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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.
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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.
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Roosma J. A comprehensive review of oncogenic Notch signaling in multiple myeloma. PeerJ 2024; 12:e18485. [PMID: 39619207 PMCID: PMC11608568 DOI: 10.7717/peerj.18485] [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: 05/01/2024] [Accepted: 10/16/2024] [Indexed: 12/13/2024] Open
Abstract
Multiple myeloma remains an incurable plasma cell cancer with radical case-by-case heterogeneity. Because of this, personalized and disease-specific biology of multiple myeloma must be understood for the discovery of effective molecular targets. The highly evolutionarily conserved Notch signaling pathway has been extensively described as a multifaceted driver of the multiple myeloma disease process-contributing to both intrinsic effects of malignant cells and to widespread remodeling of the tumor microenvironment that further facilitates disease progression. Namely, Notch signaling amongst malignant cells promotes increased proliferation, tumor-initiating capacity, drug resistance, and invasiveness. Moreover, Notch signaling between malignant cells and cells of the tumor microenvironment leads to increased osteodegenerative disease and angiogenesis. This comprehensive review will discuss both the intrinsic implications of pathological Notch signaling in multiple myeloma and the extrinsic implications of Notch signaling in the multiple myeloma tumor microenvironment. Additionally, the genetic origins of Notch signaling dysregulation in multiple myeloma and current attempts at targeting Notch therapeutically will be reviewed. While the subject has been reviewed previously, recent developments in the intervening years demand a revised synthesis of the literature. The aim of this work is to introduce and thoroughly synthesize the current state of knowledge in this vein of research and to highlight future directions for both new and in-the-field scientists.
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Affiliation(s)
- Justin Roosma
- Biology, Eastern Washington University, Cheney, Washington, United States
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Campos F, Kasper B. Examining nirogacestat for adults with progressing desmoid tumors who require systemic treatment. Expert Opin Pharmacother 2024; 25:2115-2124. [PMID: 39414771 DOI: 10.1080/14656566.2024.2418416] [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: 09/03/2024] [Revised: 10/10/2024] [Accepted: 10/15/2024] [Indexed: 10/18/2024]
Abstract
INTRODUCTION Desmoid tumor (DT) is a rare, locally aggressive, mesenchymal neoplasm that can arise at any site in the body. Medical therapies play a major role for DT's patients requiring treatment. A novel systemic approach has recently emerged with Nirogacestat, a γ-secretase inhibitor targeting the NOTCH signaling pathway. AREAS COVERED Nirogacestat is the first drug in its class to receive approval from the Food and Drug Administration (FDA) and is the first FDA-approved treatment specifically for DTs. We reviewed the data leading to its discovery, including its mechanism of action, pharmacological properties, clinical efficacy, and its positioning within the current treatment armamentarium for DTs. EXPERT OPINION High-quality evidence for systemic therapies in the management of DTs remains an unmet need. Nirogacestat now joins sorafenib as the only drugs with efficacy in DTs demonstrated by randomized phase 3 studies. Currently, there are no comparative trials of the available systemic therapies. Therefore, physicians should consider factors such as drug accessibility, cost, toxicity profile, comorbidities, and patient preferences when selecting treatment. Long-term efficacy and safety data will be essential for evaluating the duration of treatment response and monitoring late-onset side effects of Nirogacestat.
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Affiliation(s)
- Fernando Campos
- Sarcoma Reference Center, A.C.Camargo Cancer Center (ACCCC), Sao Paulo, Brazil
| | - Bernd Kasper
- Sarcoma Unit, Mannheim Cancer Center (MCC), Mannheim University Medical Center, University of Heidelberg, Mannheim, Germany
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Shi Q, Xue C, Zeng Y, Yuan X, Chu Q, Jiang S, Wang J, Zhang Y, Zhu D, Li L. Notch signaling pathway in cancer: from mechanistic insights to targeted therapies. Signal Transduct Target Ther 2024; 9:128. [PMID: 38797752 PMCID: PMC11128457 DOI: 10.1038/s41392-024-01828-x] [Citation(s) in RCA: 86] [Impact Index Per Article: 86.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/31/2024] [Accepted: 04/15/2024] [Indexed: 05/29/2024] Open
Abstract
Notch signaling, renowned for its role in regulating cell fate, organ development, and tissue homeostasis across metazoans, is highly conserved throughout evolution. The Notch receptor and its ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences, typically necessitating receptor-ligand interaction to initiate classical Notch signaling transduction. Accumulating evidence indicates that the Notch signaling pathway serves as both an oncogenic factor and a tumor suppressor in various cancer types. Dysregulation of this pathway promotes epithelial-mesenchymal transition and angiogenesis in malignancies, closely linked to cancer proliferation, invasion, and metastasis. Furthermore, the Notch signaling pathway contributes to maintaining stem-like properties in cancer cells, thereby enhancing cancer invasiveness. The regulatory role of the Notch signaling pathway in cancer metabolic reprogramming and the tumor microenvironment suggests its pivotal involvement in balancing oncogenic and tumor suppressive effects. Moreover, the Notch signaling pathway is implicated in conferring chemoresistance to tumor cells. Therefore, a comprehensive understanding of these biological processes is crucial for developing innovative therapeutic strategies targeting Notch signaling. This review focuses on the research progress of the Notch signaling pathway in cancers, providing in-depth insights into the potential mechanisms of Notch signaling regulation in the occurrence and progression of cancer. Additionally, the review summarizes pharmaceutical clinical trials targeting Notch signaling for cancer therapy, aiming to offer new insights into therapeutic strategies for human malignancies.
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Affiliation(s)
- Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Shuwen Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Jinzhi Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yaqi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Danhua Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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MacLean MR, Walker OL, Arun RP, Fernando W, Marcato P. Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways. Int J Mol Sci 2024; 25:4102. [PMID: 38612911 PMCID: PMC11012648 DOI: 10.3390/ijms25074102] [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: 02/28/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer stem cells (CSCs) represent a subpopulation within tumors that promote cancer progression, metastasis, and recurrence due to their self-renewal capacity and resistance to conventional therapies. CSC-specific markers and signaling pathways highly active in CSCs have emerged as a promising strategy for improving patient outcomes. This review provides a comprehensive overview of the therapeutic targets associated with CSCs of solid tumors across various cancer types, including key molecular markers aldehyde dehydrogenases, CD44, epithelial cellular adhesion molecule, and CD133 and signaling pathways such as Wnt/β-catenin, Notch, and Sonic Hedgehog. We discuss a wide array of therapeutic modalities ranging from targeted antibodies, small molecule inhibitors, and near-infrared photoimmunotherapy to advanced genetic approaches like RNA interference, CRISPR/Cas9 technology, aptamers, antisense oligonucleotides, chimeric antigen receptor (CAR) T cells, CAR natural killer cells, bispecific T cell engagers, immunotoxins, drug-antibody conjugates, therapeutic peptides, and dendritic cell vaccines. This review spans developments from preclinical investigations to ongoing clinical trials, highlighting the innovative targeting strategies that have been informed by CSC-associated pathways and molecules to overcome therapeutic resistance. We aim to provide insights into the potential of these therapies to revolutionize cancer treatment, underscoring the critical need for a multi-faceted approach in the battle against cancer. This comprehensive analysis demonstrates how advances made in the CSC field have informed significant developments in novel targeted therapeutic approaches, with the ultimate goal of achieving more effective and durable responses in cancer patients.
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Affiliation(s)
- Maya R. MacLean
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Olivia L. Walker
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Raj Pranap Arun
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Wasundara Fernando
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Biology, Acadia University, Wolfville, NS B4P 2R6, Canada
| | - Paola Marcato
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Nova Scotia Health Authority, Halifax, NS B3H 4R2, Canada
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Ghosh A, Mitra AK. Metastasis and cancer associated fibroblasts: taking it up a NOTCH. Front Cell Dev Biol 2024; 11:1277076. [PMID: 38269089 PMCID: PMC10806909 DOI: 10.3389/fcell.2023.1277076] [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: 08/14/2023] [Accepted: 12/27/2023] [Indexed: 01/26/2024] Open
Abstract
Metastasis is the least understood aspect of cancer biology. 90% of cancer related deaths occur due extensive metastatic burden in patients. Apart from metastasizing cancer cells, the pro-tumorigenic and pro-metastatic role of the tumor stroma plays a crucial part in this complex process often leading to disease relapse and therapy resistance. Cellular signaling processes play a crucial role in the process of tumorigenesis and metastasis when aberrantly turned on, not just in the cancer cells, but also in the cells of the tumor microenvironment (TME). One of the most conserved pathways includes the Notch signaling pathway that plays a crucial role in the development and progression of many cancers. In addition to its well documented role in cancer cells, recent evidence suggests crucial involvement of Notch signaling in the stroma as well. This review aims to highlight the current findings focusing on the oncogenic role of notch signaling in cancer cells and the TME, with a specific focus on cancer associated fibroblasts (CAFs), which constitute a major part of the tumor stroma and are important for tumor progression. Recent efforts have focused on the development of anti-cancer and anti-metastatic therapies targeting TME. Understanding the importance of Notch signaling in the TME would help identify important drivers for stromal reprogramming, metastasis and importantly, drive future research in the effort to develop TME-targeted therapies utilizing Notch.
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Affiliation(s)
- Argha Ghosh
- Indiana University School of Medicine-Bloomington, Bloomington, IN, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, United States
| | - Anirban K. Mitra
- Indiana University School of Medicine-Bloomington, Bloomington, IN, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, United States
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
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7
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Deshotels L, Safa FM, Saba NS. NOTCH Signaling in Mantle Cell Lymphoma: Biological and Clinical Implications. Int J Mol Sci 2023; 24:10280. [PMID: 37373427 DOI: 10.3390/ijms241210280] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Despite major progress in mantle cell lymphoma (MCL) therapeutics, MCL remains a deadly disease with a median survival not exceeding four years. No single driver genetic lesion has been described to solely give rise to MCL. The hallmark translocation t(11;14)(q13;q32) requires additional genetic alterations for the malignant transformation. A short list of recurrently mutated genes including ATM, CCND1, UBR5, TP53, BIRC3, NOTCH1, NOTCH2, and TRAF2 recently emerged as contributors to the pathogenesis of MCL. Notably, NOTCH1 and NOTCH2 were found to be mutated in multiple B cell lymphomas, including 5-10% of MCL, with most of these mutations occurring within the PEST domain of the protein. The NOTCH genes play a critical role in the early and late phases of normal B cell differentiation. In MCL, mutations in the PEST domain stabilize NOTCH proteins, rendering them resistant to degradation, which subsequently results in the upregulation of genes involved in angiogenesis, cell cycle progression, and cell migration and adhesion. At the clinical level, mutated NOTCH genes are associated with aggressive features in MCL, such as the blastoid and pleomorphic variants, a shorter response to treatment, and inferior survival. In this article, we explore in detail the role of NOTCH signaling in MCL biology and the ongoing efforts toward targeted therapeutic interventions.
