODS 32 treatment-naïve patients with a BRAFV600E/K-mutated advanced melanoma were treated with 2 cycles of pembrolizumab 200 mg every 3 weeks, followed by randomization to continue pembrolizumab monotherapy for six weeks in cohort-1 versus pembrolizumab plus intermittent dabrafenib 150 mg BID + trametinib 2 mg QD 2×1-week (cohort 2), 2×2-weeks (cohort 3), or 1×6-weeks (cohort 4). After week 12, all patients continued pembrolizumab monotherapy for a maximum of 2 years. RESULTS With a median follow-up of 73 months, final grade 3-4 immune-related adverse events are 12 % (cohort 1), 12 % (cohort 2), 38 % (cohort 3) and 63 % (cohort 4). Estimated 5-year PFS and OS rates were 25 % and 50 % for pembrolizumab monotherapy (cohort-1) and 46 % and 71 % for pembrolizumab + intermittent TT (cohorts 2-4). Estimated 5-year PFS and OS were 63 % and 63 % (cohort 2), 38 % and 75 % (cohort 3), and 38 % and 75 % (cohort 4), respectively. The subsequent therapies were balanced between cohorts. Patients treated with short-term/intermittent schemes achieved durable responses upon subsequent TT again. CONCLUSION This survival update from the IMPemBra trial demonstrates that combination of short-term TT and checkpoint inhibition can induce long-lasting responses, warranting further analyses in larger cohorts, and in a randomized design.
Collapse
Affiliation(s)
- L L Hoeijmakers
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - E A Rozeman
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - M Lopez-Yurda
- Department of Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | | | - B C Heeres
- Department of Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - B A van de Wiel
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - C Flohil
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - A Sari
- Department of Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - S W T P J Heijmink
- Department of Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - D van den Broek
- Department of Laboratory medicine, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - A Broeks
- Core Facility Molecular Pathology and Biobanking, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | | | - M A Vollebergh
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - S Wilgenhof
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - J V van Thienen
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - J B A G Haanen
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, Leiden University Medical Center, the Netherlands
| | - C U Blank
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, Leiden University Medical Center, the Netherlands; Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany.
| |
Collapse
|
2
|
Pham TTQ, Kuo YC, Chang WL, Weng HJ, Huang YH. Double-sided niche regulation in skin stem cell and cancer: mechanisms and clinical applications. Mol Cancer 2025; 24:147. [PMID: 40399946 PMCID: PMC12093937 DOI: 10.1186/s12943-025-02289-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 03/03/2025] [Indexed: 05/23/2025] Open
Abstract
The niche microenvironment plays a crucial role in regulating the fate of normal skin stem cells (SSCs) and cancer stem cells (CSCs). Therapeutically targeting the CSC niche holds promise as an effective strategy; however, the dual effects of shared SSC niche signaling in CSCs have contributed to the aggressive characteristics of tumors and poor survival rates in skin cancer patients. The lack of a clear underlying mechanism has significantly hindered drug development for effective treatment. This article explores recent advances in understanding how niche factors regulate cell fate determination between skin stem cells and skin CSCs, along with their clinical implications. The dual roles of key components of the adhesive niche, including the dermo-epidermal junction and adherens junction, various cell types-especially immune cells and fibroblasts-as well as major signaling pathways such as Sonic hedgehog (Shh), Wingless-related integration site (Wnt)/β-catenin, YAP (Yes-associated protein)/TAZ (transcriptional coactivator with PDZ-binding motif), and Notch, are highlighted. Additionally, recent advances in clinical trials and drug development targeting these pathways are discussed. Overall, this review provides valuable insights into the complex interactions between skin cancer stem cells and their microenvironment, laying the groundwork for future research and clinical strategies.
Collapse
Affiliation(s)
- Trang Thao Quoc Pham
- International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Yung-Che Kuo
- TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Wei-Ling Chang
- International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
| | - Hao-Jui Weng
- International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
- Department of Dermatology, Taipei Medical University-Shuang Ho Hospital, New Taipei City, 23561, Taiwan.
- Department of Dermatology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
| | - Yen-Hua Huang
- International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
- TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
- Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan.
| |
Collapse
|
3
|
Nahm WJ, Sakunchotpanit G, Nambudiri VE. Abscopal Effects and Immunomodulation in Skin Cancer Therapy. Am J Clin Dermatol 2025:10.1007/s40257-025-00943-x. [PMID: 40180765 DOI: 10.1007/s40257-025-00943-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2025] [Indexed: 04/05/2025]
Abstract
Radiation therapy (RT) is a crucial modality in cancer treatment, functioning through direct DNA damage and immune stimulation. However, RT's effects extend beyond targeted cells, influencing neighboring cells through the bystander effect (ByE) and distant sites via the abscopal effect (AbE). The AbE, first described by Mole in 1953, encompasses biological reactions at sites distant from the irradiation field. While RT can enhance antitumor immune responses, it may also contribute to an immunosuppressive microenvironment. To address this limitation, combining RT with immune checkpoint inhibitors (ICIs) has gained renewed interest, aiming to amplify antitumor immune responses. Evidence of AbEs has been observed in various metastatic or advanced cutaneous cancers, including melanoma, basal cell carcinoma, cutaneous lymphoma, Merkel cell carcinoma, and cutaneous squamous cell carcinoma. Clinical studies suggest combining RT with ICIs targeting CTLA-4 and PD-1/PD-L1 may enhance AbE incidence in these cancers. This review primarily explores the current understanding of AbEs in skin cancers, briefly acknowledging the ByE focusing on combining RT with immunomodulation. It focuses on proposed mechanisms, preclinical and clinical evidence, challenges in clinical translation, and future directions for harnessing AbEs in managing advanced skin malignancies. Alternative modalities for inducing abscopal-like responses are also explored. While promising, challenges remain in consistently reproducing AbEs in clinical practice, necessitating further research to optimize treatment combinations, timing, and patient selection.
Collapse
Affiliation(s)
- William J Nahm
- New York University Grossman School of Medicine, New York, NY, USA.
- Department of Dermatology, Brigham and Women's Hospital, 117 Western Avenue, Boston, MA, 02163, USA.
| | - Goranit Sakunchotpanit
- Department of Dermatology, Brigham and Women's Hospital, 117 Western Avenue, Boston, MA, 02163, USA
- Tufts University School of Medicine, Boston, MA, USA
| | - Vinod E Nambudiri
- Department of Dermatology, Brigham and Women's Hospital, 117 Western Avenue, Boston, MA, 02163, USA
- Harvard Medical School, Boston, MA, USA
| |
Collapse
|
4
|
Wang X, Liao Y, Liu D, Zheng J, Shi M. Presetting CAR-T cells during ex vivo biomanufacturing. Mol Ther 2025; 33:1380-1406. [PMID: 39988874 PMCID: PMC11997485 DOI: 10.1016/j.ymthe.2025.02.031] [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: 07/08/2024] [Revised: 11/21/2024] [Accepted: 02/19/2025] [Indexed: 02/25/2025] Open
Abstract
Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. However, it continues to encounter significant obstacles, including treatment relapse and limited efficacy in solid tumors. While effector T cells exhibit robust cytotoxicity, central memory T cells and stem cell-like T cells are essential for in vivo expansion, long-term survival, and persistence. Strategies such as genetic engineering to enhance CAR-T cell efficacy and durability are often accompanied by increased safety risks, which not only raise regulatory approval thresholds but also escalate CAR-T production costs. In contrast, optimizing ex vivo manufacturing conditions represents a more straightforward and practical approach, offering the potential for rapid application to commercially approved CAR-T products and enhancement of their clinical outcomes. This review examines several factors that have been shown to improve T cell memory phenotype and in vivo cytotoxic activity, including cytokines, electrolytes, signaling pathway inhibitors, metabolic modulators, and epigenetic agents. The insights provided will guide the optimization of CAR-T cell industrial production. Furthermore, considerations for selecting appropriate conditions are discussed, balancing effectiveness, cost-efficiency, safety, and regulatory compliance while addressing current challenges in the field.
Collapse
Affiliation(s)
- Xu Wang
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China
| | - Ying Liao
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China
| | - Dan Liu
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.
| | - Junnian Zheng
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.
| | - Ming Shi
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.
| |
Collapse
|
5
|
Moura LIF, Malfanti A, Matos AI, Peres C, Armiñán A, Duro‐Castaño A, Conejos‐Sánchez I, Medel M, Đorđević S, Carrascosa P, Carreira B, Acúrcio RC, Xavier‐Ferreira H, Hernández‐Barranco A, Castellano E, Roselló E, Machado JC, Peinado H, Vicent MJ, Florindo HF. Off-The-Shelf Multivalent Nanoconjugate Cancer Vaccine Rescues Host Immune Response against Melanoma. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2417348. [PMID: 39937158 PMCID: PMC12016742 DOI: 10.1002/adma.202417348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 01/18/2025] [Indexed: 02/13/2025]
Abstract
Tumor-associated antigen-based cancer vaccines suffer from limited clinical success compared to alternative immunotherapies in melanoma, an aggressive skin cancer with an immunosuppressive tumor microenvironment. The anti-tumor potential of a multivalent nanoconjugate cancer vaccine platform - a cross-linked star-shaped polyglutamate carrier (StCl) with marked lymphotropic character conjugated with melanoma-associated peptide antigens is evaluated through redox-responsive linkers. The co-delivery of melanoma-associated peptide antigens by the nanoconjugate platform induced significant effector immune responses in a mouse melanoma model. The nanoconjugate platform synergized with a PD-1 inhibitor to revert the immunosuppressive melanoma tumor microenvironment by improving cytotoxic T-cell infiltration, which prompted a superior anti-tumor effect with prolonged overall survival without acute organ toxicity. The antigen-specific anti-tumor immune response induced by the nanoconjugate platform is also validated in a melanoma patient-derived xenograft mouse model. A promising, versatile StCl-based platform is reported for generating off-the-shelf multivalent nanoconjugate cancer vaccines for the safe and efficient immunotherapeutic treatment of melanoma.
Collapse
Affiliation(s)
- Liane IF Moura
- Research Institute for Medicines (iMed.ULisboa)Faculty of PharmacyUniversidade de LisboaAv. Prof. Gama PintoLisboa1649‐003Portugal
| | - Alessio Malfanti
- Polymer Therapeutics LabPrince Felipe Research Center (CIPF)C/Eduardo Primo Yúfera 3Valencia46012Spain
- Present address:
Department of Pharmaceutical and Pharmacological SciencesUniversity of PadovaVia F. Marzolo 5Padova35131Italy
| | - Ana I Matos
- Research Institute for Medicines (iMed.ULisboa)Faculty of PharmacyUniversidade de LisboaAv. Prof. Gama PintoLisboa1649‐003Portugal
| | - Carina Peres
- Research Institute for Medicines (iMed.ULisboa)Faculty of PharmacyUniversidade de LisboaAv. Prof. Gama PintoLisboa1649‐003Portugal
| | - Ana Armiñán
- Polymer Therapeutics LabPrince Felipe Research Center (CIPF)C/Eduardo Primo Yúfera 3Valencia46012Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC)Health Institute Carlos III (IISCIII)Av. Monforte de Lemos, 3‐5. Pabellón 11. Planta 0Madrid28029Spain
| | - Aroa Duro‐Castaño
- Polymer Therapeutics LabPrince Felipe Research Center (CIPF)C/Eduardo Primo Yúfera 3Valencia46012Spain
- Present address:
CurapathAv. Benjamin Franklin 19Paterna46980Spain
| | - Inmaculada Conejos‐Sánchez
- Polymer Therapeutics LabPrince Felipe Research Center (CIPF)C/Eduardo Primo Yúfera 3Valencia46012Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC)Health Institute Carlos III (IISCIII)Av. Monforte de Lemos, 3‐5. Pabellón 11. Planta 0Madrid28029Spain
| | - María Medel
- Polymer Therapeutics LabPrince Felipe Research Center (CIPF)C/Eduardo Primo Yúfera 3Valencia46012Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC)Health Institute Carlos III (IISCIII)Av. Monforte de Lemos, 3‐5. Pabellón 11. Planta 0Madrid28029Spain
| | - Snežana Đorđević
- Polymer Therapeutics LabPrince Felipe Research Center (CIPF)C/Eduardo Primo Yúfera 3Valencia46012Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC)Health Institute Carlos III (IISCIII)Av. Monforte de Lemos, 3‐5. Pabellón 11. Planta 0Madrid28029Spain
- Present address:
Tosoh Bioscience GmbHIm Leuschnerpark 4, Griesheim64347HesseGermany
| | - Paula Carrascosa
- Polymer Therapeutics LabPrince Felipe Research Center (CIPF)C/Eduardo Primo Yúfera 3Valencia46012Spain
| | - Bárbara Carreira
- Research Institute for Medicines (iMed.ULisboa)Faculty of PharmacyUniversidade de LisboaAv. Prof. Gama PintoLisboa1649‐003Portugal
| | - Rita C Acúrcio
- Research Institute for Medicines (iMed.ULisboa)Faculty of PharmacyUniversidade de LisboaAv. Prof. Gama PintoLisboa1649‐003Portugal
| | - Helena Xavier‐Ferreira
- i3S – Instituto de Investigação e Inovação em SaúdeMedical Faculty of PortoUniversidade do PortoRua Alfredo Allen, 208Porto4200‐135Portugal
| | - Alberto Hernández‐Barranco
- Microenvironment and Metastasis LaboratoryDepartment of Molecular OncologySpanish National Cancer Research Center (CNIO)C. de Melchor Fernández Almagro, 3Madrid28029Spain
| | - Elena Castellano
- Microenvironment and Metastasis LaboratoryDepartment of Molecular OncologySpanish National Cancer Research Center (CNIO)C. de Melchor Fernández Almagro, 3Madrid28029Spain
| | - Esther Roselló
- Department of PathologyHospital General Universitario de ValenciaAv. de les Tres Creus, 2, L'OliveretaValencia46014Spain
| | - José C. Machado
- i3S – Instituto de Investigação e Inovação em SaúdeMedical Faculty of PortoUniversidade do PortoRua Alfredo Allen, 208Porto4200‐135Portugal
| | - Héctor Peinado
- Microenvironment and Metastasis LaboratoryDepartment of Molecular OncologySpanish National Cancer Research Center (CNIO)C. de Melchor Fernández Almagro, 3Madrid28029Spain
| | - María J. Vicent
- Polymer Therapeutics LabPrince Felipe Research Center (CIPF)C/Eduardo Primo Yúfera 3Valencia46012Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC)Health Institute Carlos III (IISCIII)Av. Monforte de Lemos, 3‐5. Pabellón 11. Planta 0Madrid28029Spain
| | - Helena F. Florindo
- Research Institute for Medicines (iMed.ULisboa)Faculty of PharmacyUniversidade de LisboaAv. Prof. Gama PintoLisboa1649‐003Portugal
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC)Health Institute Carlos III (IISCIII)Av. Monforte de Lemos, 3‐5. Pabellón 11. Planta 0Madrid28029Spain
| |
Collapse
|
6
|
Kumagai S, Momoi Y, Nishikawa H. Immunogenomic cancer evolution: A framework to understand cancer immunosuppression. Sci Immunol 2025; 10:eabo5570. [PMID: 40153489 DOI: 10.1126/sciimmunol.abo5570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 06/26/2024] [Accepted: 03/05/2025] [Indexed: 03/30/2025]
Abstract
The process of tumor development involves tumor cells eluding detection and suppression of immune responses, which can cause decreased tumor cell antigenicity, expression of immunosuppressive molecules, and immunosuppressive cell recruitment to the tumor microenvironment (TME). Immunologically and genomically integrated analysis (immunogenomic analysis) of patient specimens has revealed that oncogenic aberrant signaling is involved in both carcinogenesis and immune evasion. In noninflamed cancers such as epidermal growth factor receptor (EGFR)-mutated lung cancers, genetic abnormalities in cancer cells contribute to the formation of an immunosuppressive TME by recruiting immunosuppressive cells, which cannot be fully explained by the cancer immunoediting hypothesis. This review summarizes the latest findings regarding the links between cancer genetic abnormalities and immunosuppression causing clinical resistance to immunotherapy. We propose the concepts of immunogenomic cancer evolution, in which cancer cell genomic evolution shapes the immunosuppressive TME, and immunogenomic precision medicine, in which cancer immunotherapy can be combined with molecularly targeted reagents that modulate the immunosuppressive TME.