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Affiliation(s)
- Leigh Deshotels
- Section of Hematology and Medical Oncology, Deming Department of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Firas M Safa
- Service d'hématologie, Centre Hospitalier du Mans, 72037 Le Mans, France
| | - Nakhle S Saba
- Section of Hematology and Medical Oncology, Deming Department of Medicine, Tulane University, New Orleans, LA 70112, USA
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Li X, Yan X, Wang Y, Kaur B, Han H, Yu J. The Notch signaling pathway: a potential target for cancer immunotherapy. J Hematol Oncol 2023; 16:45. [PMID: 37131214 PMCID: PMC10155406 DOI: 10.1186/s13045-023-01439-z] [Citation(s) in RCA: 74] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 04/13/2023] [Indexed: 05/04/2023] Open
Abstract
Dysregulation of the Notch signaling pathway, which is highly conserved across species, can drive aberrant epigenetic modification, transcription, and translation. Defective gene regulation caused by dysregulated Notch signaling often affects networks controlling oncogenesis and tumor progression. Meanwhile, Notch signaling can modulate immune cells involved in anti- or pro-tumor responses and tumor immunogenicity. A comprehensive understanding of these processes can help with designing new drugs that target Notch signaling, thereby enhancing the effects of cancer immunotherapy. Here, we provide an up-to-date and comprehensive overview of how Notch signaling intrinsically regulates immune cells and how alterations in Notch signaling in tumor cells or stromal cells extrinsically regulate immune responses in the tumor microenvironment (TME). We also discuss the potential role of Notch signaling in tumor immunity mediated by gut microbiota. Finally, we propose strategies for targeting Notch signaling in cancer immunotherapy. These include oncolytic virotherapy combined with inhibition of Notch signaling, nanoparticles (NPs) loaded with Notch signaling regulators to specifically target tumor-associated macrophages (TAMs) to repolarize their functions and remodel the TME, combining specific and efficient inhibitors or activators of Notch signaling with immune checkpoint blockers (ICBs) for synergistic anti-tumor therapy, and implementing a customized and effective synNotch circuit system to enhance safety of chimeric antigen receptor (CAR) immune cells. Collectively, this review aims to summarize how Notch signaling intrinsically and extrinsically shapes immune responses to improve immunotherapy.
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Affiliation(s)
- Xinxin Li
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, Shaanxi, People's Republic of China
| | - Xianchun Yan
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Yufeng Wang
- Cancer Institute, The First Hospital of Jilin University, Changchun, 130021, People's Republic of China
| | - Balveen Kaur
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 77225, USA
| | - Hua Han
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, Shaanxi, People's Republic of China.
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, 1500 East Duarte, Los Angeles, CA, 91010, USA.
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You WK, Schuetz TJ, Lee SH. Targeting the DLL/Notch Signaling Pathway in Cancer: Challenges and Advances in Clinical Development. Mol Cancer Ther 2023; 22:3-11. [PMID: 36223541 PMCID: PMC9808372 DOI: 10.1158/1535-7163.mct-22-0243] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 08/28/2022] [Accepted: 10/07/2022] [Indexed: 02/03/2023]
Abstract
The DLL/Notch signaling pathway plays an important role in cancer as a key driver in maintaining cancer stemness and inducing tumor angiogenesis. Many different types of DLL/Notch inhibitors have been developed and explored in clinical trials for cancer treatment, including small-molecule compounds to inhibit gamma-secretase and antibodies targeting Notch ligands or receptors. Despite promising efficacy of these inhibitors in preclinical studies, the overall clinical outcomes have been insufficient to advance to the next stage of clinical development primarily due to safety concerns or modest efficacy. To overcome the narrow therapeutic window of DLL/Notch inhibitors, diverse strategies for improving the balance between the safety and efficacy are currently being explored. Here, we review the clinical perspective and potential of DLL/Notch inhibitors as anticancer agents based on recent results from multiple clinical studies. An antibody specifically targeting Notch ligands or receptors may offer a better approach to reduce concerns about toxicity derived from broad-spectrum DLL/Notch blockers. In addition, combination therapy with an angiogenesis inhibitor targeting VEGF could be a better option for increasing anticancer efficacy. Taken together, the results of clinical trials suggest a bispecific antibody blocking the DLL/Notch and VEGF/VEGFR signaling pathways as a promising approach for effective anticancer treatment.
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Affiliation(s)
- Weon-Kyoo You
- R&D Center, ABL Bio, Inc., Seongnam-si, Republic of Korea.,Corresponding Author: Weon-Kyoo You, R&D, R&D center, ABL Bio, Inc., 2F, 16 Daewangpangyo-ro, 712 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea. Phone: 8231-8018-9803; Fax: 8231-8018-9836; E-mail:
| | | | - Sang Hoon Lee
- R&D Center, ABL Bio, Inc., Seongnam-si, Republic of Korea
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The role of Hedgehog and Notch signaling pathway in cancer. MOLECULAR BIOMEDICINE 2022; 3:44. [PMID: 36517618 PMCID: PMC9751255 DOI: 10.1186/s43556-022-00099-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/25/2022] [Indexed: 12/23/2022] Open
Abstract
Notch and Hedgehog signaling are involved in cancer biology and pathology, including the maintenance of tumor cell proliferation, cancer stem-like cells, and the tumor microenvironment. Given the complexity of Notch signaling in tumors, its role as both a tumor promoter and suppressor, and the crosstalk between pathways, the goal of developing clinically safe, effective, tumor-specific Notch-targeted drugs has remained intractable. Drugs developed against the Hedgehog signaling pathway have affirmed definitive therapeutic effects in basal cell carcinoma; however, in some contexts, the challenges of tumor resistance and recurrence leap to the forefront. The efficacy is very limited for other tumor types. In recent years, we have witnessed an exponential increase in the investigation and recognition of the critical roles of the Notch and Hedgehog signaling pathways in cancers, and the crosstalk between these pathways has vast space and value to explore. A series of clinical trials targeting signaling have been launched continually. In this review, we introduce current advances in the understanding of Notch and Hedgehog signaling and the crosstalk between pathways in specific tumor cell populations and microenvironments. Moreover, we also discuss the potential of targeting Notch and Hedgehog for cancer therapy, intending to promote the leap from bench to bedside.
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11
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Manni W, Min W. Signaling pathways in the regulation of cancer stem cells and associated targeted therapy. MedComm (Beijing) 2022; 3:e176. [PMID: 36226253 PMCID: PMC9534377 DOI: 10.1002/mco2.176] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 11/07/2022] Open
Abstract
Cancer stem cells (CSCs) are defined as a subpopulation of malignant tumor cells with selective capacities for tumor initiation, self-renewal, metastasis, and unlimited growth into bulks, which are believed as a major cause of progressive tumor phenotypes, including recurrence, metastasis, and treatment failure. A number of signaling pathways are involved in the maintenance of stem cell properties and survival of CSCs, including well-established intrinsic pathways, such as the Notch, Wnt, and Hedgehog signaling, and extrinsic pathways, such as the vascular microenvironment and tumor-associated immune cells. There is also intricate crosstalk between these signal cascades and other oncogenic pathways. Thus, targeting pathway molecules that regulate CSCs provides a new option for the treatment of therapy-resistant or -refractory tumors. These treatments include small molecule inhibitors, monoclonal antibodies that target key signaling in CSCs, as well as CSC-directed immunotherapies that harness the immune systems to target CSCs. This review aims to provide an overview of the regulating networks and their immune interactions involved in CSC development. We also address the update on the development of CSC-directed therapeutics, with a special focus on those with application approval or under clinical evaluation.
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Affiliation(s)
- Wang Manni
- Department of Biotherapy, Cancer Center, West China HospitalSichuan UniversityChengduP. R. China
| | - Wu Min
- Department of Biomedical Sciences, School of Medicine and Health SciencesUniversity of North DakotaGrand ForksNorth DakotaUSA
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Notch signaling in malignant gliomas: supporting tumor growth and the vascular environment. Cancer Metastasis Rev 2022; 41:737-747. [PMID: 35624227 DOI: 10.1007/s10555-022-10041-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 05/18/2022] [Indexed: 11/02/2022]
Abstract
Glioblastoma is the most malignant form of glioma, which is the most commonly occurring tumor of the central nervous system. Notch signaling in glioblastoma is considered to be a marker of an undifferentiated tumor cell state, associated with tumor stem cells. Notch is also known for facilitating tumor dormancy escape, recurrence and progression after treatment. Studies in vitro suggest that reducing, removing or blocking the expression of this gene triggers tumor cell differentiation, which shifts the phenotype away from stemness status and consequently facilitates treatment. In contrast, in the vasculature, Notch appears to also function as an important receptor that defines mature non-leaking vessels, and increasing its expression promotes tumor normalization in models of cancer in vivo. Failures in clinical trials with Notch inhibitors are potentially related to their opposing effects on the tumor versus the tumor vasculature, which points to the need for a greater understanding of this signaling pathway.
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Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct Target Ther 2022; 7:95. [PMID: 35332121 PMCID: PMC8948217 DOI: 10.1038/s41392-022-00934-y] [Citation(s) in RCA: 533] [Impact Index Per Article: 177.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/16/2022] [Accepted: 02/16/2022] [Indexed: 02/07/2023] Open
Abstract
The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.
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14
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Anobile DP, Montenovo G, Pecoraro C, Franczak M, Ait Iddouch W, Peters GJ, Riganti C, Giovannetti E. Splicing deregulation, microRNA and notch aberrations: fighting the three-headed dog to overcome drug resistance in malignant mesothelioma. Expert Rev Clin Pharmacol 2022; 15:305-322. [PMID: 35533249 DOI: 10.1080/17512433.2022.2074835] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 05/04/2022] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Malignant mesothelioma (MMe) is an aggressive rare cancer of the mesothelium, associated with asbestos exposure. MMe is currently an incurable disease at all stages mainly due to resistance to treatments. It is therefore necessary to elucidate key mechanisms underlying chemoresistance, in an effort to exploit them as novel therapeutic targets. AREAS COVERED Chemoresistance is frequently elicited by microRNA (miRNA) alterations and splicing deregulations. Indeed, several miRNAs, such as miR-29c, have been shown to exert oncogenic or oncosuppressive activity. Alterations in the splicing machinery might also be involved in chemoresistance. Moreover, the Notch signaling pathway, often deregulated in MMe, plays a key role in cancer stem cells formation and self-renewal, leading to drug resistance and relapses. EXPERT OPINION The prognosis of MMe in patients varies among different tumors and patient characteristics, and novel biomarkers and therapies are warranted. This work aims at giving an overview of MMe, with a special focus on state-of-the-art treatments and new therapeutic strategies against vulnerabilities emerging from studies on epigenetics factors. Besides, this review is also the first to discuss the interplay between miRNAs and alternative splicing as well as the role of Notch as new promising frontiers to overcome drug resistance in MMe.