Collapse
Affiliation(s)
- Shogo Kumagai
- Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo 104-0045, Japan
- Division of Cancer Immunology, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chiba 277-8577, Japan
- Division of Cellular Signaling, Research Institute, National Cancer Center, Tokyo 104-0045, Japan
| | - Yusaku Momoi
- Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo 104-0045, Japan
- Department of Tumor Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo 104-0045, Japan
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
- Division of Cancer Immune Multicellular System Regulation, Center for Cancer Immunotherapy and Immunology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
- Kindai University Faculty of Medicine, Osaka-sayama 589-8511, Japan
| |
Collapse
|
7
|
Tak E, An HI, Lee AS, Han K, Choi J, Kim HD, Hong YS, Kim SY, Choi EK, Kim JE, Kim TW. Antitumor effects of immunotherapy combined with BRAF and MEK inhibitors in BRAF V600E metastatic colorectal cancer. Cancer Immunol Immunother 2025; 74:154. [PMID: 40105971 PMCID: PMC11923341 DOI: 10.1007/s00262-025-04005-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 02/26/2025] [Indexed: 03/22/2025]
Abstract
BRAF-mutated colorectal cancer correlates with poor prognosis and limited response to standard treatments. Combining immune checkpoint inhibitors with BRAF/MEK inhibitors shows promise against BRAF-mutant melanoma in both preclinical and clinical trials. Therefore, we hypothesized that the treatment would be effective against BRAF-mutant colorectal cancer. In this study, we assessed the efficacy of combining immune checkpoint inhibitors with BRAF and/or MEK inhibitors in BRAF-mutant colorectal cancers. We treated BRAF V600E colorectal cancer cells HT-29 and SNU-1235 with encorafenib (BRAF inhibitor) and binimetinib (MEK inhibitor) and assessed the degrees of MAPK inhibition, JAK/STAT inhibition, cell viability, apoptosis, and the expression of antigen presenting machinery. We also inoculated HT-29 cells into mice and treated them with an immune checkpoint inhibitor (durvalumab), encorafenib, and binimetinib for 4 weeks. We found that treatment with BRAF inhibitor, MEK inhibitor, or their combination led to significant tumor growth reduction, along with the MAPK and JAK/STAT pathway inhibition, antigen presenting machinery induction, and cytotoxic T cell activation. Our study demonstrates the potential effectiveness of combining immune checkpoint inhibitors with BRAF or MEK inhibitors for BRAF-mutated colorectal cancers.
Collapse
Affiliation(s)
- Eunyoung Tak
- Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hye-In An
- Department of Convergence Medicine, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Amy Sinyoung Lee
- Department of Convergence Medicine, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyuyoung Han
- Department of Convergence Medicine, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jiwan Choi
- Department of Convergence Medicine, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyung-Don Kim
- Department of Oncology, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Yong Sang Hong
- Department of Oncology, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Sun Young Kim
- Department of Oncology, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Eun Kyung Choi
- Department of Radiation Oncology, Asan Preclinical Evaluation Center for Cancer TherapeutiX, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeong Eun Kim
- Department of Oncology, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
| | - Tae Won Kim
- Department of Oncology, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
- Asan Preclinical Evaluation Center for Cancer TherapeutiX, Asan Medical Center, Seoul, 05505, Republic of Korea
| |
Collapse
|
8
|
Lubrano S, Cervantes-Villagrana RD, Faraji F, Ramirez S, Sato K, Adame-Garcia SR, Officer A, Arang N, Rigiracciolo DC, Anguiano Quiroz PY, Martini C, Wang Y, Ferguson FM, Bacchiocchi A, Halaban R, Coma S, Holmen SL, Pachter JA, Aplin AE, Gutkind JS. FAK inhibition combined with the RAF-MEK clamp avutometinib overcomes resistance to targeted and immune therapies in BRAF V600E melanoma. Cancer Cell 2025; 43:428-445.e6. [PMID: 40020669 PMCID: PMC11903146 DOI: 10.1016/j.ccell.2025.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 10/17/2024] [Accepted: 02/04/2025] [Indexed: 03/03/2025]
Abstract
Widespread BRAF mutations result in persistent RAS-RAF-MEK-ERK (MAPK) signaling in melanoma. BRAF (BRAFi) and MEK (MEKi) inhibitors are approved for BRAF V600E melanomas, including those progressing on immunotherapy; however, rapid resistance to these agents highlights the need for novel strategies. Here, transcriptome analysis of BRAF V600E melanomas from patients resistant to BRAFi and MEKi shows activation of focal adhesion signaling. Consistently, BRAFi, MEKi, and the RAF-MEK clamp avutometinib activate focal adhesion kinase (FAK) in melanoma cells. Mechanistically, inhibition of an MAPK-RhoE (RND3) feedback loop results in the adaptive activation of RhoA-FAK-AKT. In turn, FAK inhibitors (FAKi) exert potent pro-apoptotic activity when combined with MAPK pathway inhibition. FAKi plus avutometinib overcomes resistance in multiple models derived from BRAFi plus MEKi-resistant melanoma patients and immunotherapy-resistant syngeneic mouse models. These findings provide a rationale for the development of avutometinib in combination with FAKi for patients with BRAF V600E melanoma progressing on BRAFi plus MEKi or immunotherapy.
Collapse
Affiliation(s)
- Simone Lubrano
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
| | - Rodolfo Daniel Cervantes-Villagrana
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Farhoud Faraji
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Otolaryngology - Head and Neck Surgery, UC San Diego Health, La Jolla, CA 92037, USA
| | - Sydney Ramirez
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Kuniaki Sato
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Sendi R Adame-Garcia
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Adam Officer
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Nadia Arang
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA
| | | | - Paola Y Anguiano Quiroz
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; John Muir College, University of California, San Diego, La Jolla, CA 92093, USA
| | - Claudia Martini
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
| | - YiYu Wang
- Department of Chemistry and Biochemistry and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Fleur M Ferguson
- Department of Chemistry and Biochemistry and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | | | - Ruth Halaban
- Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA
| | | | - Sheri L Holmen
- Department of Surgery, University of Utah Health Sciences Center, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | | | - Andrew E Aplin
- Department of Pharmacology, Physiology and Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, US
| | - J Silvio Gutkind
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
| |
Collapse
|
9
|
Viel S, Vivier E, Walzer T, Marçais A. Targeting metabolic dysfunction of CD8 T cells and natural killer cells in cancer. Nat Rev Drug Discov 2025; 24:190-208. [PMID: 39668206 DOI: 10.1038/s41573-024-01098-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2024] [Indexed: 12/14/2024]
Abstract
The importance of metabolic pathways in regulating immune responses is now well established, and a mapping of the bioenergetic metabolism of different immune cell types is under way. CD8 T cells and natural killer (NK) cells contribute to cancer immunosurveillance through their cytotoxic functions and secretion of cytokines and chemokines, complementing each other in target recognition mechanisms. Several immunotherapies leverage these cell types by either stimulating their activity or redirecting their specificity against tumour cells. However, the anticancer activity of CD8 T cells and NK cells is rapidly diminished in the tumour microenvironment, closely linked to a decline in their metabolic capacities. Various strategies have been developed to restore cancer immunosurveillance, including targeting bioenergetic metabolism or genetic engineering. This Review provides an overview of metabolic dysfunction in CD8 T cells and NK cells within the tumour microenvironment, highlighting current therapies aiming to overcome these issues.
Collapse
Affiliation(s)
- Sébastien Viel
- Plateforme de Biothérapie et de Production de Médicaments de Thérapie Innovante, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Eric Vivier
- Innate Pharma Research Laboratories, Innate Pharma, Marseille, France
- Aix Marseille University, CNRS, INSERM, CIML, Marseille, France
- APHM, Hôpital de la Timone, Marseille, France
- Paris Saclay Cancer Cluster, Villejuif, France
- Université Paris-Saclay, Gustave Roussy, Inserm, Prédicteurs moléculaires et nouvelles cibles en oncologie, Villejuif, France
| | - Thierry Walzer
- CIRI, Centre International de Recherche en Infectiologie, (Team Lyacts), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS UMR5308 ENS de Lyon, Lyon, France
| | - Antoine Marçais
- CIRI, Centre International de Recherche en Infectiologie, (Team Lyacts), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS UMR5308 ENS de Lyon, Lyon, France.
| |
Collapse
|
10
|
Lu Y, Huang Y, Zhu C, Li Z, Zhang B, Sheng H, Li H, Liu X, Xu Z, Wen Y, Zhang J, Zhang L. Cancer brain metastasis: molecular mechanisms and therapeutic strategies. MOLECULAR BIOMEDICINE 2025; 6:12. [PMID: 39998776 PMCID: PMC11861501 DOI: 10.1186/s43556-025-00251-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 01/06/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Brain metastases (BMs) are the most common intracranial tumors in adults and the major cause of cancer-related morbidity and mortality. The occurrence of BMs varies according to the type of primary tumors with most frequence in lung cancer, melanoma and breast cancer. Among of them, lung cancer has been reported to have a higher risk of BMs than other types of cancers with 40 ~ 50% of such patients will develop BMs during the course of disease. BMs lead to many neurological complications and result in a poor quality of life and short life span. Although the treatment strategies were improved for brain tumors in the past decades, the prognosis of BMs patients is grim. Poorly understanding of the molecular and cellular characteristics of BMs and the complicated interaction with brain microenvironment are the major reasons for the dismal prognosis of BM patients. Recent studies have enhanced understanding of the mechanisms of BMs. The newly identified potential therapeutic targets and the advanced therapeutic strategies have brought light for a better cure of BMs. In this review, we summarized the mechanisms of BMs during the metastatic course, the molecular and cellular landscapes of BMs, and the advances of novel drug delivery systems for overcoming the obstruction of blood-brain barrier (BBB). We further discussed the challenges of the emerging therapeutic strategies, such as synergistic approach of combining targeted therapy with immunotherapy, which will provide vital clues for realizing the precise and personalized medicine for BM patients in the future.
Collapse
Affiliation(s)
- Yu Lu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yunhang Huang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chenyan Zhu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhidan Li
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
| | - Bin Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hui Sheng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Haotai Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xixi Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhongwen Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yi Wen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Zhang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Liguo Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
| |
Collapse
|
11
|
Alsaafeen BH, Ali BR, Elkord E. Resistance mechanisms to immune checkpoint inhibitors: updated insights. Mol Cancer 2025; 24:20. [PMID: 39815294 PMCID: PMC11734352 DOI: 10.1186/s12943-024-02212-7] [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: 09/06/2024] [Accepted: 12/25/2024] [Indexed: 01/18/2025] Open
Abstract
The last decade has witnessed unprecedented succusses with the use of immune checkpoint inhibitors in treating cancer. Nevertheless, the proportion of patients who respond favorably to the treatment remained rather modest, partially due to treatment resistance. This has fueled a wave of research into potential mechanisms of resistance to immune checkpoint inhibitors which can be classified into primary resistance or acquired resistance after an initial response. In the current review, we summarize what is known so far about the mechanisms of resistance in terms of being tumor-intrinsic or tumor-extrinsic taking into account the multimodal crosstalk between the tumor, immune system compartment and other host-related factors.
Collapse
Affiliation(s)
- Besan H Alsaafeen
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box: 15551, Al-Ain, United Arab Emirates
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Bassam R Ali
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box: 15551, Al-Ain, United Arab Emirates.
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain, United Arab Emirates.
| | - Eyad Elkord
- Department of Biosciences and Bioinformatics & Suzhou Municipal Key Lab of Biomedical Sciences and Translational Immunology, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China.
- College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates.
- Biomedical Research Center, School of Science, Engineering and Environment, University of Salford, Manchester, UK.
| |
Collapse
|
12
|
Gu Y, Yang R, Zhang Y, Guo M, Takehiro K, Zhan M, Yang L, Wang H. Molecular mechanisms and therapeutic strategies in overcoming chemotherapy resistance in cancer. MOLECULAR BIOMEDICINE 2025; 6:2. [PMID: 39757310 PMCID: PMC11700966 DOI: 10.1186/s43556-024-00239-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 11/26/2024] [Accepted: 12/02/2024] [Indexed: 01/07/2025] Open
Abstract
Cancer remains a leading cause of mortality globally and a major health burden, with chemotherapy often serving as the primary therapeutic option for patients with advanced-stage disease, partially compensating for the limitations of non-curative treatments. However, the emergence of chemotherapy resistance significantly limits its efficacy, posing a major clinical challenge. Moreover, heterogeneity of resistance mechanisms across cancer types complicates the development of universally effective diagnostic and therapeutic approaches. Understanding the molecular mechanisms of chemoresistance and identifying strategies to overcome it are current research focal points. This review provides a comprehensive analysis of the key molecular mechanisms underlying chemotherapy resistance, including drug efflux, enhanced DNA damage repair (DDR), apoptosis evasion, epigenetic modifications, altered intracellular drug metabolism, and the role of cancer stem cells (CSCs). We also examine specific causes of resistance in major cancer types and highlight various molecular targets involved in resistance. Finally, we discuss current strategies aiming at overcoming chemotherapy resistance, such as combination therapies, targeted treatments, and novel drug delivery systems, while proposing future directions for research in this evolving field. By addressing these molecular barriers, this review lays a foundation for the development of more effective cancer therapies aimed at mitigating chemotherapy resistance.