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Affiliation(s)
- Dario P Anobile
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
- Department of Oncology, University of Torino, Orbassano, Italy
| | - Giulia Montenovo
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Camilla Pecoraro
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
- Farmaceutiche (STEBICEF), Università degli Studi di PalermoDipartimento Di Scienze E Tecnologie Biologiche Chimiche E , Palermo, Italy
| | - Marika Franczak
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
- Department of Biochemistry, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Widad Ait Iddouch
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Godefridus J Peters
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
- Department of Biochemistry, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Chiara Riganti
- Department of Oncology, University of Torino, Orbassano, Italy
| | - Elisa Giovannetti
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
- Fondazione Pisana per la Scienza Pisa, 56100 Pisa, Italy
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15
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Cravero K, Pantone MV, Shin DH, Bergman R, Cochran R, Chu D, Zabransky DJ, Karthikeyan S, Waters IG, Hunter N, Rosen DM, Kyker-Snowman K, Dalton WB, Button B, Shinn D, Wong HY, Donaldson J, Hurley PJ, Croessmann S, Park BH. NOTCH1 PEST domain variants are responsive to standard of care treatments despite distinct transformative properties in a breast cancer model. Oncotarget 2022; 13:373-386. [PMID: 35186194 PMCID: PMC8849273 DOI: 10.18632/oncotarget.28200] [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: 12/15/2021] [Accepted: 02/07/2022] [Indexed: 12/01/2022] Open
Abstract
Activating variants in the PEST region of NOTCH1 have been associated with aggressive phenotypes in human cancers, including triple-negative breast cancer (TNBC). Previous studies suggested that PEST domain variants in TNBC patients resulted in increased cell proliferation, invasiveness, and decreased overall survival. In this study, we assess the phenotypic transformation of activating NOTCH1 variants and their response to standard of care therapies. AAV-mediated gene targeting was used to isogenically incorporate 3 NOTCH1 variants, including a novel TNBC frameshift variant, in two non-tumorigenic breast epithelial cell lines, MCF10A and hTERT-IMEC. Two different variants at the NOTCH1 A2241 site (A2441fs and A2441T) both demonstrated increased transformative properties when compared to a non-transformative PEST domain variant (S2523L). These phenotypic changes include proliferation, migration, anchorage-independent growth, and MAPK pathway activation. In contrast to previous studies, activating NOTCH1 variants did not display sensitivity to a gamma secretase inhibitor (GSI) or resistance to chemotherapies. This study demonstrates distinct transformative phenotypes are specific to a given variant within NOTCH1 and these phenotypes do not correlate with sensitivities or resistance to chemotherapies or GSIs. Although previous studies have suggested NOTCH1 variants may be prognostic for TNBC, our study does not demonstrate prognostic ability of these variants and suggests further characterization would be required for clinical applications.
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Affiliation(s)
- Karen Cravero
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- These authors contributed equally to this work
| | - Morgan V. Pantone
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
- These authors contributed equally to this work
| | - Dong Ho Shin
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
- These authors contributed equally to this work
| | - Riley Bergman
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Rory Cochran
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - David Chu
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Daniel J. Zabransky
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Swathi Karthikeyan
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ian G. Waters
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Natasha Hunter
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - D. Marc Rosen
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kelly Kyker-Snowman
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - W. Brian Dalton
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Berry Button
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Dan Shinn
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hong Yuen Wong
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Joshua Donaldson
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Paula J. Hurley
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Sarah Croessmann
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Ben Ho Park
- Division of Hematology, Oncology, Department of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
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16
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Small molecules targeting γ-secretase and their potential biological applications. Eur J Med Chem 2022; 232:114169. [DOI: 10.1016/j.ejmech.2022.114169] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 01/30/2022] [Accepted: 01/30/2022] [Indexed: 12/14/2022]
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17
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Kordbacheh F, Farah CS. Current and Emerging Molecular Therapies for Head and Neck Squamous Cell Carcinoma. Cancers (Basel) 2021; 13:cancers13215471. [PMID: 34771633 PMCID: PMC8582411 DOI: 10.3390/cancers13215471] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/09/2021] [Accepted: 10/28/2021] [Indexed: 12/24/2022] Open
Abstract
Head and neck cancer affects nearly 750,000 patients, with more than 300,000 deaths annually. Advances in first line surgical treatment have improved survival rates marginally particularly in developed countries, however survival rates for aggressive locally advanced head and neck cancer are still poor. Recurrent and metastatic disease remains a significant problem for patients and the health system. As our knowledge of the genomic landscape of the head and neck cancers continues to expand, there are promising developments occurring in molecular therapies available for advanced or recalcitrant disease. The concept of precision medicine is underpinned by our ability to accurately sequence tumour samples to best understand individual patient genomic variations and to tailor targeted therapy for them based on such molecular profiling. Not only is their purported response to therapy a factor of their genomic variation, but so is their inclusion in biomarker-driven personalised medicine therapeutic trials. With the ever-expanding number of molecular druggable targets explored through advances in next generation sequencing, the number of clinical trials assessing these targets has significantly increased over recent years. Although some trials are focussed on first-line therapeutic approaches, a greater majority are focussed on locally advanced, recurrent or metastatic disease. Similarly, although single agent monotherapy has been found effective in some cases, it is the combination of drugs targeting different signalling pathways that seem to be more beneficial to patients. This paper outlines current and emerging molecular therapies for head and neck cancer, and updates readers on outcomes of the most pertinent clinical trials in this area while also summarising ongoing efforts to bring more molecular therapies into clinical practice.
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Affiliation(s)
- Farzaneh Kordbacheh
- Broad Institute of MIT and Harvard, Boston, MA 02142, USA;
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia
| | - Camile S. Farah
- The Australian Centre for Oral Oncology Research & Education, Nedlands, WA 6009, Australia
- Genomics for Life, Milton, QLD 4064, Australia
- Anatomical Pathology, Australian Clinical Labs, Subiaco, WA 6009, Australia
- Head and Neck Cancer Signalling Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
- Correspondence:
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18
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Huang B, Yan X, Li Y. Cancer Stem Cell for Tumor Therapy. Cancers (Basel) 2021; 13:cancers13194814. [PMID: 34638298 PMCID: PMC8508418 DOI: 10.3390/cancers13194814] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/13/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Although many methods have been applied in clinical treatment for tumors, they still always show a poor prognosis. Molecule targeted therapy has revolutionized tumor therapy, and a proper target must be found urgently. With a crucial role in tumor development, metastasis and recurrence, cancer stem cells have been found to be a feasible and potential target for tumor therapy. We list the unique biological characteristics of cancer stem cells and summarize the recent strategies to target cancer stem cells for tumor therapy, through which we hope to provide a comprehensive understanding of cancer stem cells and find a better combinational strategy to target cancer stem cells for tumor therapy. Abstract Tumors pose a significant threat to human health. Although many methods, such as operations, chemotherapy and radiotherapy, have been proposed to eliminate tumor cells, the results are unsatisfactory. Targeting therapy has shown potential due to its specificity and efficiency. Meanwhile, it has been revealed that cancer stem cells (CSCs) play a crucial role in the genesis, development, metastasis and recurrence of tumors. Thus, it is feasible to inhibit tumors and improve prognosis via targeting CSCs. In this review, we provide a comprehensive understanding of the biological characteristics of CSCs, including mitotic pattern, metabolic phenotype, therapeutic resistance and related mechanisms. Finally, we summarize CSCs targeted strategies, including targeting CSCs surface markers, targeting CSCs related signal pathways, targeting CSC niches, targeting CSC metabolic pathways, inducing differentiation therapy and immunotherapy (tumor vaccine, CAR-T, oncolytic virus, targeting CSCs–immune cell crosstalk and immunity checkpoint inhibitor). We highlight the potential of immunity therapy and its combinational anti-CSC therapies, which are composed of different drugs working in different mechanisms.
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Affiliation(s)
- Binjie Huang
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China; (B.H.); (X.Y.)
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou 730030, China
| | - Xin Yan
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China; (B.H.); (X.Y.)
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou 730030, China
| | - Yumin Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, China; (B.H.); (X.Y.)
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou 730030, China
- Correspondence: ; Tel.: +86-138-9361-5421
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19
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Alvarez-Trotta A, Guerrant W, Astudillo L, Lahiry M, Diluvio G, Shersher E, Kaneku H, Robbins DJ, Orton D, Capobianco AJ. Pharmacological Disruption of the Notch1 Transcriptional Complex Inhibits Tumor Growth by Selectively Targeting Cancer Stem Cells. Cancer Res 2021; 81:3347-3357. [PMID: 33820800 PMCID: PMC8655881 DOI: 10.1158/0008-5472.can-20-3611] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 03/08/2021] [Accepted: 04/01/2021] [Indexed: 11/16/2022]
Abstract
In many human cancers, deregulation of the Notch pathway has been shown to play a role in the initiation and maintenance of the neoplastic phenotype. Aberrant Notch activity also plays a central role in the maintenance and survival of cancer stem cells (CSC), which underlie metastasis and resistance to therapy. For these reasons, inhibition of Notch signaling has become an exceedingly attractive target for cancer therapeutic development. However, attempts to develop Notch pathway-specific drugs have largely failed in the clinic, in part due to intestinal toxicity. Here, we report the discovery of NADI-351, the first specific small-molecule inhibitor of Notch1 transcriptional complexes. NADI-351 selectively disrupted Notch1 transcription complexes and reduced Notch1 recruitment to target genes. NADI-351 demonstrated robust antitumor activity without inducing intestinal toxicity in mouse models, and CSCs were ablated by NADI-351 treatment. Our study demonstrates that NADI-351 is an orally available and potent inhibitor of Notch1-mediated transcription that inhibits tumor growth with low toxicity, providing a potential therapeutic approach for improved cancer treatment. SIGNIFICANCE: This study showcases the first Notch1-selective inhibitor that suppresses tumor growth with limited toxicity by selectively ablating cancer stem cells.
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Affiliation(s)
- Annamil Alvarez-Trotta
- The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida
- Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | | | - Luisana Astudillo
- The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida
- Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | - Mohini Lahiry
- The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida
- Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | - Giulia Diluvio
- The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida
- Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | - Elena Shersher
- The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida
- Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | - Hugo Kaneku
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - David J Robbins
- The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida
- Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | | | - Anthony J Capobianco
- The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida.
- Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
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20
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Allen F, Maillard I. Therapeutic Targeting of Notch Signaling: From Cancer to Inflammatory Disorders. Front Cell Dev Biol 2021; 9:649205. [PMID: 34124039 PMCID: PMC8194077 DOI: 10.3389/fcell.2021.649205] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 04/26/2021] [Indexed: 12/20/2022] Open
Abstract
Over the past two decades, the Notch signaling pathway has been investigated as a therapeutic target for the treatment of cancers, and more recently in the context of immune and inflammatory disorders. Notch is an evolutionary conserved pathway found in all metazoans that is critical for proper embryonic development and for the postnatal maintenance of selected tissues. Through cell-to-cell contacts, Notch orchestrates cell fate decisions and differentiation in non-hematopoietic and hematopoietic cell types, regulates immune cell development, and is integral to shaping the amplitude as well as the quality of different types of immune responses. Depriving some cancer types of Notch signals has been shown in preclinical studies to stunt tumor growth, consistent with an oncogenic function of Notch signaling. In addition, therapeutically antagonizing Notch signals showed preclinical potential to prevent or reverse inflammatory disorders, including autoimmune diseases, allergic inflammation and immune complications of life-saving procedures such allogeneic bone marrow and solid organ transplantation (graft-versus-host disease and graft rejection). In this review, we discuss some of these unique approaches, along with the successes and challenges encountered so far to target Notch signaling in preclinical and early clinical studies. Our goal is to emphasize lessons learned to provide guidance about emerging strategies of Notch-based therapeutics that could be deployed safely and efficiently in patients with immune and inflammatory disorders.
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Affiliation(s)
- Frederick Allen
- Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
- Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
| | - Ivan Maillard
- Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
- Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
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21
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Collins M, Michot JM, Bellanger C, Mussini C, Benhadji K, Massard C, Carbonnel F. Notch inhibitors induce diarrhea, hypercrinia and secretory cell metaplasia in the human colon. EXCLI JOURNAL 2021; 20:819-827. [PMID: 34121974 PMCID: PMC8192874 DOI: 10.17179/excli2021-3572] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/21/2021] [Indexed: 11/20/2022]
Abstract
In humans, inhibition of Notch oncogenic signaling leads to tumor regression. Preclinical studies indicate that Notch signaling contributes to the maintenance of intestinal homeostasis. Here, we sought to describe the intestinal effects of a first-in-human Notch inhibitor in an indication of refractory cancer. Between 2014 and 2017, adult patients treated for refractory cancer with the novel Notch inhibitor LY3039478 and who had grade ≥ 2 diarrhea were referred to the gastroenterology department of a tertiary hospital in the Paris region of France. Eleven patients (median (range) age: 72 (29-83)) were included in the study. All patients had advanced cancer: adenoid cystic carcinoma (n=3, 27 %), sarcoma (n=3, 27 %), and other types (n=5, 46 %). In all cases, digestive tract endoscopy revealed abundant mucus in the intestinal lumen, and digestive tract biopsies showed an abnormally low proportion of enterocytes and marked elevation of the proportion of pseudostratified goblet cells. Microscopic inflammation was seen in colon biopsies from 2 of the 11 patients (18 %). The clinical, endoscopic and histological abnormalities were dependent on the dose of Notch inhibitor. All patients resolved their digestive signs or symptoms after discontinuing the dose and the median (range) time interval between discontinuation of the Notch inhibitor and resolution of all the gastrointestinal signs and symptoms was 7 days (4-24). Likewise, the median time interval between discontinuation and resolution of the histological abnormalities was 7 days (1-10). Blocking Notch signaling induces secretory cell metaplasia of the intestinal epithelium, which in turn leads to transient diarrhea. Our results confirm the role of Notch signaling in intestinal homeostasis in humans.
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Affiliation(s)
- Michael Collins
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hopitaux de Paris, Le Kremlin Bicêtre, France.,Paris Sud University, Le Kremlin Bicêtre, France.,INSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif, France; University Paris-Sud, Université Paris-Saclay, Faculté de Médecine Le Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Pôle de Biologie Médicale, Paul-Brousse University Hospital, Villejuif, France
| | - Jean-Marie Michot
- Drug Development Department (DITEP), Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, Villejuif, France
| | - Christophe Bellanger
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hopitaux de Paris, Le Kremlin Bicêtre, France.,Paris Sud University, Le Kremlin Bicêtre, France
| | - Charlotte Mussini
- Department of Pathology, Kremlin Bicêtre Hospital, Assistance Publique-Hopitaux de Paris, Le Kremlin Bicêtre, France
| | | | - Christophe Massard
- Drug Development Department (DITEP), Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, Villejuif, France
| | - Franck Carbonnel
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hopitaux de Paris, Le Kremlin Bicêtre, France.,Paris Sud University, Le Kremlin Bicêtre, France
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22
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Kumar V, Vashishta M, Kong L, Wu X, Lu JJ, Guha C, Dwarakanath BS. The Role of Notch, Hedgehog, and Wnt Signaling Pathways in the Resistance of Tumors to Anticancer Therapies. Front Cell Dev Biol 2021; 9:650772. [PMID: 33968932 PMCID: PMC8100510 DOI: 10.3389/fcell.2021.650772] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/19/2021] [Indexed: 12/19/2022] Open
Abstract
Resistance to therapy is the major hurdle in the current cancer management. Cancer cells often rewire their cellular process to alternate mechanisms to resist the deleterious effect mounted by different therapeutic approaches. The major signaling pathways involved in the developmental process, such as Notch, Hedgehog, and Wnt, play a vital role in development, tumorigenesis, and also in the resistance to the various anticancer therapies. Understanding how cancer utilizes these developmental pathways in acquiring the resistance to the multi-therapeutic approach cancer can give rise to a new insight of the anti-therapy resistance mechanisms, which can be explored for the development of a novel therapeutic approach. We present a brief overview of Notch, Hedgehog, and Wnt signaling pathways in cancer and its role in providing resistance to various cancer treatment modalities such as chemotherapy, radiotherapy, molecular targeted therapy, and immunotherapy. Understanding the importance of these molecular networks will provide a rational basis for novel and safer combined anticancer therapeutic approaches for the improvement of cancer treatment by overcoming drug resistance.
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Affiliation(s)
- Vivek Kumar
- R&D Dept, Shanghai Proton and Heavy Ion Center (SPHIC), Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Mohit Vashishta
- R&D Dept, Shanghai Proton and Heavy Ion Center (SPHIC), Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Lin Kong
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.,Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
| | - Xiaodong Wu
- R&D Dept, Shanghai Proton and Heavy Ion Center (SPHIC), Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
| | - Jiade J Lu
- Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.,Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China
| | - Chandan Guha
- Albert Einstein College of Medicine, The Bronx, NY, United States
| | - B S Dwarakanath
- R&D Dept, Shanghai Proton and Heavy Ion Center (SPHIC), Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, China.,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China
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23
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Raghav PK, Mann Z. Cancer stem cells targets and combined therapies to prevent cancer recurrence. Life Sci 2021; 277:119465. [PMID: 33831426 DOI: 10.1016/j.lfs.2021.119465] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/01/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) control the dynamics of tumorigenesis by self-renewal ability and differentiation potential. These properties contribute towards tumor malignancy, metastasis, cellular heterogeneity, and immune escape, which are regulated by multiple signaling pathways. The CSCs are chemoresistant and cause cancer recurrence, generally recognized as a small side-population that eventually leads to tumor relapse. Despite many treatment options available, none can be considered entirely efficient due to a lack of specificity and dose limitation. This review primarily highlights the processes involved in CSCs development and maintenance. Secondly, the current effective therapies based on stem cells, cell-free therapies that involve exosomes and miRNAs, and photodynamic therapy have been discussed. Also, the inhibitors that specifically target various signaling pathways, which can be used in combination to control CSCs kinetics have been highlighted. Conclusively, this comprehensive review is a detailed study of recently developed novel treatment strategies that will facilitate in coming up with better-targeted approaches against CSCs.
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Affiliation(s)
| | - Zoya Mann
- Independent Researcher, New Delhi, India
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McCaw TR, Inga E, Chen H, Jaskula‐Sztul R, Dudeja V, Bibb JA, Ren B, Rose JB. Gamma Secretase Inhibitors in Cancer: A Current Perspective on Clinical Performance. Oncologist 2021; 26:e608-e621. [PMID: 33284507 PMCID: PMC8018325 DOI: 10.1002/onco.13627] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/13/2020] [Indexed: 01/01/2023] Open
Abstract
Gamma secretase inhibitors (GSIs), initially developed as Alzheimer's therapies, have been repurposed as anticancer agents given their inhibition of Notch receptor cleavage. The success of GSIs in preclinical models has been ascribed to induction of cancer stem-like cell differentiation and apoptosis, while also impairing epithelial-to-mesenchymal transition and sensitizing cells to traditional chemoradiotherapies. The promise of these agents has yet to be realized in the clinic, however, as GSIs have failed to demonstrate clinical benefit in most solid tumors with the notable exceptions of CNS malignancies and desmoid tumors. Disappointing clinical performance to date reflects important questions that remain to be answered. For example, what is the net impact of these agents on antitumor immune responses, and will they require concurrent targeting of tumor-intrinsic compensatory pathways? Addressing these limitations in our current understanding of GSI mechanisms will undoubtedly facilitate their rational incorporation into combinatorial strategies and provide a valuable tool with which to combat Notch-dependent cancers. In the present review, we provide a current understanding of GSI mechanisms, discuss clinical performance to date, and suggest areas for future investigation that might maximize the utility of these agents. IMPLICATIONS FOR PRACTICE: The performance of gamma secretase inhibitors (GSIs) in clinical trials generally has not reflected their encouraging performance in preclinical studies. This review provides a current perspective on the clinical performance of GSIs across various solid tumor types alongside putative mechanisms of antitumor activity. Through exploration of outstanding gaps in knowledge as well as reasons for success in certain cancer types, the authors identify areas for future investigation that will likely enable incorporation of GSIs into rational combinatorial strategies for superior tumor control and patient outcomes.
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Affiliation(s)
- Tyler R. McCaw
- Divisions of Surgical Oncology, The University of Alabama at BirminghamBirminghamAlabamaUSA
| | - Evelyn Inga
- Divisions of Surgical Oncology, The University of Alabama at BirminghamBirminghamAlabamaUSA
| | - Herbert Chen
- Breast & Endocrine Surgery, The University of Alabama at BirminghamBirminghamAlabamaUSA
| | - Renata Jaskula‐Sztul
- Breast & Endocrine Surgery, The University of Alabama at BirminghamBirminghamAlabamaUSA
| | - Vikas Dudeja
- Divisions of Surgical Oncology, The University of Alabama at BirminghamBirminghamAlabamaUSA
| | - James A. Bibb
- Gastrointestinal Surgery, The University of Alabama at BirminghamBirminghamAlabamaUSA
| | - Bin Ren
- Vascular Surgery & Endovascular Therapy, Department of Surgery, The University of Alabama at BirminghamBirminghamAlabamaUSA
| | - J. Bart Rose
- Divisions of Surgical Oncology, The University of Alabama at BirminghamBirminghamAlabamaUSA
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25
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Gaillard D, Barlow LA. A Mechanistic Overview of Taste Bud Maintenance and Impairment in Cancer Therapies. Chem Senses 2021; 46:6161548. [PMID: 33693542 DOI: 10.1093/chemse/bjab011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Since the early 20th century, progress in cancer therapies has significantly improved disease prognosis. Nonetheless, cancer treatments are often associated with side effects that can negatively affect patient well-being and disrupt the course of treatment. Among the main side effects, taste impairment is associated with depression, malnutrition, and morbid weight loss. Although relatively common, taste disruption associated with cancer therapies remains poorly understood. Here, we review the current knowledge related to the molecular mechanisms underlying taste maintenance and disruption in the context of cancer therapies.