Collapse
Affiliation(s)
- Yixiang Gu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
- Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Ruifeng Yang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Yang Zhang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
- Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Miaomiao Guo
- The Core Laboratory in Medical Center of Clinical Research, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China
| | | | - Ming Zhan
- The Core Laboratory in Medical Center of Clinical Research, State Key Laboratory of Medical Genomics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China
- Department of Systems Biology, Beckman Research Institute, City of Hope, Monrovia, CA, 91016, USA
| | - Linhua Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
- Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
| | - Hui Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
- Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
| |
Collapse
|
13
|
Al-Humaidi JY, Gomha SM, Albedair LA, Zaki MEA, Mukhrish YE, Mohamed MA. Green Synthesis and Anticancer Activity of New Bis-imidazole-thiazole Hybrids Targeting Hepatocellular Carcinoma. Curr Org Synth 2025; 22:371-382. [PMID: 40259590 DOI: 10.2174/0115701794310949240607113838] [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: 03/12/2024] [Revised: 05/01/2024] [Accepted: 05/13/2024] [Indexed: 04/23/2025]
Abstract
BACKGROUND Given the inadequacies of current chemotherapy, there is a need for more effective anticancer agents. Imidazole and thiazole compounds have demonstrated significant biological activity, making them promising candidates. AIMS AND OBJECTIVES This study investigates the anticancer potential of imidazole and thiazole derivatives, focusing on liver cancer. The aim is to synthesize bis-imidazole-thiazole hybrids and evaluate their efficacy as anticancer agents against hepatocellular carcinoma. METHODS The hybrids were synthesized using (2,2'-((1,4-phenylenebis(2-mercapto-4-methyl- 1H-imidazole-1,5-diyl))bis(ethan-1-yl-1-ylidene))bis(hydrazine-1-carbothioamide), hydrazonoyl halides, and α-halo ketones, catalyzed by DABCO. This method is designed to be fast, yield high amounts of product, and be environmentally friendly. Structural confirmation was provided by FT IR, NMR, and MS spectroscopy. RESULTS The synthesized hybrids were tested in vitro against HepG-2 and WI-38 cell lines. Compounds 16b, 14a, 16a, and 7b showed significant inhibitory activity, with IC50 values indicating strong inhibition comparable to or better than the standard drug Sorafenib. CONCLUSION The bis-imidazole-thiazole hybrids exhibit potent anticancer properties, particularly against hepatocellular carcinoma, making them potential candidates for future cancer therapies. Their selectivity and safety were further demonstrated by their effects on normal WI-38 human fibroblasts.
Collapse
Affiliation(s)
- Jehan Y Al-Humaidi
- Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, P.O. BOX 84428, Riyadh 11671, Saudi Arabia
| | - Sobhi M Gomha
- Chemistry Department, Faculty of Science, Islamic University of Madinah, Madinah, 42351, Saudi Arabia
- Department of Chemistry, Faculty of Science, Cairo University, Cairo, 12613, Egypt
| | - Lamia A Albedair
- Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, P.O. BOX 84428, Riyadh 11671, Saudi Arabia
| | - Magdi E A Zaki
- Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, 11623, Saudi Arabia
| | - Yousef E Mukhrish
- Department of Physical Sciences, Chemistry Division, College of Science, Jazan University, P.O. Box. 114, Jazan, 45142, Kingdom of Saudi Arabia
| | - Mahmoud A Mohamed
- Technology of Textile Department, Faculty of Technology and Education, Beni-Suef University, Beni-Suef, Egypt
- Chemistry Department, Faculty of Science and Humanity study-Afif, Shaqra University, Shaqra, Saudi Arabia
| |
Collapse
|
14
|
Pham TD, Metropulos AE, Mubin N, Becker JH, Shah D, Spaulding C, Shields MA, Bentrem DJ, Munshi HG. Trametinib Potentiates Anti-PD-1 Efficacy in Tumors Established from Chemotherapy-Primed Pancreatic Cancer Cells. Mol Cancer Ther 2024; 23:1854-1865. [PMID: 39162011 PMCID: PMC11614707 DOI: 10.1158/1535-7163.mct-23-0833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 05/07/2024] [Accepted: 08/08/2024] [Indexed: 08/21/2024]
Abstract
Despite advances in immune checkpoint inhibitors, chemotherapy remains the standard therapy for patients with pancreatic ductal adenocarcinoma (PDAC). As the combinations of chemotherapy, including the FOLFIRINOX [5-fluorouracil, F; irinotecan, I; and oxaliplatin, O (FIO)] regimen, and immune checkpoint inhibitors have failed to demonstrate clinical benefit in patients with metastatic PDAC tumors, there is increasing interest in identifying therapeutic approaches to potentiate ICI efficacy in patients with PDAC. In this study, we report that neoadjuvant FOLFIRINOX-treated human PDAC tumors exhibit increased MEK/ERK activation. We also show elevated MEK/ERK signaling in ex vivo PDAC slice cultures and cell lines treated with a combination of FIO. In addition, we find that the KPC-FIO cells, established from repeated treatment of mouse PDAC cell lines with six to eight cycles of FIO, display enhanced ERK phosphorylation and demonstrate increased sensitivity to MEK inhibition in vitro and in vivo. Significantly, the KPC-FIO cells develop tumors with a proinflammatory immune profile similar to human PDAC tumors after neoadjuvant FOLFIRINOX treatment. Furthermore, we found that the MEK inhibitor trametinib enables additional infiltration of highly functional CD8+ T cells into the KPC-FIO tumors and potentiates the efficacy of anti-PD-1 antibody in syngeneic mouse models. Our findings provide a rationale for combining trametinib and anti-PD-1 antibodies in patients with PDAC after neoadjuvant or short-term FOLFIRINOX treatment to achieve effective antitumor responses.
Collapse
Affiliation(s)
- Thao D. Pham
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
| | - Anastasia E. Metropulos
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Nida Mubin
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Jeffrey H. Becker
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Dhavan Shah
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Christina Spaulding
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Mario A. Shields
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
| | - David J. Bentrem
- The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Hidayatullah G. Munshi
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
- Jesse Brown VA Medical Center, Chicago, IL, USA
| |
Collapse
|
15
|
Liu M, Liu Q, Hu K, Dong Y, Sun X, Zou Z, Ji D, Liu T, Yu Y. Colorectal cancer with BRAF V600E mutation: Trends in immune checkpoint inhibitor treatment. Crit Rev Oncol Hematol 2024; 204:104497. [PMID: 39245296 DOI: 10.1016/j.critrevonc.2024.104497] [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: 04/02/2024] [Revised: 08/29/2024] [Accepted: 08/31/2024] [Indexed: 09/10/2024] Open
Abstract
Colorectal cancer (CRC) with BRAF V600E mutation presents a formidable scientific and clinical challenge due to its aggressive nature and poor response to standard therapeutic approaches. BRAF V600E mutation-induced conspicuous activation of the MAPK pathway contributes to the relentless tumor progression. Nevertheless, the efficacy of multi-targeted MAPK pathway inhibition remains suboptimal in clinical practice. Patients with high microsatellite instability (MSI-H) have shown favorable results with immune checkpoint inhibitors (ICIs). The combination of the MAPK pathway inhibition with ICIs has recently emerged as a promising regimen to improve clinical outcomes in the microsatellite stable (MSS) subgroup of BRAF V600E-mutant metastatic CRC patients. In this review, we elucidate the unique tumor biology of BRAF V600E-mutant CRC, with a particular focus on the immune features underlying the rationale for ICI treatments in the MSI-H and MSS subpopulations, then highlight the trends in clinical trials of the ICI therapy for BRAF V600E-mutant metastatic CRC.
Collapse
Affiliation(s)
- Mengling Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qing Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Keshu Hu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yu Dong
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xun Sun
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhiguo Zou
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Dingkun Ji
- Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Yiyi Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| |
Collapse
|
16
|
Ebaid MS, Abdelsattar Ibrahim HA, Kassem AF, Sabt A. Recent studies on protein kinase signaling inhibitors based on thiazoles: review to date. RSC Adv 2024; 14:36989-37018. [PMID: 39569127 PMCID: PMC11575478 DOI: 10.1039/d4ra05601a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 11/10/2024] [Indexed: 11/22/2024] Open
Abstract
Due to the important role of protein kinases in protein phosphorylation within vital cellular processes, their abnormal function, especially in cancer situations, has underscored their importance in therapy. Thiazole structures are versatile frameworks present in numerous bioactive compounds. Thiazole derivatives, as a highly favored structural motif, have garnered considerable interest from both industrial and medicinal researchers and have demonstrated notable success over past decades due to their diverse biological properties, including anticancer, antibacterial, antifungal, anti-HIV, antiulcer, and anti-inflammatory activities. Moreover, several thiazole-based drugs are widely recognized pharmaceuticals on the market. Due to their specific structural features, thiazole derivatives have a high potential for interacting with different protein kinases, leading researchers to investigate a variety of structural changes. This thorough review thoroughly examines the design and biological evaluations of small molecules utilizing thiazole as potential agents that target various kinases for anti-cancer applications. These compounds are categorized into two classes: inhibitors of serine/threonine and tyrosine kinases. The goal is to promote the development and progress of more effective, targeted compounds for cancer treatment by highlighting the potential of thiazole in inhibiting kinases.
Collapse
Affiliation(s)
- Manal S Ebaid
- Department of Chemistry, College of Science, Northern Border University Arar Saudi Arabia
| | | | - Asmaa F Kassem
- Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University Al-Kharj 11942 Saudi Arabia
| | - Ahmed Sabt
- Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Center Dokki Cairo 12622 Egypt
| |
Collapse
|
17
|
Wang Q, Su T, Cheng F, Zhou S, Liu X, Wang M, Xu Y, Tang R, Liao S, Dailey J, Xiao G, Yang C, Wen H, Zheng W, Wen B, Tyc KM, Liu J, Sun D, Wang S, Zhu G. Proteolysis-targeting vaccines (PROTAVs) for robust combination immunotherapy of melanoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.01.616069. [PMID: 39574605 PMCID: PMC11580958 DOI: 10.1101/2024.10.01.616069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2024]
Abstract
Protein/peptide subunit vaccines are promising to promote the tumor therapeutic efficacy of immune checkpoint blockade (ICB). However, current protein/peptide vaccines elicit limited antitumor T cell responses, leading to suboptimal therapeutic efficacy. Here, we present proteolysis-targeting vaccines (PROTAVs) that facilitate antigen proteolytic processing and cross-presentation to potentiate T cell responses for robust ICB combination immunotherapy of melanoma. PROTAVs are modular conjugates of protein/peptide antigens, E3 ligase-binding ligands, and linkers. In antigen-presenting cells (APCs), PROTAVs bind to E3 ligases to rapidly ubiquitinate PROTAV antigens, facilitating antigen proteolytic processing by proteasome, and thereby promoting antigen cross-presentation to T cells and potentiating CD8+ T cell responses. We developed a melanoma PROTAV using a tandem peptide of trivalent melanoma-associated antigens. Co-delivered by lipid nanoparticles (LNPs) with bivalent immunostimulant adjuvants, this PROTAV promotes the quantity and quality of melanoma-specific CD8+ T cells in mice. Further, combining PROTAV and ICB ameliorates the immunosuppressive melanoma microenvironment. As a result, PROTAV and ICB combination enhances melanoma complete regression rates and eradicated 100% large Braf V600E melanoma without recurrence in syngeneic mice. PROTAVs hold the potential for robust tumor combination immunotherapy.
Collapse
Affiliation(s)
- Qiyan Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ting Su
- Department of Pharmaceutics and Center for Pharmaceutical Engineering, College of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, China
| | - Furong Cheng
- Department of Pharmaceutics and Center for Pharmaceutical Engineering, College of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Shurong Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Xiang Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Mi Wang
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - You Xu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ri Tang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shimiao Liao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jordan Dailey
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Guolan Xiao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Chunpeng Yang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Hanning Wen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Weijia Zheng
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Bo Wen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Katarzyna M Tyc
- Department of Biostatistics, School of Public Health; Bioinformatics Shared Resource, Massey Comprehensive Cancer Center; Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Jinze Liu
- Department of Biostatistics, School of Public Health; Bioinformatics Shared Resource, Massey Comprehensive Cancer Center; Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Duxin Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shaomeng Wang
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Guizhi Zhu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
- Bioinnovations in Brain Cancer, Biointerfaces Institute; Center for RNA Biomedicine. University of Michigan, Ann Arbor, MI 48109, USA
| |
Collapse
|
18
|
Jalil A, Donate MM, Mattei J. Exploring resistance to immune checkpoint inhibitors and targeted therapies in melanoma. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:42. [PMID: 39534873 PMCID: PMC11555183 DOI: 10.20517/cdr.2024.54] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 09/30/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024]
Abstract
Melanoma is the most aggressive form of skin cancer, characterized by a poor prognosis, and its incidence has risen rapidly over the past 30 years. Recent therapies, notably immunotherapy and targeted therapy, have significantly improved the outcome of patients with metastatic melanoma. Previously dismal five-year survival rates of below 5% have shifted to over 50% of patients surviving the five-year mark, marking a significant shift in the landscape of melanoma treatment and survival. Unfortunately, about 50% of patients either do not respond to therapy or experience early or late relapses following an initial response. The underlying mechanisms for primary and secondary resistance to targeted therapies or immunotherapy and relapse patterns remain not fully identified. However, several molecular pathways and genetic factors have been associated with melanoma resistance to these treatments. Understanding these mechanisms paves the way for creating novel treatments that can address resistance and ultimately enhance patient outcomes in melanoma. This review explores the mechanisms behind immunotherapy and targeted therapy resistance in melanoma patients. Additionally, it describes the treatment strategies to overcome resistance, which have improved patients' outcomes in clinical trials and practice.