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Affiliation(s)
- Dany Gaillard
- Department of Cell & Developmental Biology, and the Rocky Mountain Taste & Smell Center, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Mail Stop 8108, Aurora, CO 80045, USA
| | - Linda A Barlow
- Department of Cell & Developmental Biology, and the Rocky Mountain Taste & Smell Center, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Mail Stop 8108, Aurora, CO 80045, USA
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26
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Peng X, Wei Z, Gerweck LE. Making radiation therapy more effective in the era of precision medicine. PRECISION CLINICAL MEDICINE 2020; 3:272-283. [PMID: 35692625 PMCID: PMC8982539 DOI: 10.1093/pcmedi/pbaa038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 11/18/2020] [Accepted: 11/22/2020] [Indexed: 02/05/2023] Open
Abstract
Cancer has become a leading cause of death and constitutes an enormous burden worldwide. Radiation is a principle treatment modality used alone or in combination with other forms of therapy, with 50%–70% of cancer patients receiving radiotherapy at some point during their illness. It has been suggested that traditional radiotherapy (daily fractions of approximately 1.8–2 Gy over several weeks) might select for radioresistant tumor cell sub-populations, which, if not sterilized, give rise to local treatment failure and distant metastases. Thus, the challenge is to develop treatment strategies and schedules to eradicate the resistant subpopulation of tumorigenic cells rather than the predominant sensitive tumor cell population. With continued technological advances including enhanced conformal treatment technology, radiation oncologists can increasingly maximize the dose to tumors while sparing adjacent normal tissues, to limit toxicity and damage to the latter. Increased dose conformality also facilitates changes in treatment schedules, such as changes in dose per treatment fraction and number of treatment fractions, to enhance the therapeutic ratio. For example, the recently developed large dose per fraction treatment schedules (hypofractionation) have shown clinical advantage over conventional treatment schedules in some tumor types. Experimental studies suggest that following large acute doses of radiation, recurrent tumors, presumably sustained by the most resistant tumor cell populations, may in fact be equally or more radiation sensitive than the primary tumor. In this review, we summarize the related advances in radiotherapy, including the increasing understanding of the molecular mechanisms of radioresistance, and the targeting of these mechanisms with potent small molecule inhibitors, which may selectively sensitize tumor cells to radiation.
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Affiliation(s)
- Xingchen Peng
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Zhigong Wei
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Leo E Gerweck
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
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Nisar S, Hashem S, Macha MA, Yadav SK, Muralitharan S, Therachiyil L, Sageena G, Al-Naemi H, Haris M, Bhat AA. Exploring Dysregulated Signaling Pathways in Cancer. Curr Pharm Des 2020; 26:429-445. [PMID: 31939726 DOI: 10.2174/1381612826666200115095937] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 11/27/2019] [Indexed: 02/08/2023]
Abstract
Cancer cell biology takes advantage of identifying diverse cellular signaling pathways that are disrupted in cancer. Signaling pathways are an important means of communication from the exterior of cell to intracellular mediators, as well as intracellular interactions that govern diverse cellular processes. Oncogenic mutations or abnormal expression of signaling components disrupt the regulatory networks that govern cell function, thus enabling tumor cells to undergo dysregulated mitogenesis, to resist apoptosis, and to promote invasion to neighboring tissues. Unraveling of dysregulated signaling pathways may advance the understanding of tumor pathophysiology and lead to the improvement of targeted tumor therapy. In this review article, different signaling pathways and how their dysregulation contributes to the development of tumors have been discussed.
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Affiliation(s)
- Sabah Nisar
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Sheema Hashem
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Muzafar A Macha
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States.,Department of Biotechnology, Central University of Kashmir, Ganderbal, Jammu and Kashmir, India
| | - Santosh K Yadav
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | | | - Lubna Therachiyil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | | | - Hamda Al-Naemi
- Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Mohammad Haris
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar.,Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Ajaz A Bhat
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
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Sodium Tanshinone IIA Silate Exerts Microcirculation Protective Effects against Spinal Cord Injury In Vitro and In Vivo. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:3949575. [PMID: 33101588 PMCID: PMC7568160 DOI: 10.1155/2020/3949575] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/10/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023]
Abstract
Spinal cord microcirculation involves functioning endothelial cells at the blood spinal cord barrier (BSCB) and maintains normal functioning of spinal cord neurons, axons, and glial cells. Protection of both the function and integrity of endothelial cells as well as the prevention of BSCB disruption may be a strong strategy for the treatment of spinal cord injury (SCI) cases. Sodium Tanshinone IIA silate (STS) is used for the treatment of coronary heart disease and improves microcirculation. Whether STS exhibits protective effects for SCI microcirculation is not yet clear. The purpose of this study is to investigate the protective effects of STS on oxygen-glucose deprivation- (OGD-) induced injury of spinal cord endothelial cells (SCMECs) in vitro and to explore effects on BSCB and neurovascular protection in vivo. SCMECs were treated with various concentrations of STS (1 μM, 3 μM, and 10 μM) for 24 h with or without OGD-induction. Cell viability, tube formation, migration, and expression of Notch signaling pathway components were evaluated. Histopathological evaluation (H&E), Nissl staining, BSCB permeability, and the expression levels of von Willebrand Factor (vWF), CD31, NeuN, and Notch signaling pathway components were analyzed. STS was found to improve SCMEC functions and reduce inflammatory mediators after OGD. STS also relieved histopathological damage, increased zonula occludens-1 (ZO-1), inhibited BSCB permeability, rescued microvessels, protected motor neuromas, and improved functional recovery in a SCI model. Moreover, we uncovered that the Notch signaling pathway plays an important role during these processes. These results indicated that STS protects microcirculation in SCI, which may be used as a therapeutic strategy for SCI in the future.
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Phase 1 study of 2 high dose intensity schedules of the pan-Notch inhibitor crenigacestat (LY3039478) in combination with prednisone in patients with advanced or metastatic cancer. Invest New Drugs 2020; 39:193-201. [PMID: 32915419 DOI: 10.1007/s10637-020-00944-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 05/04/2020] [Indexed: 12/14/2022]
Abstract
Background Crenigacestat is a potent Notch inhibitor that decreases Notch signaling and its downstream biological effects. Here, we report the results from Part F of study 16F-MC-JJCA designed to evaluate the safety, pharmacokinetics (PK), and antitumor activity of crenigacestat with prednisone in advanced or metastatic cancer. The combination was planned to mitigate gastrointestinal toxicities. Methods Eligible patients (Study Part F) received crenigacestat loading dose (75 mg, escalating to 150 mg) administered thrice weekly (TIW) (F1) or twice weekly (BIW) (F2) for 2 weeks during Cycle 1, followed by 50 mg TIW from week 3 onwards. Prednisone was co-administered for 2 weeks in Cycle 1. Results Twenty-eight patients were enrolled; 11 in F1 (median age, 63 years), 17 in F2 (median age, 50 years). Dose-limiting toxicities were Grade 3 increased serum amylase and Grade 2 fatigue in F1, and Grade 4 hypophosphatemia and Grade 3 rash maculo-papular in F2. The maximum tolerated dose was 75 mg in F1 and 100 mg in F2. Best overall response was stable disease (F1, 6 [54.5%] patients; F2, 11 [64.7%] patients). Pharmacokinetic was dose proportional. Prednisone did not modify PK of crenigacestat, and both F1 and F2 achieved pharmacodynamics effects on evaluable tumor tissue samples. Conclusions This study demonstrated the potential use of prednisone to reduce gastrointestinal (GI) toxicities of a Notch inhibitor without affecting its PK. The safety profile observed was consistent with Notch pathway inhibitors, and the maximum tolerated dose was 75 mg TIW and 100 mg BIW in F1 and F2, respectively. ClinicalTrials.gov: NCT01695005.
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30
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Mechanisms of cancer stem cell therapy. Clin Chim Acta 2020; 510:581-592. [PMID: 32791136 DOI: 10.1016/j.cca.2020.08.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 08/01/2020] [Accepted: 08/07/2020] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) are responsible for carcinogenesis and tumorigenesis and are involved in drug and radiation resistance, metastasis, tumor relapse and initiation. Remarkably, they have other abilities such as inheritance of self-renewal and de-differentiation. Hence, targeting CSCs is considered a potential anti-cancer therapeutic strategy. Recent advances in the identification of biomarkers to recognize CSCs and the development of new techniques to evaluate tumorigenic and carcinogenic roles of CSCs are instrumental to this approach. Elucidation of signaling pathways that regulate CSCs colony progression and drug resistance are critical in establishing effective targeted therapies. CSCs play a central key role in immunomodulation, immune evasion and effector immunity, which alters immune system balancing. These include mTOR, SHH, NOTCH and Wnt/β-catering in cancer progression. In this review article, we discuss the importance of these CSCs pathways in cancer therapy.
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Li Y, Wang D, Liu J, Li Y, Chen D, Zhou L, Lang T, Zhou Q. Baicalin Attenuates YAP Activity to Suppress Ovarian Cancer Stemness. Onco Targets Ther 2020; 13:7151-7163. [PMID: 32801747 PMCID: PMC7386807 DOI: 10.2147/ott.s254607] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 06/29/2020] [Indexed: 12/25/2022] Open
Abstract
Purpose This study aims to reveal the mechanism underlying baicalin-suppressing ovarian cancer stemness. Methods OVCAR-3 and the primary ovarian cancer cells were used for cell model. The ovarian cancer stem cells were isolated by suspension culture. Cell viability and clonogenicity were examined by CCK-8 assay and colony formation assay. The self-renewal of the cells was evaluated by the determination of sphere-forming capacity and the frequency of in vitro sphere-forming and in vivo tumor-initiating cells. The mRNA and protein levels were relatively quantified by qRT-PCR and Western blot. The transcription regulation of target genes was tested by luciferase reporter assay and a modified nuclear rn-on qRT-PCR assay. Results Treatment with a non-toxic dose of baicalin significantly inhibited the spherogenicity of ovarian cancer cells. Moreover, a non-toxic dose of baicalin treatment suppressed the frequency of sphere-forming and tumor-initiating ovarian cancer cells. Furthermore, the expression of ovarian cancer stem cell markers (CD133 and ALDH1A1) was inhibited by a non-toxic dose of baicalin treatment. Baicalin inhibits YAP activity and suppresses RASSF6, a positive regulator of YAP, at the transcriptional level. Overexpression of both YAP and RASSF6 abolished the inhibitory effect of baicalin on the proliferation and stemness of ovarian cancer cells. Conclusion The results in this study demonstrated that baicalin suppresses the stemness of ovarian cancer cells by attenuating YAP activity via inhibiting RASSF6 at the transcriptional level. This finding revealed baicalin as a novel YAP inhibitor that could serve as an anti-cancer drug for eradicating ovarian cancer stem cells.