Collapse
Affiliation(s)
- Anum Jalil
- Department of Medicine, UT Health Science Center San Antonio, San Antonio, TA 78229, USA
| | - Melissa M Donate
- Long School of Medicine, UT Health Science Center San Antonio, San Antonio, TA 78229, USA
| | - Jane Mattei
- Department of Hematology Oncology, UT Health Science Center San Antonio, San Antonio, TA 78229, USA
| |
Collapse
|
19
|
Dong L, Choi H, Budhu S, Schulze I, Verma S, Mangarin LM, Estrada Nevarro V, Mehanna N, Khan JF, Venkatesh D, Thach D, Rosen N, Wolchok JD, Merghoub T. Intermittent MEK Inhibition with GITR Costimulation Rescues T-cell Function for Increased Efficacy with CTLA-4 Blockade in Solid Tumor Models. Cancer Immunol Res 2024; 12:1392-1408. [PMID: 38885362 DOI: 10.1158/2326-6066.cir-23-0729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 03/14/2024] [Accepted: 06/14/2024] [Indexed: 06/20/2024]
Abstract
MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway-dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression in tumor cells and improved T cell-mediated killing. Yet, CKI27 also decreased T-cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T-cell receptor signaling. Therefore, we aimed to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. Intermittent administration of CKI27 allowed T cells to partially recover and costimulation via GITR and OX-40 agonist antibodies completely alleviated inhibition of function. In Kras mutant lung and colon tumor mouse models, intermittent CKI27 and anti-GITR significantly decreased tumor growth and prolonged survival when further combined with CTLA-4 immune checkpoint blockade. Moreover, this triple combination increased CD8+ and CD4+ T-cell proliferation, activation, and effector/memory subsets in the tumor-draining lymph nodes and tumors and led to intratumoral regulatory T-cell destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses.
Collapse
Affiliation(s)
- Lauren Dong
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Hyejin Choi
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Sadna Budhu
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Isabell Schulze
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Svena Verma
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Levi M Mangarin
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Valeria Estrada Nevarro
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Nezar Mehanna
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Jonathan F Khan
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Divya Venkatesh
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Daniel Thach
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Neal Rosen
- Department of Medicine, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, New York
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jedd D Wolchok
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Taha Merghoub
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| |
Collapse
|
20
|
Chaudhary HA, Cannon TL, Winer A. Targeting Non-V600 Mutations in BRAF: A Single Institution Retrospective Analysis and Review of the Literature. Drugs R D 2024; 24:395-403. [PMID: 39177935 PMCID: PMC11455815 DOI: 10.1007/s40268-024-00475-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/23/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND AND OBJECTIVE While successful treatment paradigms for BRAF V600 mutations have been developed, 10% of BRAF mutations are not at V600 and lack a standard treatment regimen. This study summarizes the current body of knowledge on the treatment of non-V600 mutations and reports a single institution experience. METHODS We conducted a literature review to summarize relevant preclinical and clinical published data on the response of non-V600 mutations to targeted therapies. We performed a retrospective analysis of INOVA Schar Cancer patients registered in our Molecular Tumor Board database with non-V600 BRAF mutations who were recipients of targeted therapy and assessed their time to next treatment and best response. RESULTS Published preclinical and clinical data have demonstrated limiting results in the response of non-V600 mutated cancers to targeted therapies. Response rates were variable for the major classes of BRAF mutations including class II and class III mutations as well as, BRAF fusions. Data collected from our INOVA cohort offered promising results with one patient achieving partial remission and two patients achieving stable disease. CONCLUSIONS This article reflects the current understanding of targeted therapies in non-V600 mutations. Further large-scale studies separating BRAF mutations based on their mechanism of activation will expand our understanding.
Collapse
Affiliation(s)
- Hirra A Chaudhary
- INOVA, Schar Cancer Institute, Fairfax, VA, USA.
- UVA School of Medicine, INOVA Fairfax Medical Campus, Fairfax, VA, USA.
| | | | | |
Collapse
|
21
|
Nakamura K, Yaguchi T, Murata M, Ota Y, Mikoshiba A, Kiniwa Y, Okuyama R, Kawakami Y. Tumor eradication by triplet therapy with BRAF inhibitor, TLR 7 agonist, and PD-1 antibody for BRAF-mutated melanoma. Cancer Sci 2024; 115:2879-2892. [PMID: 38894534 PMCID: PMC11462939 DOI: 10.1111/cas.16251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 05/14/2024] [Accepted: 06/02/2024] [Indexed: 06/21/2024] Open
Abstract
Programmed death 1 (PD-1)/programmed death-ligand 1 inhibitors are commonly used to treat various cancers, including melanoma. However, their efficacy as monotherapy is limited, and combination immunotherapies are being explored to improve outcomes. In this study, we investigated a combination immunotherapy involving an anti-PD-1 antibody that blocks the major adaptive immune-resistant mechanisms, a BRAF inhibitor that inhibits melanoma cell proliferation, and multiple primary immune-resistant mechanisms, such as cancer cell-derived immunosuppressive cytokines, and a Toll-like receptor 7 agonist that enhances innate immune responses that promote antitumor T-cell induction and functions. Using a xenogeneic nude mouse model implanted with human BRAF-mutated melanoma, a BRAF inhibitor vemurafenib was found to restore T-cell-stimulatory activity in conventional dendritic cells by reducing immunosuppressive cytokines, including interleukin 6, produced by human melanoma. Additionally, intravenous administration of the Toll-like receptor 7 agonist DSR6434 enhanced tumor growth inhibition by vemurafenib through stimulating the plasmacytoid dendritic cells/interferon-α/natural killer cell pathways and augmenting the T-cell-stimulatory activity of conventional dendritic cells. In a syngeneic mouse model implanted with murine BRAF-mutated melanoma, the vemurafenib and DSR6434 combination synergistically augmented the induction of melanoma antigen gp100-specific T cells and inhibited tumor growth. Notably, only triplet therapy with vemurafenib, DSR6434, and the anti-PD-1 antibody resulted in complete regression of SIY antigen-transduced BRAF-mutated melanoma in a CD8 T-cell-dependent manner. These findings indicate that a triple-combination strategy targeting adaptive and primary resistant mechanisms while enhancing innate immune responses that promote tumor-specific T cells may be crucial for effective tumor eradication.
Collapse
Affiliation(s)
- Kenta Nakamura
- Division of Cellular Signaling, Institute for Advanced Medical Research, School of MedicineKeio UniversityTokyoJapan
- Department of DermatologyShinshu University School of MedicineNaganoJapan
| | - Tomonori Yaguchi
- Division of Cellular Signaling, Institute for Advanced Medical Research, School of MedicineKeio UniversityTokyoJapan
- Department of Immunology and Genomic MedicineKyoto University Graduate School of MedicineKyotoJapan
| | | | - Yosuke Ota
- Cancer Research UnitSumitomo Pharma Co. Ltd.OsakaJapan
| | - Asuka Mikoshiba
- Department of DermatologyShinshu University School of MedicineNaganoJapan
| | - Yukiko Kiniwa
- Department of DermatologyShinshu University School of MedicineNaganoJapan
| | - Ryuhei Okuyama
- Department of DermatologyShinshu University School of MedicineNaganoJapan
| | - Yutaka Kawakami
- Division of Cellular Signaling, Institute for Advanced Medical Research, School of MedicineKeio UniversityTokyoJapan
- Department of Immunology, School of MedicineInternational University of Health and WelfareChibaJapan
| |
Collapse
|
22
|
Kennedy LB, Salama AKS. Multiple Options: How to Choose Therapy in Frontline Metastatic Melanoma. Curr Oncol Rep 2024; 26:915-923. [PMID: 38837107 DOI: 10.1007/s11912-024-01547-0] [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] [Accepted: 05/10/2024] [Indexed: 06/06/2024]
Abstract
PURPOSE OF REVIEW Given the rapid development of multiple targeted and immune therapies for patients with advanced melanoma, it can be challenging to select a therapy based on currently available data. This review aims to provide an overview of frontline options for metastatic melanoma, with practical guidance for selecting a treatment regimen. RECENT FINDINGS Recently reported data from randomized trials suggests that the majority of patients with unresectable melanoma should receive a PD-1 checkpoint inhibitor as part of their first line therapy, irrespective of BRAF mutation status. Additional data also suggests that combination immunotherapies result in improved outcomes compared to single agent, albeit at the cost of increased toxicity, though to date no biomarker exists to help guide treatment selection. As the number therapeutic options continue to grow for patients with advanced melanoma, there is likely to be a continued focus on combination strategies. Defining the optimal treatment approach in order to maximize efficacy while minimizing toxicity remains an area of active investigation.
Collapse
Affiliation(s)
- Lucy Boyce Kennedy
- Department of Hematology and Medical Oncology, Cleveland Clinic Foundation, Taussig Cancer Institute, Cleveland, OH, 44195, USA
| | - April K S Salama
- Division of Medical Oncology, Duke University Hospital, Durham, NC, 27710, USA.
| |
Collapse
|
23
|
Salmaninejad A, Layeghi SM, Falakian Z, Golestani S, Kobravi S, Talebi S, Yousefi M. An update to experimental and clinical aspects of tumor-associated macrophages in cancer development: hopes and pitfalls. Clin Exp Med 2024; 24:156. [PMID: 39003350 PMCID: PMC11246281 DOI: 10.1007/s10238-024-01417-w] [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: 06/20/2024] [Accepted: 06/24/2024] [Indexed: 07/15/2024]
Abstract
Tumor-associated macrophages (TAMs) represent one of the most abundant tumor-infiltrating stromal cells, and their normal function in tumor microenvironment (TME) is to suppress tumor cells by producing cytokines which trigger both direct cell cytotoxicity and antibody-mediated immune response. However, upon prolonged exposure to TME, the classical function of these so-called M1-type TAMs can be converted to another type, "M2-type," which are recruited by tumor cells so that they promote tumor growth and metastasis. This is the reason why the accumulation of TAMs in TME is correlated with poor prognosis in cancer patients. Both M1- and M2-types have high degree of plasticity, and M2-type cells can be reprogrammed to M1-type for therapeutic purposes. This characteristic introduces TAMs as promising target for developing novel cancer treatments. In addition, inhibition of M2-type cells and blocking their recruitment in TME, as well as their depletion by inducing apoptosis, are other approaches for effective immunotherapy of cancer. In this review, we summarize the potential of TAMs to be targeted for cancer immunotherapy and provide an up-to-date about novel strategies for targeting TAMs.
Collapse
Affiliation(s)
- Arash Salmaninejad
- Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Pediatric Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran.
| | - Sepideh Mehrpour Layeghi
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zeinab Falakian
- Department of Laboratory Science, Lahijan Branch, Islamic Azad University, Lahijan, Iran
| | - Shahin Golestani
- Department of Ophthalmology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sepehr Kobravi
- Department of Oral and Maxillofacial Surgery, Tehran Azad University, Tehran, Iran
| | - Samaneh Talebi
- Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Yousefi
- Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| |
Collapse
|
24
|
Choi JE, Qiao Y, Kryczek I, Yu J, Gurkan J, Bao Y, Gondal M, Tien JCY, Maj T, Yazdani S, Parolia A, Xia H, Zhou J, Wei S, Grove S, Vatan L, Lin H, Li G, Zheng Y, Zhang Y, Cao X, Su F, Wang R, He T, Cieslik M, Green MD, Zou W, Chinnaiyan AM. PIKfyve, expressed by CD11c-positive cells, controls tumor immunity. Nat Commun 2024; 15:5487. [PMID: 38942798 PMCID: PMC11213953 DOI: 10.1038/s41467-024-48931-9] [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: 08/17/2023] [Accepted: 05/15/2024] [Indexed: 06/30/2024] Open
Abstract
Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c+ cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c+ cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c+ cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
Collapse
Affiliation(s)
- Jae Eun Choi
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pediatrics, University of California, San Francisco, CA, USA
| | - Yuanyuan Qiao
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Ilona Kryczek
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI, USA
| | - Jiali Yu
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI, USA
| | - Jonathan Gurkan
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Yi Bao
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Mahnoor Gondal
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Jean Ching-Yi Tien
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Tomasz Maj
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI, USA
| | - Sahr Yazdani
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Abhijit Parolia
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Houjun Xia
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI, USA
| | - JiaJia Zhou
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI, USA
| | - Shuang Wei
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI, USA
| | - Sara Grove
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI, USA
| | - Linda Vatan
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI, USA
| | - Heng Lin
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI, USA
| | - Gaopeng Li
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI, USA
| | - Yang Zheng
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Yuping Zhang
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Xuhong Cao
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA
| | - Fengyun Su
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Rui Wang
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Tongchen He
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Marcin Cieslik
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Michael D Green
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI, USA
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
- Department of Radiation Oncology Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA
| | - Weiping Zou
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
- Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan, Ann Arbor, MI, USA.
| | - Arul M Chinnaiyan
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
- Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA.
- Department of Urology, University of Michigan, Ann Arbor, MI, USA.
| |
Collapse
|
25
|
Norgard RJ, Budhani P, O'Brien SA, Xia Y, Egan JN, Flynn B, Tagore JR, Seco J, Peet GW, Mikucka A, Wasti R, Chan LC, Hinkel M, Martinez-Morilla S, Pignatelli J, Trapani F, Corse E, Feng D, Kostyrko K, Hofmann MH, Liu K, Kashyap AS. Reshaping the Tumor Microenvironment of KRASG12D Pancreatic Ductal Adenocarcinoma with Combined SOS1 and MEK Inhibition for Improved Immunotherapy Response. CANCER RESEARCH COMMUNICATIONS 2024; 4:1548-1560. [PMID: 38727236 PMCID: PMC11191876 DOI: 10.1158/2767-9764.crc-24-0172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 05/02/2024] [Accepted: 05/07/2024] [Indexed: 06/23/2024]
Abstract
KRAS inhibitors have demonstrated exciting preclinical and clinical responses, although resistance occurs rapidly. Here, we investigate the effects of KRAS-targeting therapies on the tumor microenvironment using a library of KrasG12D, p53-mutant, murine pancreatic ductal adenocarcinoma-derived cell lines (KPCY) to leverage immune-oncology combination strategies for long-term tumor efficacy. Our findings show that SOS1 and MEK inhibitors (SOS1i+MEKi) suppressed tumor growth in syngeneic models and increased intratumoral CD8+ T cells without durable responses. Single-cell RNA sequencing revealed an increase in inflammatory cancer-associated fibroblasts (iCAF), M2 macrophages, and a decreased dendritic cell (DC) quality that ultimately resulted in a highly immunosuppressive microenvironment driven by IL6+ iCAFs. Agonist CD40 treatment was effective to revert macrophage polarization and overcome the lack of mature antigen-presenting DCs after SOS1i+MEKi therapy. Treatment increased the overall survival of KPCY tumor-bearing mice. The addition of checkpoint blockade to SOS1i+MEKi combination resulted in tumor-free mice with established immune memory. Our data suggest that KRAS inhibition affects myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance and prolong antitumor effects. SIGNIFICANCE Combination of SOS1 and MEK inhibitors increase T cell infiltration while blunting pro-immune myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance and prolong anti-tumor effects.