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Affiliation(s)
- Yucong Li
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital, Chongqing 400030, People's Republic of China.,Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, People's Republic of China.,Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, Chongqing 400044, People's Republic of China
| | - Dong Wang
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital, Chongqing 400030, People's Republic of China
| | - Jingshu Liu
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital, Chongqing 400030, People's Republic of China
| | - Yunzhe Li
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital, Chongqing 400030, People's Republic of China
| | - Duke Chen
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital, Chongqing 400030, People's Republic of China
| | - Lei Zhou
- Singapore Eye Research Institute, Singapore, 169856, Singapore
| | - Tingyuan Lang
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital, Chongqing 400030, People's Republic of China.,Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, People's Republic of China.,Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, Chongqing 400044, People's Republic of China
| | - Qi Zhou
- Department of Gynecologic Oncology, Chongqing University Cancer Hospital, Chongqing 400030, People's Republic of China.,Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, People's Republic of China.,Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, Chongqing 400044, People's Republic of China
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Keyghobadi F, Mehdipour M, Nekoukar V, Firouzi J, Kheimeh A, Nobakht Lahrood F, Azimian Zavareh V, Azimi M, Mohammadi M, Sodeifi N, Ebrahimi M. Long-Term Inhibition of Notch in A-375 Melanoma Cells Enhances Tumor Growth Through the Enhancement of AXIN1, CSNK2A3, and CEBPA2 as Intermediate Genes in Wnt and Notch Pathways. Front Oncol 2020; 10:531. [PMID: 32695658 PMCID: PMC7338939 DOI: 10.3389/fonc.2020.00531] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Accepted: 03/25/2020] [Indexed: 12/14/2022] Open
Abstract
Notch suppression by gamma-secretase inhibitors is a valid approach against melanoma. However, most of studies have evaluated the short-term effect of DAPT on tumor cells or even cancer stem cells. In the present study, we surveyed the short-term and long-term effects of DAPT on the stem cell properties of A375 and NA8 as melanoma cell lines. The effects of DAPT were tested both in vitro and in vivo using xenograft models. In A375 with B-raf mutation, DAPT decreased the level of NOTCH1, NOTH2, and HES1 as downstream genes of the Notch pathway. This was accompanied by enhanced apoptosis after 24 h treatment, arrest in the G2-M phase, and impaired ability of colony and melanosphere formation at the short term. Moreover, tumor growth also reduced during 13 days of treatment. However, long-term treatment of DAPT promoted tumor growth in the xenograft model and enhanced the number and size of colonies and spheroids in vitro. The gene expression studies confirmed the up-regulation of Wnt and Notch downstream genes as well as AXIN1, CSNK2A3, and CEBPA2 following the removal of Notch inhibitor in vitro and in the xenograft model. Moreover, the Gompertz-based mathematical model determined a new drug resistance term in the present study. Our data supported that the long-term and not short-term inhibition of Notch by DAPT may enhance tumor growth and motility through up-regulation of AXIN1, CSNK2A3, and CEBPA2 genes in B-raf mutated A375 cells.
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Affiliation(s)
- Faezeh Keyghobadi
- Department of Developmental Biology, University of Science and Culture, ACECR, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Maryam Mehdipour
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Vahab Nekoukar
- School of Electrical Engineering, Shahid Rajaee Teacher Training University, Tehran, Iran
| | - Javad Firouzi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Abolfazl Kheimeh
- Animal Core Facility, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Tehran, Iran
| | - Fatemeh Nobakht Lahrood
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Vajihe Azimian Zavareh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Masoumeh Azimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mahsa Mohammadi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Niloofar Sodeifi
- Department of Pathology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Marzieh Ebrahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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Moore G, Annett S, McClements L, Robson T. Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives. Cells 2020; 9:cells9061503. [PMID: 32575680 PMCID: PMC7349363 DOI: 10.3390/cells9061503] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/05/2020] [Accepted: 06/11/2020] [Indexed: 12/17/2022] Open
Abstract
Evolutionarily conserved Notch plays a critical role in embryonic development and cellular self-renewal. It has both tumour suppressor and oncogenic activity, the latter of which is widely described. Notch-activating mutations are associated with haematological malignancies and several solid tumours including breast, lung and adenoid cystic carcinoma. Moreover, upregulation of Notch receptors and ligands and aberrant Notch signalling is frequently observed in cancer. It is involved in cancer hallmarks including proliferation, survival, migration, angiogenesis, cancer stem cell renewal, metastasis and drug resistance. It is a key component of cell-to-cell interactions between cancer cells and cells of the tumour microenvironment, such as endothelial cells, immune cells and fibroblasts. Notch displays diverse crosstalk with many other oncogenic signalling pathways, and may drive acquired resistance to targeted therapies as well as resistance to standard chemo/radiation therapy. The past 10 years have seen the emergence of different classes of drugs therapeutically targeting Notch including receptor/ligand antibodies, gamma secretase inhibitors (GSI) and most recently, the development of Notch transcription complex inhibitors. It is an exciting time for Notch research with over 70 cancer clinical trials registered and the first-ever Phase III trial of a Notch GSI, nirogacestat, currently at the recruitment stage.
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Affiliation(s)
- Gillian Moore
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, Royal College of Surgeons, D02 YN77 Dublin, Ireland; (G.M.); (S.A.)
| | - Stephanie Annett
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, Royal College of Surgeons, D02 YN77 Dublin, Ireland; (G.M.); (S.A.)
| | - Lana McClements
- The School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia;
| | - Tracy Robson
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, Royal College of Surgeons, D02 YN77 Dublin, Ireland; (G.M.); (S.A.)
- Correspondence:
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Cho Y, Kim YK. Cancer Stem Cells as a Potential Target to Overcome Multidrug Resistance. Front Oncol 2020; 10:764. [PMID: 32582535 PMCID: PMC7280434 DOI: 10.3389/fonc.2020.00764] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 04/21/2020] [Indexed: 12/21/2022] Open
Abstract
Multidrug resistance (MDR), which is a significant impediment to the success of cancer chemotherapy, is attributable to various defensive mechanisms in cancer. Initially, overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp) was considered the most important mechanism for drug resistance; hence, many investigators for a long time focused on the development of specific ABC transporter inhibitors. However, to date their efforts have failed to develop a clinically applicable drug, leaving only a number of problems. The concept of cancer stem cells (CSCs) has provided new directions for both cancer and MDR research. MDR is known to be one of the most important features of CSCs and thus plays a crucial role in cancer recurrence and exacerbation. Therefore, in recent years, research targeting CSCs has been increasing rapidly in search of an effective cancer treatment. Here, we review the drugs that have been studied and developed to overcome MDR and CSCs, and discuss the limitations and future perspectives.
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Affiliation(s)
| | - Yong Kee Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women's University, Seoul, South Korea
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Wasson CW, Abignano G, Hermes H, Malaab M, Ross RL, Jimenez SA, Chang HY, Feghali-Bostwick CA, Del Galdo F. Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH. Ann Rheum Dis 2020; 79:507-517. [PMID: 32041748 PMCID: PMC7147169 DOI: 10.1136/annrheumdis-2019-216542] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 01/08/2020] [Accepted: 01/09/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Systemic sclerosis (SSc) is characterised by autoimmune activation, tissue and vascular fibrosis in the skin and internal organs. Tissue fibrosis is driven by myofibroblasts, that are known to maintain their phenotype in vitro, which is associated with epigenetically driven trimethylation of lysine 27 of histone 3 (H3K27me3). METHODS Full-thickness skin biopsies were surgically obtained from the forearms of 12 adult patients with SSc of recent onset. Fibroblasts were isolated and cultured in monolayers and protein and RNA extracted. HOX transcript antisense RNA (HOTAIR) was expressed in healthy dermal fibroblasts by lentiviral induction employing a vector containing the specific sequence. Gamma secretase inhibitors were employed to block Notch signalling. Enhancer of zeste 2 (EZH2) was blocked with GSK126 inhibitor. RESULTS SSc myofibroblasts in vitro and SSc skin biopsies in vivo display high levels of HOTAIR, a scaffold long non-coding RNA known to direct the histone methyltransferase EZH2 to induce H3K27me3 in specific target genes. Overexpression of HOTAIR in dermal fibroblasts induced EZH2-dependent increase in collagen and α-SMA expression in vitro, as well as repression of miRNA-34A expression and consequent NOTCH pathway activation. Consistent with these findings, we show that SSc dermal fibroblast display decreased levels of miRNA-34a in vitro. Further, EZH2 inhibition rescued miRNA-34a levels and mitigated the profibrotic phenotype of both SSc and HOTAIR overexpressing fibroblasts in vitro. CONCLUSIONS Our data indicate that the EZH2-dependent epigenetic phenotype of myofibroblasts is driven by HOTAIR and is linked to miRNA-34a repression-dependent activation of NOTCH signalling.
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Affiliation(s)
- Christopher W Wasson
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, West Yorkshire, UK
| | - Giuseppina Abignano
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, West Yorkshire, UK
- Rheumatology Department of Lucania San Carlo Hospital, Potenza, Italy, Rheumatology Institute of Lucania (IReL), Potenza, Italy
- Scleroderma Programme, NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds, UK
| | - Heidi Hermes
- Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Maya Malaab
- Rheumatology, Medical University of South Carolina, Charlestown, South Carolina, USA
| | - Rebecca L Ross
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, West Yorkshire, UK
| | - Sergio A Jimenez
- Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Howard Y Chang
- Center for Personal Dynamic Regulomes, University of Stanford, San Francisco, California, USA
| | | | - Francesco Del Galdo
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, West Yorkshire, UK
- Scleroderma Programme, NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds, UK
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Cole AJ, Fayomi AP, Anyaeche VI, Bai S, Buckanovich RJ. An evolving paradigm of cancer stem cell hierarchies: therapeutic implications. Theranostics 2020; 10:3083-3098. [PMID: 32194856 PMCID: PMC7053211 DOI: 10.7150/thno.41647] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 01/22/2020] [Indexed: 02/07/2023] Open
Abstract
Over a decade of research has confirmed the critical role of cancer stem-like cells (CSCs) in tumor initiation, chemoresistance, and metastasis. Increasingly, CSC hierarchies have begun to be defined with some recurring themes. This includes evidence that these hierarchies are 'flexible,' with both cell state transitions and dedifferentiation events possible. These findings pose therapeutic hurdles and opportunities. Here, we review cancer stem cell hierarchies and their interactions with the tumor microenvironment. We also discuss the current therapeutic approaches designed to target CSC hierarchies and initial clinical trial results for CSC targeting agents. While cancer stem cell targeted therapies are still in their infancy, we are beginning to see encouraging results that suggest a positive outlook for CSC-targeting approaches.