Collapse
Affiliation(s)
- Robert J. Norgard
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Pratha Budhani
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Sarah A. O'Brien
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Youli Xia
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Jessica N. Egan
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Brianna Flynn
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Joshua R. Tagore
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Joseph Seco
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Gregory W. Peet
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Ania Mikucka
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Ruby Wasti
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Li-Chuan Chan
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Melanie Hinkel
- Late Stage Cancer Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Sandra Martinez-Morilla
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Jeanine Pignatelli
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Francesca Trapani
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Emily Corse
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Di Feng
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Kaja Kostyrko
- Late Stage Cancer Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Marco H. Hofmann
- Cancer Pharmacology and Disease Positioning Department, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Kang Liu
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Abhishek S. Kashyap
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| |
Collapse
|
26
|
Wu Z, Chen S, Wang Y, Li F, Xu H, Li M, Zeng Y, Wu Z, Gao Y. Current perspectives and trend of computer-aided drug design: a review and bibliometric analysis. Int J Surg 2024; 110:3848-3878. [PMID: 38502850 PMCID: PMC11175770 DOI: 10.1097/js9.0000000000001289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 02/22/2024] [Indexed: 03/21/2024]
Abstract
AIM Computer-aided drug design (CADD) is a drug design technique for computing ligand-receptor interactions and is involved in various stages of drug development. To better grasp the frontiers and hotspots of CADD, we conducted a review analysis through bibliometrics. METHODS A systematic review of studies published between 2000 and 20 July 2023 was conducted following the PRISMA guidelines. Literature on CADD was selected from the Web of Science Core Collection. General information, publications, output trends, countries/regions, institutions, journals, keywords, and influential authors were visually analyzed using software such as Excel, VOSviewer, RStudio, and CiteSpace. RESULTS A total of 2031 publications were included. These publications primarily originated from 99 countries or regions led by the U.S. and China. Among the contributors, MacKerell AD had the highest number of articles and the greatest influence. The Journal of Medicinal Chemistry was the most cited journal, whereas the Journal of Chemical Information and Modeling had the highest number of publications. CONCLUSIONS Influential authors in the field were identified. Current research shows active collaboration between countries, institutions, and companies. CADD technologies such as homology modeling, pharmacophore modeling, quantitative conformational relationships, molecular docking, molecular dynamics simulation, binding free energy prediction, and high-throughput virtual screening can effectively improve the efficiency of new drug discovery. Artificial intelligence-assisted drug design and screening based on CADD represent key topics that will influence future development. Furthermore, this paper will be helpful in better understanding the frontiers and hotspots of CADD.
Collapse
Affiliation(s)
- Zhenhui Wu
- School of Pharmacy, Jiangxi University of Chinese Medicine
- School of Clinical Medicine, Jiangxi University of Chinese Medicine, Nanchang
- Beijing Institute of Radiation Medicine, Academy of Military Sciences, Beijing, People’s Republic of China
| | - Shupeng Chen
- School of Clinical Medicine, Jiangxi University of Chinese Medicine, Nanchang
| | - Yihao Wang
- Beijing Institute of Radiation Medicine, Academy of Military Sciences, Beijing, People’s Republic of China
| | - Fangyang Li
- Beijing Institute of Radiation Medicine, Academy of Military Sciences, Beijing, People’s Republic of China
| | - Huanhua Xu
- School of Pharmacy, Jiangxi University of Chinese Medicine
| | - Maoxing Li
- Beijing Institute of Radiation Medicine, Academy of Military Sciences, Beijing, People’s Republic of China
| | - Yingjian Zeng
- School of Clinical Medicine, Jiangxi University of Chinese Medicine, Nanchang
| | - Zhenfeng Wu
- School of Pharmacy, Jiangxi University of Chinese Medicine
| | - Yue Gao
- School of Pharmacy, Jiangxi University of Chinese Medicine
- Beijing Institute of Radiation Medicine, Academy of Military Sciences, Beijing, People’s Republic of China
| |
Collapse
|
27
|
Gargett T, Truong NTH, Gardam B, Yu W, Ebert LM, Johnson A, Yeo ECF, Wittwer NL, Tapia Rico G, Logan J, Sivaloganathan P, Collis M, Ruszkiewicz A, Brown MP. Safety and biological outcomes following a phase 1 trial of GD2-specific CAR-T cells in patients with GD2-positive metastatic melanoma and other solid cancers. J Immunother Cancer 2024; 12:e008659. [PMID: 38754916 PMCID: PMC11097842 DOI: 10.1136/jitc-2023-008659] [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] [Accepted: 04/28/2024] [Indexed: 05/18/2024] Open
Abstract
BACKGROUND Chimeric antigen receptor (CAR) T cell therapies specific for the CD19 and B-cell maturation antigen have become an approved standard of care worldwide for relapsed and refractory B-cell malignancies. If CAR-T cell therapy for non-hematological malignancies is to achieve the same stage of clinical development, then iterative early-phase clinical testing can add value to the clinical development process for evaluating CAR-T cell products containing different CAR designs and manufactured under differing conditions. METHODS We conducted a phase 1 trial of third-generation GD2-specific CAR-T cell therapy, which has previously been tested in neuroblastoma patients. In this study, the GD2-CAR-T therapy was evaluated for the first time in metastatic melanoma patients in combination with BRAF/MEK inhibitor therapy, and as a monotherapy in patients with colorectal cancer and a patient with fibromyxoid sarcoma. Feasibility and safety were determined and persistence studies, multiplex cytokine arrays on sera and detailed immune phenotyping of the original CAR-T products, the circulating CAR-T cells, and, in select patients, the tumor-infiltrating CAR-T cells were performed. RESULTS We demonstrate the feasibility of manufacturing CAR-T products at point of care for patients with solid cancer and show that a single intravenous infusion was well tolerated with no dose-limiting toxicities or severe adverse events. In addition, we note significant improvements in CAR-T cell immune phenotype, and expansion when a modified manufacturing procedure was adopted for the latter 6 patients recruited to this 12-patient trial. We also show evidence of CAR-T cell-mediated immune activity and in some patients expanded subsets of circulating myeloid cells after CAR-T cell therapy. CONCLUSIONS This is the first report of third-generation GD2-targeting CAR-T cells in patients with metastatic melanoma and other solid cancers such as colorectal cancer, showing feasibility, safety and immune activity, but limited clinical effect. TRIAL REGISTRATION NUMBER ACTRN12613000198729.
Collapse
Affiliation(s)
- Tessa Gargett
- University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Nga T H Truong
- University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Bryan Gardam
- University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
| | - Wenbo Yu
- University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Lisa M Ebert
- University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Amy Johnson
- Flinders University, Adelaide, South Australia, Australia
| | - Erica C F Yeo
- University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia
| | - Nicole L Wittwer
- University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Gonzalo Tapia Rico
- Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Jesikah Logan
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Purany Sivaloganathan
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Maria Collis
- Surgical Pathology, SA Pathology, Adelaide, South Australia, Australia
| | - Andrew Ruszkiewicz
- Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
- Surgical Pathology, SA Pathology, Adelaide, South Australia, Australia
- School of Pharmacy and Medical Science, University of South Australia, Adelaide, South Australia, Australia
| | - Michael P Brown
- University of South Australia, Translational Oncology Laboratory, Centre for Cancer Biology, SA Pathology, Rundle Mall, South Australia, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
- Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| |
Collapse
|
28
|
Albrecht LJ, Dimitriou F, Grover P, Hassel JC, Erdmann M, Forschner A, Johnson DB, Váraljai R, Lodde G, Placke JM, Krefting F, Zaremba A, Ugurel S, Roesch A, Schulz C, Berking C, Pöttgen C, Menzies AM, Long GV, Dummer R, Livingstone E, Schadendorf D, Zimmer L. Anti-PD-(L)1 plus BRAF/MEK inhibitors (triplet therapy) after failure of immune checkpoint inhibition and targeted therapy in patients with advanced melanoma. Eur J Cancer 2024; 202:113976. [PMID: 38484692 DOI: 10.1016/j.ejca.2024.113976] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 04/21/2024]
Abstract
BACKGROUND Effective treatment options are limited for patients with advanced melanoma who have progressed on immune checkpoint inhibitors (ICI) and targeted therapies (TT). Preclinical models support the combination of ICI with TT; however, clinical trials evaluating the efficacy of triplet combinations in first-line setting showed limited advantage compared to TT only. METHODS We conducted a retrospective, multicenter study, that included patients with advanced melanoma who were treated with BRAF/MEK inhibitors in combination with an anti-PD-(L)1 antibody (triplet therapy) after failure of at least one anti-PD-(L)1-based therapy and one TT in seven major melanoma centers between February 2016 and July 2022. RESULTS A total of 48 patients were included, of which 32 patients, 66.7% had brain metastases, 37 patients (77.1%) had three or more metastatic organs and 21 patients (43.8%) had three or more treatment lines. The median follow-up time was 31.4 months (IQR, 22.27-40.45 months). The treatment with triplet therapy resulted in an ORR of 35.4% (n = 17) and a DCR of 47.9% (n = 23). The median DOR was 5.9 months (range, 3.39-14.27 months). Patients treated with BRAF/MEK inhibitors as the last treatment line showed a slightly lower ORR (29.6%) compared to patients who received ICI or chemotherapy last (ORR: 42.9%). Grade 3-4 treatment-related adverse events occurred in 25% of patients (n = 12), with seven patients (14.6%) requiring discontinuation of treatment with both or either drug. CONCLUSIONS Triplet therapy has shown activity in heavily pretreated patients with advanced melanoma and may represent a potential treatment regimen after failure of ICI and TT.
Collapse
Affiliation(s)
- Lea Jessica Albrecht
- Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany
| | - Florentia Dimitriou
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
| | - Piyush Grover
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia
| | - Jessica C Hassel
- Department of Dermatology and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Michael Erdmann
- Department of Dermatology, Uniklinikum Erlangen and the Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
| | - Andrea Forschner
- Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Douglas B Johnson
- Department of Medicine, Division of Hematology and Oncology, VUMC, and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Renáta Váraljai
- Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany
| | - Georg Lodde
- Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany
| | - Jan Malte Placke
- Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany
| | - Frederik Krefting
- Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany
| | - Anne Zaremba
- Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany
| | - Selma Ugurel
- Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany
| | - Alexander Roesch
- Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany
| | - Carsten Schulz
- Department of Dermatology and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Carola Berking
- Department of Dermatology, Uniklinikum Erlangen and the Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
| | - Christoph Pöttgen
- Department of Radiotherapy, West German Cancer Centre, University Hospital Essen, Essen, Germany
| | - Alexander M Menzies
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia
| | - Georgina V Long
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia
| | - Reinhard Dummer
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
| | - Elisabeth Livingstone
- Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany
| | - Dirk Schadendorf
- Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany; National Center for Tumor Diseases (NCT)-West, Campus Essen, & Research Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Essen, Germany
| | - Lisa Zimmer
- Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany.
| |
Collapse
|
29
|
Kumarasamy V, Wang J, Frangou C, Wan Y, Dynka A, Rosenheck H, Dey P, Abel EV, Knudsen ES, Witkiewicz AK. The Extracellular Niche and Tumor Microenvironment Enhance KRAS Inhibitor Efficacy in Pancreatic Cancer. Cancer Res 2024; 84:1115-1132. [PMID: 38294344 PMCID: PMC10982648 DOI: 10.1158/0008-5472.can-23-2504] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 11/28/2023] [Accepted: 01/25/2024] [Indexed: 02/01/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that lacks effective treatment options, highlighting the need for developing new therapeutic interventions. Here, we assessed the response to pharmacologic inhibition of KRAS, the central oncogenic driver of PDAC. In a panel of PDAC cell lines, inhibition of KRASG12D with MRTX1133 yielded variable efficacy in suppressing cell growth and downstream gene expression programs in 2D cultures. On the basis of CRISPR-Cas9 loss-of-function screens, ITGB1 was identified as a target to enhance the therapeutic response to MRTX1133 by regulating mechanotransduction signaling and YAP/TAZ expression, which was confirmed by gene-specific knockdown and combinatorial drug synergy. Interestingly, MRTX1133 was considerably more efficacious in 3D cell cultures. Moreover, MRTX1133 elicited a pronounced cytostatic effect in vivo and controlled tumor growth in PDAC patient-derived xenografts. In syngeneic models, KRASG12D inhibition led to tumor regression that did not occur in immune-deficient hosts. Digital spatial profiling on tumor tissues indicated that MRTX1133-mediated KRAS inhibition enhanced IFNγ signaling and induced antigen presentation that modulated the tumor microenvironment. Further investigation of the immunologic response using single-cell sequencing and multispectral imaging revealed that tumor regression was associated with suppression of neutrophils and influx of effector CD8+ T cells. Together, these findings demonstrate that both tumor cell-intrinsic and -extrinsic events contribute to response to MRTX1133 and credential KRASG12D inhibition as a promising therapeutic strategy for a large percentage of patients with PDAC. SIGNIFICANCE Pharmacologic inhibition of KRAS elicits varied responses in pancreatic cancer 2D cell lines, 3D organoid cultures, and xenografts, underscoring the importance of mechanotransduction and the tumor microenvironment in regulating therapeutic responses.
Collapse
Affiliation(s)
- Vishnu Kumarasamy
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Jianxin Wang
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Costakis Frangou
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Yin Wan
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Andrew Dynka
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Hanna Rosenheck
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Prasenjit Dey
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Ethan V. Abel
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Erik S. Knudsen
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Agnieszka K. Witkiewicz
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| |
Collapse
|
30
|
Li C, Wang Z, Yao L, Lin X, Jian Y, Li Y, Zhang J, Shao J, Tran PD, Hagman JR, Cao M, Cong Y, Li HY, Goding CR, Xu ZX, Liao X, Miao X, Cui R. Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation. Nat Commun 2024; 15:2163. [PMID: 38461299 PMCID: PMC10924921 DOI: 10.1038/s41467-024-46422-5] [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: 10/18/2023] [Accepted: 02/27/2024] [Indexed: 03/11/2024] Open
Abstract
Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitive will provide a significant improvement in patient outcome. Here we identify Mi-2β as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Studies in genetically engineered mouse melanoma models indicate that loss of Mi-2β rescues the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq analysis shows that Mi-2β controls the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2β binds to EZH2 and promotes K510 methylation of EZH2, subsequently activating the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2β-targeted inhibitor, Z36-MP5, which reduces Mi-2β ATPase activity and reactivates ISG transcription. Consequently, Z36-MP5 induces a response to immune checkpoint inhibitors in otherwise resistant melanoma models. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones.