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Affiliation(s)
- Alexander J Cole
- Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Adetunji P Fayomi
- Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Shoumei Bai
- Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ronald J Buckanovich
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
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Zhou L, Wang D, Sheng D, Xu J, Chen W, Qin Y, Du R, Yang X, He X, Xie N, Liu S, Zhang L. NOTCH4 maintains quiescent mesenchymal-like breast cancer stem cells via transcriptionally activating SLUG and GAS1 in triple-negative breast cancer. Theranostics 2020; 10:2405-2421. [PMID: 32104513 PMCID: PMC7019177 DOI: 10.7150/thno.38875] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 12/21/2019] [Indexed: 12/18/2022] Open
Abstract
Rationale: NOTCH4 receptor has been implicated in triple-negative breast cancer (TNBC) development and breast cancer stem cell (BCSC) regulation. However, the potential of NOTCH4 as a BCSC marker and the underlying mechanisms remain unclear. Methods: In this study, we determined the expression and activation of NOTCH4 in breast cancer cell lines and tumor samples by qRT-PCR, western blotting and immunohistochemistry. Subsequently, in vitro and in vivo serial dilution experiments were performed to demonstrate the application of NOTCH4 as an efficient mesenchymal-like (ML)-BCSC marker in TNBC. Stable overexpression of activated NOTCH4 and knockdown cell lines were established using lentivirus. RNA-seq and qRT-PCR were employed to reveal the downstream effectors of NOTCH4, followed by dual-luciferase reporter and chromatin immunoprecipitation assays to identify the genuine binding sites of NOTCH4 on SLUG and GAS1 promoters. Transwell assay, mammosphere formation and chemoresistance experiments were performed to determine the effects of SLUG, GAS1 and NOTCH4 on the mesenchymal-like characteristics of TNBC cells. Survival analysis was used to study the relation of NOTCH4, SLUG and GAS1 with prognosis of breast cancer. Results: NOTCH4 is aberrantly highly expressed and activated in TNBC, which contributes to the maintenance of ML-BCSCs. Furthermore, NOTCH4 shows significantly higher efficiency in labeling ML-BCSCs than the currently commonly used CD24-CD44+ marker. Mechanistically, NOTCH4 transcriptionally upregulates SLUG and GAS1 to promote EMT and quiescence in TNBC, respectively. The effects of NOTCH4 can be mimicked by simultaneous overexpression of SLUG and GAS1. Moreover, SLUG is also involved in harnessing GAS1, a known tumor suppressor gene, via its anti-apoptotic function. Conclusions: Our findings reveal that the NOTCH4-SLUG-GAS1 circuit serves as a potential target for tumor intervention by overcoming stemness of ML-BCSCs and by conquering the lethal chemoresistance and metastasis of TNBC.
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Sardesai S, Badawi M, Mrozek E, Morgan E, Phelps M, Stephens J, Wei L, Kassem M, Ling Y, Lustberg M, Stover D, Williams N, Layman R, Reinbolt R, VanDeusen J, Cherian M, Grever M, Carson W, Ramaswamy B, Wesolowski R. A phase I study of an oral selective gamma secretase (GS) inhibitor RO4929097 in combination with neoadjuvant paclitaxel and carboplatin in triple negative breast cancer. Invest New Drugs 2020; 38:1400-1410. [PMID: 31953695 DOI: 10.1007/s10637-020-00895-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 01/10/2020] [Indexed: 12/20/2022]
Abstract
Upregulation of Notch pathway is associated with poor prognosis in breast cancer. We present the results of a phase I study of an oral selective gamma secretase (GS) inhibitor (critical to Notch signaling), RO4929097 in combination with neoadjuvant chemotherapy for operable triple negative breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) of RO4929097. Secondary objectives were to determine real-time pharmacokinetics of RO4929097 and paclitaxel, safety and pathologic (pCR) complete response to study treatment. Eligible patients, initiated carboplatin at AUC 6 administered intravenously (IV) on day 1, weekly paclitaxel at 80 mg/m2 IV and RO4929097 10 mg daily given orally (PO) on days 1-3, 8-10 and 15-17 for six 21-day cycles. RO4929097 was escalated in 10 mg increments using the 3 + 3 dose escalation design. Two DLTs were observed in 14 patients - Grade (G) 4 thrombocytopenia in dose level 1 (10 mg) and G3 hypertension in dose level 2 (20 mg). Protocol-defined MTD was not determined due to discontinuation of RO4929097 development. However, 4 of 5 patients enrolled to 20 mg dose of RO4929097 required dose reduction to 10 mg due to toxicities (including neutropenia, thrombocytopenia and hypertension) occurring during and beyond the DLT observation period. Thus, 10 mg would have been the likely dose level for further development. G3 or higher hematologic toxicities included neutropenia (N = 8, 57%) and thrombocytopenia (N = 5, 36%) patients. Six (43%) patients had G2-3 neuropathy requiring paclitaxel dose reduction. No signs of drug-drug interaction between paclitaxel and RO4929097 were evident. Five patients (36%) had pCR.
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Affiliation(s)
- Sagar Sardesai
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Mohamed Badawi
- The Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Ewa Mrozek
- Medical Oncology, Mercy Health, St. Rita's Cancer Center, Lima, OH, USA
| | - Evan Morgan
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Mitch Phelps
- The Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Julie Stephens
- Medical Oncology, Mercy Health, St. Rita's Cancer Center, Lima, OH, USA
| | - Lai Wei
- The Center for Biostatistics, Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Mahmoud Kassem
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Yonghua Ling
- The Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Maryam Lustberg
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Daniel Stover
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Nicole Williams
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Rachel Layman
- Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Raquel Reinbolt
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Jeffrey VanDeusen
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Mathew Cherian
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Michael Grever
- The Division of Hematology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - William Carson
- The Division of Surgical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Bhuvaneswari Ramaswamy
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Robert Wesolowski
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA.
- The Ohio State University Comprehensive Cancer Center, Suite 1204, Lincoln Tower, 1800 Cannon Drive, Columbus, OH, 43210, USA.
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Massard C, Azaro A, Soria JC, Lassen U, Le Tourneau C, Sarker D, Smith C, Ohnmacht U, Oakley G, Patel BKR, Yuen ESM, Benhadji KA, Rodon J. First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer. Ann Oncol 2019; 29:1911-1917. [PMID: 30060061 DOI: 10.1093/annonc/mdy244] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Background Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. γ-Secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer. Methods This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5-100 mg, thrice weekly (TIW) on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478. Results A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis, and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared with 75 mg. The PKs of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an ∼80% inhibition of plasma Aβ, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1, and Notch-regulated ankyrin repeat at 45-100-mg dose. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma. Conclusion Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing. Clinicaltrials.gov ID NCT01695005.
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Affiliation(s)
- C Massard
- Drug Development Department (DITEP), Inserm Unit U981, Université Paris Saclay, Université Paris-Sud, Gustave Roussy, Villejuif, France.
| | - A Azaro
- Molecular Therapeutics Research Unit, Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona; Department of Pharmacology, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - J-C Soria
- Drug Development Department (DITEP), Inserm Unit U981, Université Paris Saclay, Université Paris-Sud, Gustave Roussy, Villejuif, France
| | - U Lassen
- Phase 1 Unit, Department of Oncology, The Finsen Centre - Rigshospitalet, Copenhagen, Denmark
| | - C Le Tourneau
- Department of Drug Development and Innovation, Institut Curie, Saint-Cloud, Paris; INSERM U900 Research unit, Saint-Cloud, Montigny-le-Bretonneux, France; Versailles-Saint-Quentin-en-Yvelines University, Montigny-le-Bretonneux, France
| | - D Sarker
- King's College London, Guy's Hospital, London, UK
| | - C Smith
- Eli Lilly and Company, Indianapolis, USA
| | - U Ohnmacht
- Eli Lilly and Company, Indianapolis, USA
| | - G Oakley
- Eli Lilly and Company, Indianapolis, USA
| | | | - E S M Yuen
- Eli Lilly and Company, Indianapolis, USA
| | | | - J Rodon
- Early Clinical Drug Development Group, Vall d´Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain
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40
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Epithelial-Mesenchymal Transition in Skin Cancers: A Review. Anal Cell Pathol (Amst) 2019; 2019:3851576. [PMID: 31934531 PMCID: PMC6942705 DOI: 10.1155/2019/3851576] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 10/07/2019] [Accepted: 11/09/2019] [Indexed: 12/28/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is involved in physiologic processes such as embryogenesis and wound healing. A similar mechanism occurs in some tumors where cells leave the epithelial layer and gain mesenchymal particularities in order to easily migrate to other tissues. This process can explain the invasiveness and aggressiveness of these tumors which metastasize, by losing the epithelial phenotype (loss of E-cadherin, desmoplakin, and laminin-1) and acquiring mesenchymal markers (N-cadherin). Complex changes and interactions happen between the tumor cells and the microenvironment involving different pathways, transcription factors, altered expression of adhesion molecules, reorganization of cytoskeletal proteins, production of ECM-degrading enzymes, and changes in specific microRNAs. The purpose of this review is to determine particularities of the EMT process in the most common malignant cutaneous tumors (squamous cell carcinoma, basal cell carcinoma, and melanoma) which still have an increasingly high incidence. More studies are required on this topic in order to establish clear correlations. High costs related to skin cancer therapies in general as well as high impact on patients' quality of life demand finding new, reliable prognostic and therapeutic markers with significant public health impact.
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41
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Ferrarotto R, Eckhardt G, Patnaik A, LoRusso P, Faoro L, Heymach JV, Kapoun AM, Xu L, Munster P. A phase I dose-escalation and dose-expansion study of brontictuzumab in subjects with selected solid tumors. Ann Oncol 2019; 29:1561-1568. [PMID: 29726923 DOI: 10.1093/annonc/mdy171] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Background Brontictuzumab is a monoclonal antibody that targets Notch1 and inhibits pathway activation. The purpose of this first-in-human study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, immunogenicity and preliminary efficacy of brontictuzumab in patients with solid tumors. Patients and methods Subjects with selected refractory solid tumors were eligible. Brontictuzumab was administered intravenously at various dose levels and schedule during dose escalation, and at 1.5 mg/kg every 3 weeks (Q3W) during expansion. Evidence of Notch1 pathway activation as determined by an immunohistochemistry assay was required for entry in the expansion cohort. Adverse events were graded according to the NCI-CTCAE v 4.03. Efficacy was assessed by RECIST 1.1. Results Forty-eight subjects enrolled (33 in dose escalation and 15 in the expansion phase). The MTD was 1.5 mg/kg Q3W. Dose-limiting toxicities were grade 3 diarrhea in two subjects and grade 3 fatigue in one subject. The most common drug-related adverse events of any grade were diarrhea (71%), fatigue (44%), nausea (40%), vomiting (21%), and AST increase (21%). Brontictuzumab exhibited nonlinear pharmacokinetics with dose-dependent terminal half-life ranging 1-4 days. Clinical benefit was seen in 6 of 36 (17%) assessable subjects: 2 had unconfirmed partial response (PR) and 4 subjects had prolonged (≥ 6 months) disease stabilization (SD). Both PRs and three prolonged SD occurred in adenoid cystic carcinoma (ACC) subjects with evidence of Notch1 pathway activation. Pharmacodynamic effects of brontictuzumab were seen in patients' blood and tumor. Conclusion Brontictuzumab was well tolerated at the MTD. The main toxicity was diarrhea, an on-target effect of Notch1 inhibition. An efficacy signal was noted in subjects with ACC and Notch1 pathway activation. ClinicalTrials.gov identifier NCT01778439.