Collapse
Affiliation(s)
- Cang Li
- Skin Disease Research Institute, The 2nd Hospital and School of Medicine, Zhejiang University, Hangzhou, 310058, China
- Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou, 310053, China
| | - Zhengyu Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Science, Little Rock, AR, 72205, USA
| | - Licheng Yao
- State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Science, Tsinghua University, Beijing, 100084, China
| | - Xingyu Lin
- Zhuhai Yu Fan Biotechnologies Co. Ltd, Zhuhai, Guangdong, 51900, China
| | - Yongping Jian
- School of Life Sciences, Henan University, Kaifeng, 475000, China
| | - Yujia Li
- School of Life Sciences, Henan University, Kaifeng, 475000, China
| | - Jie Zhang
- National Key Laboratory for Novel Software Technology, Nanjing University, Nanjing, Jiangsu, China
| | - Jingwei Shao
- National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, International Academy of Targeted Therapeutics and Innovation, College of Pharmacy, Chongqing University of Arts and Sciences, Chongqing, 402160, China
| | - Phuc D Tran
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Science, Little Rock, AR, 72205, USA
| | - James R Hagman
- Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO, 80206, USA
| | - Meng Cao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yusheng Cong
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Hangzhou Normal University School of Basic Medical Sciences, Hangzhou, 310058, China
| | - Hong-Yu Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Science, Little Rock, AR, 72205, USA.
| | - Colin R Goding
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford, OX3 7DQ, UK.
| | - Zhi-Xiang Xu
- School of Life Sciences, Henan University, Kaifeng, 475000, China.
| | - Xuebin Liao
- State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Tsinghua-Peking Center for Life Science, Tsinghua University, Beijing, 100084, China.
| | - Xiao Miao
- Department of Dermatology, Shuguang Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Jiangxi Medical College, Nanchang University, Nanchang, China.
| | - Rutao Cui
- Skin Disease Research Institute, The 2nd Hospital and School of Medicine, Zhejiang University, Hangzhou, 310058, China.
| |
Collapse
|
31
|
Tawfeek HN, Tawfeek AM, Bräse S, Nieger M, El-Sheref EM. Stereoselective synthesis and X-ray structure determination of novel 1,2-dihydroquinolinehydrazonopropanoate derivatives. Heliyon 2024; 10:e25248. [PMID: 38404815 PMCID: PMC10884343 DOI: 10.1016/j.heliyon.2024.e25248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 02/27/2024] Open
Abstract
A novel series of 1,2-dihydroquinolinhydrazonopropanoate have been synthesized via a convenient aza-Michael addition reaction between hydrazinylquinolinones and ethyl propiolate in ethanol under refluxing temperature. The structures for all obtained products were confirmed with FTIR, NMR spectrums, as well as mass spectrometry. In addition, the monoclinic structure for compounds 8a, 8c, and 8d was also confirmed via X-ray crystallography analyses. The E-configuration for the obtained products was confirmed form the X-ray analysis. On the other hand, the crystal packing shows that the intermolecular and hydrogen bonds between atoms are parallel to the bc plan.
Collapse
Affiliation(s)
- Hendawy N. Tawfeek
- Chemistry Department, Faculty of Science, Minia University, El-Minia, 61519, Egypt
| | - Ahmed M. Tawfeek
- Chemistry Department, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Stefan Bräse
- Institute of Biological and Chemical Systems, IBCS-FMS, Karlsruhe Institute of Technology, 76131, Karlsruhe, Germany
| | - Martin Nieger
- Department of Chemistry, University of Helsinki, PO Box 55, A. I. Virtasen Aukio 1, 00014, Helsinki, Finland
| | - Essmat M. El-Sheref
- Chemistry Department, Faculty of Science, Minia University, El-Minia, 61519, Egypt
| |
Collapse
|
32
|
Pellegrino M, Secli V, D’Amico S, Petrilli LL, Caforio M, Folgiero V, Tumino N, Vacca P, Vinci M, Fruci D, de Billy E. Manipulating the tumor immune microenvironment to improve cancer immunotherapy: IGF1R, a promising target. Front Immunol 2024; 15:1356321. [PMID: 38420122 PMCID: PMC10899349 DOI: 10.3389/fimmu.2024.1356321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 01/26/2024] [Indexed: 03/02/2024] Open
Abstract
Cancer immunotherapy has made impressive advances in improving the outcome of patients affected by malignant diseases. Nonetheless, some limitations still need to be tackled to more efficiently and safely treat patients, in particular for those affected by solid tumors. One of the limitations is related to the immunosuppressive tumor microenvironment (TME), which impairs anti-tumor immunity. Efforts to identify targets able to turn the TME into a milieu more auspicious to current immuno-oncotherapy is a real challenge due to the high redundancy of the mechanisms involved. However, the insulin-like growth factor 1 receptor (IGF1R), an attractive drug target for cancer therapy, is emerging as an important immunomodulator and regulator of key immune cell functions. Here, after briefly summarizing the IGF1R signaling pathway in cancer, we review its role in regulating immune cells function and activity, and discuss IGF1R as a promising target to improve anti-cancer immunotherapy.
Collapse
Affiliation(s)
- Marsha Pellegrino
- Oncohematology and Pharmaceutical Factory Research Area, Pediatric Cancer Genetics and Epigenetics Unit, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| | - Valerio Secli
- Oncohematology and Pharmaceutical Factory Research Area, Pediatric Cancer Genetics and Epigenetics Unit, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| | - Silvia D’Amico
- Oncohematology and Pharmaceutical Factory Research Area, Pediatric Cancer Genetics and Epigenetics Unit, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| | - Lucia Lisa Petrilli
- Oncohematology and Pharmaceutical Factory Research Area, Pediatric Cancer Genetics and Epigenetics Unit, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| | - Matteo Caforio
- Oncohematology and Pharmaceutical Factory Research Area, Pediatric Cancer Genetics and Epigenetics Unit, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| | - Valentina Folgiero
- Oncohematology and Pharmaceutical Factory Research Area, Pediatric Cancer Genetics and Epigenetics Unit, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| | - Nicola Tumino
- Immunology Research Area, Innate Lymphoid Cells Unit, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| | - Paola Vacca
- Immunology Research Area, Innate Lymphoid Cells Unit, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| | - Maria Vinci
- Oncohematology and Pharmaceutical Factory Research Area, Pediatric Cancer Genetics and Epigenetics Unit, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| | - Doriana Fruci
- Oncohematology and Pharmaceutical Factory Research Area, Pediatric Cancer Genetics and Epigenetics Unit, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| | - Emmanuel de Billy
- Oncohematology and Pharmaceutical Factory Research Area, Pediatric Cancer Genetics and Epigenetics Unit, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy
| |
Collapse
|
33
|
Bahar ME, Kim HJ, Kim DR. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal Transduct Target Ther 2023; 8:455. [PMID: 38105263 PMCID: PMC10725898 DOI: 10.1038/s41392-023-01705-z] [Citation(s) in RCA: 203] [Impact Index Per Article: 101.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 11/03/2023] [Accepted: 11/12/2023] [Indexed: 12/19/2023] Open
Abstract
Metastatic dissemination of solid tumors, a leading cause of cancer-related mortality, underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis, chemoresistance, and the mechanistic backgrounds of individuals whose cancers are prone to migration. The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase (MAPK) pathway, encompassing the RAS-RAF-MAPK kinase (MEK)-extracellular signal-related kinase (ERK) pathway. RAF kinase is a primary mediator of the MAPK pathway, responsible for the sequential activation of downstream targets, such as MEK and the transcription factor ERK, which control numerous cellular and physiological processes, including organism development, cell cycle control, cell proliferation and differentiation, cell survival, and death. Defects in this signaling cascade are associated with diseases such as cancer. RAF inhibitors (RAFi) combined with MEK blockers represent an FDA-approved therapeutic strategy for numerous RAF-mutant cancers, including melanoma, non-small cell lung carcinoma, and thyroid cancer. However, the development of therapy resistance by cancer cells remains an important barrier. Autophagy, an intracellular lysosome-dependent catabolic recycling process, plays a critical role in the development of RAFi resistance in cancer. Thus, targeting RAF and autophagy could be novel treatment strategies for RAF-mutant cancers. In this review, we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and RAFi-resistance. Furthermore, we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic profiles. Additionally, this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.
Collapse
Affiliation(s)
- Md Entaz Bahar
- Department of Biochemistry and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea
| | - Hyun Joon Kim
- Department of Anatomy and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea
| | - Deok Ryong Kim
- Department of Biochemistry and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea.
| |
Collapse
|
34
|
Wong RSJ, Ong RJM, Lim JSJ. Immune checkpoint inhibitors in breast cancer: development, mechanisms of resistance and potential management strategies. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:768-787. [PMID: 38263984 PMCID: PMC10804393 DOI: 10.20517/cdr.2023.58] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 10/14/2023] [Accepted: 10/31/2023] [Indexed: 01/25/2024]
Abstract
The use of immune checkpoint inhibitors (ICIs) has increased exponentially in the past decade, although its progress specifically for breast cancer has been modest. The first U.S. Food and Drug Administration approval for ICI in breast cancer came in 2019, eight years after the first-ever approval of an ICI. At present, current indications for ICIs are relevant only to a subset of patients with triple-negative breast cancer, or those displaying high microsatellite instability or deficiency in the mismatch repair protein pathway. With an increasing understanding of the limitations of using ICIs, which stem from breast cancer being innately poorly immunogenic, as well as the presence of various intrinsic and acquired resistance pathways, ongoing trials are evaluating different combination therapies to overcome these barriers. In this review, we aim to describe the development timeline of ICIs and resistance mechanisms limiting their utility, and summarise the available approaches and ongoing trials relevant to overcoming each resistance mechanism.
Collapse
Affiliation(s)
- Rachel SJ Wong
- Department of Haematology-Oncology, National University Cancer Institute, National University Hospital, Singapore 119228, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Rebecca JM Ong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Joline SJ Lim
- Department of Haematology-Oncology, National University Cancer Institute, National University Hospital, Singapore 119228, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| |
Collapse
|
35
|
Shiloh R, Lubin R, David O, Geron I, Okon E, Hazan I, Zaliova M, Amarilyo G, Birger Y, Borovitz Y, Brik D, Broides A, Cohen-Kedar S, Harel L, Kristal E, Kozlova D, Ling G, Shapira Rootman M, Shefer Averbuch N, Spielman S, Trka J, Izraeli S, Yona S, Elitzur S. Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling. Blood 2023; 142:1740-1751. [PMID: 37738562 DOI: 10.1182/blood.2023020714] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/11/2023] [Accepted: 08/24/2023] [Indexed: 09/24/2023] Open
Abstract
Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germ line loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular, and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss of function of ENT3 activates nucleoside-sensing toll-like receptors (TLR) and downstream MAPK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation.
Collapse
Affiliation(s)
- Ruth Shiloh
- The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petach Tikva, Israel
- Felsenstein Medical Research Center, Faculty of Medicine, Tel Aviv University, Petach Tikva, Israel
| | - Ruth Lubin
- The Institute of Biomedical and Oral Research, Hebrew University, Jerusalem, Israel
| | - Odeya David
- Pediatric Endocrinology Unit, Soroka University Medical Center, Beer Sheva, Israel
- Pediatric Ambulatory Center, Soroka University Medical Center, Beer Sheva, Israel
- Joyce and Irving Goldman Medical School, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
| | - Ifat Geron
- The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petach Tikva, Israel
- Felsenstein Medical Research Center, Faculty of Medicine, Tel Aviv University, Petach Tikva, Israel
| | - Elimelech Okon
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Idit Hazan
- The Institute of Biomedical and Oral Research, Hebrew University, Jerusalem, Israel
| | - Marketa Zaliova
- Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine of Charles University Prague and University Hospital Motol, Prague, Czech Republic
| | - Gil Amarilyo
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pediatric Rheumatology Unit, Schneider Children's Medical Center, Petach Tikva, Israel
| | - Yehudit Birger
- The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petach Tikva, Israel
- Felsenstein Medical Research Center, Faculty of Medicine, Tel Aviv University, Petach Tikva, Israel
| | - Yael Borovitz
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Institute of Nephrology, Schneider Children's Medical Center, Petach Tikva, Israel
| | - Dafna Brik
- The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petach Tikva, Israel
| | - Arnon Broides
- Pediatric Ambulatory Center, Soroka University Medical Center, Beer Sheva, Israel
- Joyce and Irving Goldman Medical School, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
- Pediatric Immunology Clinic, Soroka University Medical Center, Beer Sheva, Israel
| | - Sarit Cohen-Kedar
- Felsenstein Medical Research Center, Faculty of Medicine, Tel Aviv University, Petach Tikva, Israel
- Division of Gastroenterology, Rabin Medical Center, Petach Tikva, Israel
| | - Liora Harel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pediatric Rheumatology Unit, Schneider Children's Medical Center, Petach Tikva, Israel
| | - Eyal Kristal
- Pediatric Ambulatory Center, Soroka University Medical Center, Beer Sheva, Israel
- Joyce and Irving Goldman Medical School, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
- Pediatric Immunology Clinic, Soroka University Medical Center, Beer Sheva, Israel
| | - Daria Kozlova
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Pathology, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel
| | - Galina Ling
- Pediatric Ambulatory Center, Soroka University Medical Center, Beer Sheva, Israel
- Joyce and Irving Goldman Medical School, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
| | | | - Noa Shefer Averbuch
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
- The Jesse and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
| | - Shiri Spielman
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Pediatrics A, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
| | - Jan Trka
- Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, Second Faculty of Medicine of Charles University Prague and University Hospital Motol, Prague, Czech Republic
| | - Shai Izraeli
- The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petach Tikva, Israel
- Felsenstein Medical Research Center, Faculty of Medicine, Tel Aviv University, Petach Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Beckman Research Institute, City of Hope, Duarte, CA
| | - Simon Yona
- The Institute of Biomedical and Oral Research, Hebrew University, Jerusalem, Israel
| | - Sarah Elitzur
- The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petach Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| |
Collapse
|
36
|
Das S, Acharya D. Immunological Assessment of Recent Immunotherapy for Colorectal Cancer. Immunol Invest 2023; 52:1065-1095. [PMID: 37812224 DOI: 10.1080/08820139.2023.2264906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Colorectal cancer (CRC) is the third most prevalent malignancy with increased incidence and mortality rates worldwide. Traditional treatment approaches have attempted to efficiently target CRC; however, they have failed in most cases, owing to the cytotoxicity and non-specificity of these therapies. Therefore, it is essential to develop an effective alternative therapy to improve the clinical outcomes in heterogeneous CRC cases. Immunotherapy has transformed cancer treatment with remarkable efficacy and overcomes the limitations of traditional treatments. With an understanding of the cancer-immunity cycle and tumor microenvironment evolution, current immunotherapy approaches have elicited enhanced antitumor immune responses. In this comprehensive review, we outline the latest advances in immunotherapy targeting CRC and provide insights into antitumor immune responses reported in landmark clinical studies. We focused on highlighting the combination approaches that synergistically induce immune responses and eliminate immunosuppression. This review aimed to understand the limitations and potential of recent immunotherapy clinical studies conducted in the last five years (2019-2023) and to transform this knowledge into a rational design of clinical trials intended for effective antitumor immune responses in CRC.
Collapse
Affiliation(s)
- Subhadeep Das
- Department of Biotechnology, GIET University, Gunupur, India
| | | |
Collapse
|
37
|
Yao S, Han Y, Yang M, Jin K, Lan H. It's high-time to re-evaluate the value of induced-chemotherapy for reinforcing immunotherapy in colorectal cancer. Front Immunol 2023; 14:1241208. [PMID: 37920463 PMCID: PMC10619163 DOI: 10.3389/fimmu.2023.1241208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 10/09/2023] [Indexed: 11/04/2023] Open
Abstract
Immunotherapy has made significant advances in the treatment of colorectal cancer (CRC), revolutionizing the therapeutic landscape and highlighting the indispensable role of the tumor immune microenvironment. However, some CRCs have shown poor response to immunotherapy, prompting investigation into the underlying reasons. It has been discovered that certain chemotherapeutic agents possess immune-stimulatory properties, including the induction of immunogenic cell death (ICD), the generation and processing of non-mutated neoantigens (NM-neoAgs), and the B cell follicle-driven T cell response. Based on these findings, the concept of inducing chemotherapy has been introduced, and the combination of inducing chemotherapy and immunotherapy has become a standard treatment option for certain cancers. Clinical trials have confirmed the feasibility and safety of this approach in CRC, offering a promising method for improving the efficacy of immunotherapy. Nevertheless, there are still many challenges and difficulties ahead, and further research is required to optimize its use.
Collapse
Affiliation(s)
- Shiya Yao
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Yuejun Han
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Mengxiang Yang
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
| |
Collapse
|
38
|
Al-Humaidi J, Gomha SM, Riyadh SM, Ibrahim MS, Zaki MEA, Abolibda TZ, Jefri OA, Abouzied AS. Synthesis, Biological Evaluation, and Molecular Docking of Novel Azolylhydrazonothiazoles as Potential Anticancer Agents. ACS OMEGA 2023; 8:34044-34058. [PMID: 37744790 PMCID: PMC10515364 DOI: 10.1021/acsomega.3c05038] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 08/09/2023] [Indexed: 09/26/2023]
Abstract
A novel set of thiazolylhydrazonothiazoles bearing an indole moiety were synthesized by subjection reactions of carbothioamide derivative and hydrazonoyl chlorides (or α-haloketones). The cytotoxicity of the synthesized compounds was evaluated against the colon carcinoma cell line (HCT-116), liver carcinoma cell line (HepG2), and breast carcinoma cell line (MDA-MB-231), and demonstrated encouraging activity. Furthermore, when representative products were assessed for toxicity against normal cells, minimal toxic effects were observed, indicating their potential safety for use in pharmacological studies. The mechanism of action of the tested products, as inhibitors of the epidermal growth factor receptor tyrosine kinase domain (EGFR TK) protein, was suggested through docking studies that assessed their binding scores and modes, in comparison to a reference standard (W19), thus endorsing their anticancer activity.
Collapse
Affiliation(s)
- Jehan
Y. Al-Humaidi
- Department
of Chemistry, College of Science, Princess
Nourah Bint Abdulrahman University, P.O. .BOX 84428, Riyadh 11671, Saudi Arabia
| | - Sobhi M. Gomha
- Department
of Chemistry, Faculty of Science, Islamic
University of Madinah, Madinah 42351, Saudi Arabia
| | - Sayed M. Riyadh
- Department
of Chemistry, Faculty of Science, Cairo
University, Cairo 12613, Egypt
| | - Mohamed S. Ibrahim
- Department
of Chemistry, Faculty of Science, Islamic
University of Madinah, Madinah 42351, Saudi Arabia
| | - Magdi E. A. Zaki
- Department
of Chemistry, Faculty of Science, Imam Mohammad
Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia
| | - Tariq Z. Abolibda
- Department
of Chemistry, Faculty of Science, Islamic
University of Madinah, Madinah 42351, Saudi Arabia
| | - Ohoud A. Jefri
- Department
of Biological Science, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Amr S. Abouzied
- Department
of Pharmaceutical Chemistry, College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia
- Department
of Pharmaceutical Chemistry, National Organization
for Drug Control and Research (NODCAR), Giza 12311, Egypt
| |
Collapse
|
39
|
Li L, Zhao M, Kiernan CH, Castro Eiro MD, van Meurs M, Brouwers-Haspels I, Wilmsen MEP, Grashof DGB, van de Werken HJG, Hendriks RW, Mueller YM, Katsikis PD. Ibrutinib directly reduces CD8+T cell exhaustion independent of BTK. Front Immunol 2023; 14:1201415. [PMID: 37771591 PMCID: PMC10523025 DOI: 10.3389/fimmu.2023.1201415] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 08/28/2023] [Indexed: 09/30/2023] Open
Abstract
Introduction Cytotoxic CD8+ T cell (CTL) exhaustion is a dysfunctional state of T cells triggered by persistent antigen stimulation, with the characteristics of increased inhibitory receptors, impaired cytokine production and a distinct transcriptional profile. Evidence from immune checkpoint blockade therapy supports that reversing T cell exhaustion is a promising strategy in cancer treatment. Ibrutinib, is a potent inhibitor of BTK, which has been approved for the treatment of chronic lymphocytic leukemia. Previous studies have reported improved function of T cells in ibrutinib long-term treated patients but the mechanism remains unclear. We investigated whether ibrutinib directly acts on CD8+ T cells and reinvigorates exhausted CTLs. Methods We used an established in vitro CTL exhaustion system to examine whether ibrutinib can directly ameliorate T cell exhaustion. Changes in inhibitory receptors, transcription factors, cytokine production and killing capacity of ibrutinib-treated exhausted CTLs were detected by flow cytometry. RNA-seq was performed to study transcriptional changes in these cells. Btk deficient mice were used to confirm that the effect of ibrutinib was independent of BTK expression. Results We found that ibrutinib reduced exhaustion-related features of CTLs in an in vitro CTL exhaustion system. These changes included decreased inhibitory receptor expression, enhanced cytokine production, and downregulation of the transcription factor TOX with upregulation of TCF1. RNA-seq further confirmed that ibrutinib directly reduced the exhaustion-related transcriptional profile of these cells. Importantly, using btk deficient mice we showed the effect of ibrutinib was independent of BTK expression, and therefore mediated by one of its other targets. Discussion Our study demonstrates that ibrutinib directly ameliorates CTL exhaustion, and provides evidence for its synergistic use with cancer immunotherapy.
Collapse
Affiliation(s)
- Ling Li
- Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Manzhi Zhao
- Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Caoimhe H. Kiernan
- Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands
| | | | - Marjan van Meurs
- Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands
| | | | - Merel E. P. Wilmsen
- Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Dwin G. B. Grashof
- Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Harmen J. G. van de Werken
- Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands
- Cancer Computational Biology Center, Erasmus Medical Center (MC) Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Rudi W. Hendriks
- Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Yvonne M. Mueller
- Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Peter D. Katsikis
- Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands
| |
Collapse
|
40
|
Buchbinder EI, Giobbie-Hurder A, Haq R, Ott PA. A phase I/II study of LY3022855 with BRAF/MEK inhibition in patients with Melanoma. Invest New Drugs 2023; 41:551-555. [PMID: 37247116 DOI: 10.1007/s10637-023-01374-3] [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: 03/29/2023] [Accepted: 05/18/2023] [Indexed: 05/30/2023]
Abstract
BRAF/MEK targeted therapies and immune checkpoint inhibition have dramatically improved disease control and survival of patients with advanced melanoma. However, most patients do not have durable benefit from either of these therapies. BRAF targeted therapy often has a limited duration of efficacy due to the development of resistance. Pre-clinical data suggest that one possible way to overcome resistance to BRAF/MEK targeted therapy may be the addition of CSF1R inhibition. In this phase I/II study we evaluated the safety and efficacy of LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody in combination with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib in patients with BRAF V600E/K mutant metastatic melanoma. The trial was terminated early due to discontinuation of the development program for LY3022855 by the sponsor. Between August 2017 and May 2018 five pts were enrolled. Three patients experienced grade 3 events that were deemed possibly related to LY3022855. There were no grade 4 or grade 5 events related to LY3022855. One of the 5 patients had a complete response (CR), whereas the other 4 had progressive disease (PD). Median progression free survival was 3.9 months (90% CI: 1.9-37.2 mos). CSF1R inhibition with LY3022855 in combination with BRAF/MEK inhibition with vemurafenib and cobimetinib was difficult to tolerate in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration.
Collapse
Affiliation(s)
- Elizabeth I Buchbinder
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
- , 450 Brookline Ave, Boston, MA, 02215, USA.
| | - Anita Giobbie-Hurder
- Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Rizwan Haq
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Patrick A Ott
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| |
Collapse
|
41
|
Jahandideh A, Yarizadeh M, Noei-Khesht Masjedi M, Fatehnejad M, Jahandideh R, Soheili R, Eslami Y, Zokaei M, Ahmadvand A, Ghalamkarpour N, Kumar Pandey R, Nabi Afjadi M, Payandeh Z. Macrophage's role in solid tumors: two edges of a sword. Cancer Cell Int 2023; 23:150. [PMID: 37525217 PMCID: PMC10391843 DOI: 10.1186/s12935-023-02999-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 07/24/2023] [Indexed: 08/02/2023] Open
Abstract
The tumor microenvironment is overwhelmingly dictated by macrophages, intimately affiliated with tumors, exercising pivotal roles in multiple processes, including angiogenesis, extracellular matrix reconfiguration, cellular proliferation, metastasis, and immunosuppression. They further exhibit resilience to chemotherapy and immunotherapy via meticulous checkpoint blockades. When appropriately stimulated, macrophages can morph into a potent bidirectional component of the immune system, engulfing malignant cells and annihilating them with cytotoxic substances, thus rendering them intriguing candidates for therapeutic targets. As myelomonocytic cells relentlessly amass within tumor tissues, macrophages rise as prime contenders for cell therapy upon the development of chimeric antigen receptor effector cells. Given the significant incidence of macrophage infiltration correlated with an unfavorable prognosis and heightened resistance to chemotherapy in solid tumors, we delve into the intricate role of macrophages in cancer propagation and their promising potential in confronting four formidable cancer variants-namely, melanoma, colon, glioma, and breast cancers.
Collapse
Affiliation(s)
- Arian Jahandideh
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
- Usern Office, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mahsa Yarizadeh
- Islamic Azad University, Tehran Medical Branch, Tehran, Iran
| | - Maryam Noei-Khesht Masjedi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Fatehnejad
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Romina Jahandideh
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Roben Soheili
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Yeganeh Eslami
- Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Maryam Zokaei
- Department of Food Science and Technology, Faculty of Nutrition Science, Food Science and Technology/National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ardavan Ahmadvand
- Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nogol Ghalamkarpour
- Department of Clinical Laboratory Sciences, School of Allied Medicine, Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Rajan Kumar Pandey
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
| | - Mohsen Nabi Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden.
| |
Collapse
|
42
|
Rozeman EA, Versluis JM, Sikorska K, Hoefsmit EP, Dimitriadis P, Rao D, Lacroix R, Grijpink-Ongering LG, Lopez-Yurda M, Heeres BC, van de Wiel BA, Flohil C, Sari A, Heijmink SWTPJ, van den Broek D, Broeks A, de Groot JWB, Vollebergh MA, Wilgenhof S, van Thienen JV, Haanen JBAG, Blank CU. IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation. J Immunother Cancer 2023; 11:e006821. [PMID: 37479483 PMCID: PMC10364170 DOI: 10.1136/jitc-2023-006821] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2023] [Indexed: 07/23/2023] Open
Abstract
BACKGROUND Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with BRAFV600-mutated melanoma. Short-term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD-1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab. METHODS Patients with treatment-naïve BRAFV600E/K-mutant advanced melanoma started pembrolizumab 200 mg every 3 weeks. In week 6, patients were randomized to continue pembrolizumab only (cohort 1), or to receive, in addition, intermittent dabrafenib 150 mg two times per day plus trametinib 2 mg one time per day for two cycles of 1 week (cohort 2), two cycles of 2 weeks (cohort 3), or continuously for 6 weeks (cohort 4). All cohorts continued pembrolizumab for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR) at week 6, 12, 18 and PFS. RESULTS Between June 2016 and August 2018, 33 patients with advanced melanoma have been included and 32 were randomized. Grade 3-4 TRAE were observed in 12%, 12%, 50%, and 63% of patients in cohort 1, 2, 3, and 4, respectively. All planned targeted therapy was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4. After a median follow-up of 43.5 months, median PFS was 10.6 months for pembrolizumab monotherapy and not reached for patients treated with pembrolizumab and intermittent dabrafenib and trametinib (p=0.17). The 2-year and 3-year landmark PFS were both 25% for cohort 1, both 63% for cohort 2, 50% and 38% for cohort 3 and 75% and 60% for cohort 4. CONCLUSIONS The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy. TRIAL REGISTRATION NUMBER NCT02625337.
Collapse
Affiliation(s)
- Elisa A Rozeman
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Judith M Versluis
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Karolina Sikorska
- Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Esmée P Hoefsmit
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Petros Dimitriadis
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Disha Rao
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ruben Lacroix
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | | | - Marta Lopez-Yurda
- Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Birthe C Heeres
- Department of Radiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Bart A van de Wiel
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Claudie Flohil
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Aysegul Sari
- Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | | | - Daan van den Broek
- Department of Laboratory Medicine, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Annegien Broeks
- Core Facility and Biobanking, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | | | - Marieke A Vollebergh
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Sofie Wilgenhof
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Johannes V van Thienen
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - John B A G Haanen
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Christian U Blank
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Medical Oncology, Leiden University Medical center, Leiden, The Netherlands
| |
Collapse
|
43
|
Zheng Y, Li S, Tang H, Meng X, Zheng Q. Molecular mechanisms of immunotherapy resistance in triple-negative breast cancer. Front Immunol 2023; 14:1153990. [PMID: 37426654 PMCID: PMC10327275 DOI: 10.3389/fimmu.2023.1153990] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 06/07/2023] [Indexed: 07/11/2023] Open
Abstract
The emergence of immunotherapy has profoundly changed the treatment model for triple-negative breast cancer (TNBC). But the heterogeneity of this disease resulted in significant differences in immunotherapy efficacy, and only some patients are able to benefit from this therapeutic modality. With the recent explosion in studies on the mechanism of cancer immunotherapy drug resistance, this article will focus on the processes of the immune response; summarize the immune evasion mechanisms in TNBC into three categories: loss of tumor-specific antigen, antigen presentation deficiency, and failure to initiate an immune response; together with the aberrant activation of a series of immune-critical signaling pathways, we will discuss how these activities jointly shape the immunosuppressive landscape within the tumor microenvironment. This review will attempt to elucidate the molecular mechanism of drug resistance in TNBC, identify potential targets that may assist in reversing drug resistance, and lay a foundation for research on identifying biomarkers for predicting immune efficacy and selection of breast cancer populations that may benefit from immunotherapy.
Collapse
Affiliation(s)
- Yiwen Zheng
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Shujin Li
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Hongchao Tang
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Xuli Meng
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Qinghui Zheng
- General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China
| |
Collapse
|
44
|
Salem ME, Mahrous EM, Ragab EA, Nafie MS, Dawood KM. Synthesis of novel mono- and bis-pyrazolylthiazole derivatives as anti-liver cancer agents through EGFR/HER2 target inhibition. BMC Chem 2023; 17:51. [PMID: 37291635 DOI: 10.1186/s13065-023-00921-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 02/23/2023] [Indexed: 06/10/2023] Open
Abstract
3-Bromoacetyl-4-(2-naphthoyl)-1-phenyl-1H-pyrazole (6) was synthesized from 2-acetylnaphthalene and was used as a new key building block for constructing the title targets. Thus, the reaction of 6 with the thiosemicarbazones 7a-d and 9-11 afforded the corresponding simple naphthoyl-(3-pyrazolyl)thiazole hybrids 8a-d and 12 ~ 14. The symmetric bis-(2-naphthoyl-pyrazol-3-yl)thiazol-2-yl)hydrazono)methyl)phenoxy)alkanes 18a-c and 21a-c were similarly synthesized from reaction of 6 with the appropriate bis-thiosemicarbazones 17a-c and 19a-c, respectively. The synthesized two series of simple and symmetrical bis-molecular hybrid merging naphthalene, thiazole, and pyrazole were evaluated for their cytotoxicity. Compounds 18b,c and 21a showed the most potent cytotoxicity (IC50 = 0.97-3.57 µM) compared to Lapatinib (IC50 = 7.45 µM). Additionally, they were safe (non-cytotoxic) against the THLE2 cells with higher IC50 values. Compounds 18c exhibited promising EGFR and HER-2 inhibitory activities with IC50 = 4.98 and 9.85 nM, respectively, compared to Lapatinib (IC50 = 6.1 and 17.2 nM). Apoptosis investigation revealed that 18c significantly activated apoptotic cell death in HepG2 cells, increasing the death rate by 63.6-fold and arresting cell proliferation at the S-phase. Compound 18c upregulated P53 by 8.6-fold, Bax by 8.9-fold, caspase-3,8,9 by 9, 2.3, and 7.6-fold, while it inhibited the Bcl-2 expression by 0.34-fold. Thereby, compound 18c exhibited promising cytotoxicity against EGFR/HER2 inhibition against liver cancer.
Collapse
Affiliation(s)
- Mostafa E Salem
- Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613, Egypt
| | - Esraa M Mahrous
- Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613, Egypt
| | - Eman A Ragab
- Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613, Egypt
| | - Mohamed S Nafie
- Department of Chemistry (Biochemistry program), Faculty of Science, Suez Canal University, Ismailia, 41522, Egypt
| | - Kamal M Dawood
- Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613, Egypt.
| |
Collapse
|
45
|
Piper M, Kluger H, Ruppin E, Hu-Lieskovan S. Immune Resistance Mechanisms and the Road to Personalized Immunotherapy. Am Soc Clin Oncol Educ Book 2023; 43:e390290. [PMID: 37459578 DOI: 10.1200/edbk_390290] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Abstract
What does the future of cancer immunotherapy look like and how do we get there? Find out where we've been and where we're headed in A Report on Resistance: The Road to personalized immunotherapy.
Collapse
Affiliation(s)
- Miles Piper
- School of Medicine, University of Utah, Salt Lake City, UT
| | | | - Eytan Ruppin
- Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Siwen Hu-Lieskovan
- School of Medicine, University of Utah, Salt Lake City, UT
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| |
Collapse
|
46
|
Du F, Yang LH, Liu J, Wang J, Fan L, Duangmano S, Liu H, Liu M, Wang J, Zhong X, Zhang Z, Wang F. The role of mitochondria in the resistance of melanoma to PD-1 inhibitors. J Transl Med 2023; 21:345. [PMID: 37221594 DOI: 10.1186/s12967-023-04200-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 05/14/2023] [Indexed: 05/25/2023] Open
Abstract
Malignant melanoma is one of the most common tumours and has the highest mortality rate of all types of skin cancers worldwide. Traditional and novel therapeutic approaches, including surgery, targeted therapy and immunotherapy, have shown good efficacy in the treatment of melanoma. At present, the mainstay of treatment for melanoma is immunotherapy combined with other treatment strategies. However, immune checkpoint inhibitors, such as PD-1 inhibitors, are not particularly effective in the clinical treatment of patients with melanoma. Changes in mitochondrial function may affect the development of melanoma and the efficacy of PD-1 inhibitors. To elucidate the role of mitochondria in the resistance of melanoma to PD-1 inhibitors, this review comprehensively summarises the role of mitochondria in the occurrence and development of melanoma, targets related to the function of mitochondria in melanoma cells and changes in mitochondrial function in different cells in melanoma resistant to PD-1 inhibitors. This review may help to develop therapeutic strategies for improving the clinical response rate of PD-1 inhibitors and prolonging the survival of patients by activating mitochondrial function in tumour and T cells.
Collapse
Affiliation(s)
- Fei Du
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Lu-Han Yang
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Jiao Liu
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
- Department of Pharmacy, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Jian Wang
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Lianpeng Fan
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Suwit Duangmano
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Hao Liu
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Minghua Liu
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Jun Wang
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Xiaolin Zhong
- Department of Pharmacy, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Zhuo Zhang
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China.
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand.
| | - Fang Wang
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China.
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand.
| |
Collapse
|
47
|
Kim J, Archer PA, Manspeaker MP, Avecilla ARC, Pollack BP, Thomas SN. Sustained release hydrogel for durable locoregional chemoimmunotherapy for BRAF-mutated melanoma. J Control Release 2023; 357:655-668. [PMID: 37080489 PMCID: PMC10328138 DOI: 10.1016/j.jconrel.2023.04.028] [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: 01/26/2023] [Revised: 04/10/2023] [Accepted: 04/17/2023] [Indexed: 04/22/2023]
Abstract
The wide prevalence of BRAF mutations in diagnosed melanomas drove the clinical advancement of BRAF inhibitors in combination with immune checkpoint blockade for treatment of advanced disease. However, deficits in therapeutic potencies and safety profiles motivate the development of more effective strategies that improve the combination therapy's therapeutic index. Herein, we demonstrate the benefits of a locoregional chemoimmunotherapy delivery system, a novel thermosensitive hydrogel comprised of gelatin and Pluronic® F127 components already widely used in humans in both commercial and clinical products, for the co-delivery of a small molecule BRAF inhibitor with immune checkpoint blockade antibody for the treatment of BRAF-mutated melanoma. In vivo evaluation of administration route and immune checkpoint target effects revealed intratumoral administration of antagonistic programmed cell death protein 1 antibody (aPD-1) lead to potent antitumor therapy in combination with BRAF inhibitor vemurafenib. The thermosensitive F127-g-Gelatin hydrogel that was evaluated in multiple murine models of BRAF-mutated melanoma that facilitated prolonged local drug release within the tumor (>1 week) substantially improved local immunomodulation, tumor control, rates of tumor response, and animal survival. Thermosensitive F127-g-Gelatin hydrogels thus improve upon the clinical benefits of vemurafenib and aPD-1 in a locoregional chemoimmunotherapy approach for the treatment of BRAF-mutated melanoma.
Collapse
Affiliation(s)
- Jihoon Kim
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, GA 30332, USA; Division of Biological Science and Technology, Yonsei University, Wonju 26493, South Korea
| | - Paul A Archer
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, GA 30332, USA; School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, United States
| | - Margaret P Manspeaker
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, GA 30332, USA; School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, United States
| | - Alexa R C Avecilla
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, 313 Ferst Dr NW, Atlanta, Georgia 30332, USA and Emory University, 201 Dowman Drive, Atlanta, GA 30322, USA
| | - Brian P Pollack
- Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road NE, Atlanta, GA 30322, USA; Departments of Dermatology and Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Susan N Thomas
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, GA 30332, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, 313 Ferst Dr NW, Atlanta, Georgia 30332, USA and Emory University, 201 Dowman Drive, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road NE, Atlanta, GA 30322, USA; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, GA 30332, USA.
| |
Collapse
|
48
|
Buchbinder EI, Giobbie-Hurder A, Ott PA. A phase I/II study of MCS110 with BRAF/MEK inhibition in patients with melanoma after progression on BRAF/MEK inhibition. Invest New Drugs 2023:10.1007/s10637-023-01364-5. [PMID: 37097370 DOI: 10.1007/s10637-023-01364-5] [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: 03/29/2023] [Accepted: 04/20/2023] [Indexed: 04/26/2023]
Abstract
BACKGROUND Prognosis for patients with metastatic melanoma has been improved dramatically with the development of BRAF/MEK directed therapy and immune checkpoint inhibition. However, resistance to therapy remains a challenge, particularly with BRAF/MEK targeted therapy which often has a limited duration of efficacy. Pre-clinical data suggest that adding CSF1 inhibition to BRAF/MEK targeted therapy may reduce resistance and increase efficacy. METHODS We performed a phase I/II study to determine the safety and efficacy of CSF1 inhibition with MCS110 in combination with BRAF/MEK inhibition with dabrafenib/trametinib in patients with BRAF V600E/K mutant metastatic melanoma. The trial was terminated early due to a decision by the study sponsor to cease further development of MCS110. RESULTS Between September 2018 to July 2019 six patients were enrolled on the study. Patients were evenly split between female (50%) and male (50%) with a median age of 59.5 yrs. (26-71). Five patients experienced grade 3 toxicities that were possibly related to one of the therapies, there were no grade 4 or grade 5 events. One patient had a partial response (PR) by RECIST 1.1, one patient had stable disease (SD), 3 patients had disease progression (PD). Median progression free survival was 2.3 months (90% CI: 1.3 mos to not reached). CONCLUSION MCS110 in combination with dabrafenib and trametinib was reasonably well tolerated in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration.
Collapse
Affiliation(s)
- Elizabeth I Buchbinder
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
| | - Anita Giobbie-Hurder
- Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Patrick A Ott
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| |
Collapse
|
49
|
Kumarasamy V, Frangou C, Wang J, Wan Y, Dynka A, Rosenheck H, Dey P, Abel EV, Knudsen ES, Witkiewicz AK. Pharmacologically targeting KRAS G12D in PDAC models: tumor cell intrinsic and extrinsic impact. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.18.533261. [PMID: 37162905 PMCID: PMC10168422 DOI: 10.1101/2023.03.18.533261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which new therapeutic interventions are needed. Here we assessed the cellular response to pharmacological KRAS inhibition, which target the central oncogenic factor in PDAC. In a panel of PDAC cell lines, pharmaceutical inhibition of KRAS G12D allele, with MRTX1133 yields variable efficacy in the suppression of cell growth and downstream gene expression programs in 2D culture. CRISPR screens identify new drivers for enhanced therapeutic response that regulate focal adhesion and signaling cascades, which were confirmed by gene specific knockdowns and combinatorial drug synergy. Interestingly, MRTX1133 is considerably more efficacious in the context of 3D cell cultures and in vivo PDAC patient-derived xenografts. In syngeneic models, KRAS G12D inhibition elicits potent tumor regression that did not occur in immune-deficient hosts. Digital spatial profiling on tumor tissues indicates that MRTX1133 activates interferon-γ signaling and induces antigen presentation that modulate the tumor microenvironment. Further investigation on the immunological response using single cell sequencing and multispectral imaging reveals that tumor regression is associated with suppression of neutrophils and influx of effector CD8 + T-cells. Thus, both tumor cell intrinsic and extrinsic events contribute to response and credential KRAS G12D inhibition as promising strategy for a large percentage of PDAC tumors.
Collapse
|
50
|
Patel RP, Somasundram PM, Smith LK, Sheppard KE, McArthur GA. The therapeutic potential of targeting minimal residual disease in melanoma. Clin Transl Med 2023; 13:e1197. [PMID: 36967556 PMCID: PMC10040726 DOI: 10.1002/ctm2.1197] [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: 10/17/2022] [Revised: 01/18/2023] [Accepted: 01/29/2023] [Indexed: 03/28/2023] Open
Abstract
Background Cutaneous melanoma is a lethal form of skin cancer with morbidity and mortality rates highest amongst European, North American and Australasian populations. The developments of targeted therapies (TTs) directed at the oncogene BRAF and its downstream mediator MEK, and immune checkpoint inhibitors (ICI), have revolutionized the treatment of metastatic melanoma, improving patient outcomes. However, both TT and ICI have their limitations. Although TTs are associated with high initial response rates, these are typically short‐lived due to resistance. Conversely, although ICIs provide more durable responses, they have lower initial response rates. Due to these distinct yet complementary response profiles, it has been proposed that sequencing ICI with TT could lead to a high frequency of durable responses whilst circumventing the toxicity associated with combined ICI + TT treatment. However, several questions remain unanswered, including the mechanisms underpinning this synergy and the optimal sequencing strategy. The key to determining this is to uncover the biology of each phase of the therapeutic response. Aims and methods In this review, we show that melanoma responds to TT and ICI in three phases: early response, minimal residual disease (MRD) and disease progression. We explore the effects of ICI and TT on melanoma cells and the tumour immune microenvironment, with a particular focus on MRD which is predicted to underpin the development of acquired resistance in the third phase of response. Conclusion In doing so, we provide a new framework which may inform novel therapeutic approaches for melanoma, including optimal sequencing strategies and agents that target MRD, thereby ultimately improving clinical outcomes for patients.
Collapse
Affiliation(s)
- Riyaben P Patel
- Cancer Research DivisionPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneParkvilleVictoriaAustralia
| | - Pretashini M Somasundram
- Faculty of MedicineDentistry and Health Sciences, University of MelbourneParkvilleVictoriaAustralia
| | - Lorey K. Smith
- Cancer Research DivisionPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneParkvilleVictoriaAustralia
| | - Karen E. Sheppard
- Cancer Research DivisionPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneParkvilleVictoriaAustralia
| | - Grant A. McArthur
- Cancer Research DivisionPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneParkvilleVictoriaAustralia
- Department of Medical OncologyPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
| |
Collapse
|