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Affiliation(s)
- R Ferrarotto
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.
| | - G Eckhardt
- Division of Medical Oncology, University of Colorado Denver School of Medicine, Denver, USA
| | - A Patnaik
- Phase I Medical Oncology Program, South Texas Accelerated Research Therapeutics (START), San Antonio, USA
| | - P LoRusso
- Yale School of Medicine, Experimental Therapeutics, New Haven, USA
| | - L Faoro
- OncoMed Pharmaceuticals Inc, Redwood City, USA
| | - J V Heymach
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - A M Kapoun
- OncoMed Pharmaceuticals Inc, Redwood City, USA
| | - L Xu
- OncoMed Pharmaceuticals Inc, Redwood City, USA
| | - P Munster
- Division of Hematology and Oncology, University of California San Francisco, San Francisco, USA
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42
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Du FY, Zhou QF, Sun WJ, Chen GL. Targeting cancer stem cells in drug discovery: Current state and future perspectives. World J Stem Cells 2019; 11:398-420. [PMID: 31396368 PMCID: PMC6682504 DOI: 10.4252/wjsc.v11.i7.398] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 06/18/2019] [Accepted: 06/27/2019] [Indexed: 02/06/2023] Open
Abstract
In recent decades, cancer stem cells (CSCs) have been increasingly identified in many malignancies. CSC-related signaling pathways and their functions provide new strategies for treating cancer. The aberrant activation of related signaling pathways (e.g., Wnt, Notch, and Hedgehog pathways) has been linked to multiple types of malignant tumors, which makes these pathways attractive targets for cancer therapy. CSCs display many characteristic features, such as self-renewal, differentiation, high tumorigenicity, and drug resistance. Therefore, there is an urgent need to develop new therapeutic strategies to target these pathways to control stem cell replication, survival, and differentiation. Notable crosstalk occurs among different signaling pathways and potentially leads to compensatory escape. Therefore, multitarget inhibitors will be one of the main methods to overcome the drug resistance of CSCs. Many small molecule inhibitors of components of signaling pathways in CSCs have entered clinical trials, and some inhibitors, such as vismodegib, sonidegib, and glasdegib, have been approved. Tumor cells are susceptible to sonidegib and vismodegib resistance due to mutations in the Smo protein. The signal transducers and activators of transcription 3 (STAT3) inhibitor BBI608 is being evaluated in a phase III trial for a variety of cancers. Structural derivatives of BBI608 are the main focus of STAT3 inhibitor development, which is another strategy for CSC therapy. In addition to the potential pharmacological inhibitors targeting CSC-related signaling pathways, other methods of targeting CSCs are available, such as nano-drug delivery systems, mitochondrion targeting, autophagy, hyperthermia, immunotherapy, and CSC microenvironment targeting. In addition, we summarize the latest advances in the clinical development of agents targeting CSC-related signaling pathways and other methods of targeting CSCs.
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Affiliation(s)
- Fang-Yu Du
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
| | - Qi-Fan Zhou
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
| | - Wen-Jiao Sun
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
| | - Guo-Liang Chen
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
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Molecular background of skin melanoma development and progression: therapeutic implications. Postepy Dermatol Alergol 2019; 36:129-138. [PMID: 31320844 PMCID: PMC6627250 DOI: 10.5114/ada.2019.84590] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 02/18/2018] [Indexed: 12/19/2022] Open
Abstract
Melanoma is the most aggressive skin cancer with an increasing number of cases worldwide and curable mostly in its early stage. The improvement in patients' survival in advanced melanoma has been achieved only recently, due to development of new biological drugs for targeted therapies and immunotherapy. Further progress in the treatment of melanoma is clearly dependent on the better understanding of its complex biology. This review describes the most important molecular mechanisms and genetic events underlying skin melanoma development and progression, depicts the way of action of newly developed drugs and indicates new potential therapeutic targets.
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Mikheil DM, Prabhakar K, Arshad A, Rodriguez CI, Newton MA, Setaluri V. Notch signaling activation induces cell death in MAPKi-resistant melanoma cells. Pigment Cell Melanoma Res 2019; 32:528-539. [PMID: 30614626 DOI: 10.1111/pcmr.12764] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 12/09/2018] [Accepted: 12/20/2018] [Indexed: 01/12/2023]
Abstract
The role of Notch signaling in melanoma drug resistance is not well understood. In this study, we show that although NOTCH proteins are upregulated in metastatic melanoma cell lines, Notch signaling inhibition had no effect on cell survival, growth, migration or the sensitivity of BRAFV600E-melanoma cells to MAPK inhibition (MAPKi). We found that NOTCH1 is downregulated in melanoma cell lines with intrinsic and acquired resistance to MAPKi. Forced expression of NICD1, the active form of Notch1, caused apoptosis of the NOTCHlo , MAPKi-resistant cells, but not the NOTCHhi , MAPKi-sensitive melanoma cell lines. Whole transcriptome-sequencing analyses of NICD1-transduced MAPKi-sensitive and MAPKi-resistant cells revealed differential regulation of endothelin 1 (EDN1) by NICD1, that is, downregulation in MAPKi-resistant cells and upregulation in MAPKi-sensitive cells. Knockdown of EDN1 partially mimicked the effect of NICD1 on the survival of MAPKi-resistant cells. We show that the opposite regulation of EDN1 by Notch signaling is mediated by the differential regulation of c-JUN by NICD1. Our data show that MAPKi-resistant melanoma cells acquire vulnerability to Notch signaling activation and suggest that Notch-c-JUN-EDN1 axis is a potential therapeutic target in MAPKi-resistant melanoma.
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Affiliation(s)
- Dareen M Mikheil
- Comparative Biomedical Sciences Graduate Program, University of Wisconsin, Madison, Wisconsin.,Department of Dermatology, University of Wisconsin, Madison, Wisconsin.,William S. Middleton Veterans Hospital, Madison, Wisconsin
| | | | - Ayyan Arshad
- Department of Dermatology, University of Wisconsin, Madison, Wisconsin
| | | | - Michael A Newton
- Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, Wisconsin
| | - Vijayasaradhi Setaluri
- Comparative Biomedical Sciences Graduate Program, University of Wisconsin, Madison, Wisconsin.,Department of Dermatology, University of Wisconsin, Madison, Wisconsin.,William S. Middleton Veterans Hospital, Madison, Wisconsin
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45
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Cho ES, Kang HE, Kim NH, Yook JI. Therapeutic implications of cancer epithelial-mesenchymal transition (EMT). Arch Pharm Res 2019; 42:14-24. [PMID: 30649699 DOI: 10.1007/s12272-018-01108-7] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 12/27/2018] [Indexed: 12/19/2022]
Abstract
The epithelial-mesenchymal transition (EMT) comprises an essential biological process involving cancer progression as well as initiation. While the EMT has been regarded as a phenotypic conversion from epithelial to mesenchymal cells, recent evidence indicates that it plays a critical role in stemness, metabolic reprogramming, immune evasion and therapeutic resistance of cancer cells. Interestingly, several transcriptional repressors including Snail (SNAI1), Slug (SNAI2) and the ZEB family constitute key players for EMT in cancer as well as in the developmental process. Note that the dynamic conversion between EMT and epithelial reversion (mesenchymal-epithelial transition, MET) occurs through variable intermediate-hybrid states rather than being a binary process. Given the close connection between oncogenic signaling and EMT repressors, the EMT has emerged as a therapeutic target or goal (in terms of MET reversion) in cancer therapy. Here we review the critical role of EMT in therapeutic resistance and the importance of EMT as a therapeutic target for human cancer.
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Affiliation(s)
- Eunae Sandra Cho
- Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea
| | - Hee Eun Kang
- Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea
| | - Nam Hee Kim
- Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea.
| | - Jong In Yook
- Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea.
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46
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Davis RB, Pahl K, Datto NC, Smith SV, Shawber C, Caron KM, Blatt J. Notch signaling pathway is a potential therapeutic target for extracranial vascular malformations. Sci Rep 2018; 8:17987. [PMID: 30573741 PMCID: PMC6302123 DOI: 10.1038/s41598-018-36628-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 11/20/2018] [Indexed: 12/22/2022] Open
Abstract
Notch expression has been shown to be aberrant in brain arteriovenous malformations (AVM), and targeting Notch has been suggested as an approach to their treatment. It is unclear whether extracranial vascular malformations follow the same patterning and Notch pathway defects. In this study, we examined human extracranial venous (VM) (n = 3), lymphatic (LM) (n = 10), and AV (n = 6) malformations, as well as sporadic brain AVMs (n = 3). In addition to showing that extracranial AVMs demonstrate interrupted elastin and that AVMs and LMs demonstrate abnormal α-smooth muscle actin just as brain AVMS do, our results demonstrate that NOTCH1, 2, 3 and 4 proteins are overexpressed to varying degrees in both the endothelial and mural lining of the malformed vessels in all types of malformations. We further show that two gamma secretase inhibitors (GSIs), DAPT (GSI-IX) and RO4929097, cause dose-dependent inhibition of Notch target gene expression (Hey1) and rate of migration of monolayer cultures of lymphatic endothelial cells (hLECs) and blood endothelial cells (HUVEC). GSIs also inhibit HUVEC network formation. hLECs are more sensitive to GSIs compared to HUVEC. GSIs have been found to be safe in clinical trials in patients with Alzheimer’s disease or cancer. Our results provide further rationale to support testing of Notch inhibitors in patients with extracranial vascular malformations.
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Affiliation(s)
- Reema B Davis
- Departments of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kristy Pahl
- Pediatrics (Division of Pediatric Hematology Oncology), University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Nicholas C Datto
- Departments of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Scott V Smith
- Surgical Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,Pathology and Laboratory Medicine (Translational Pathology Laboratory), University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Carrie Shawber
- Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA
| | - Kathleen M Caron
- Departments of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Julie Blatt
- Pediatrics (Division of Pediatric Hematology Oncology), University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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Exploring major signaling cascades in melanomagenesis: a rationale route for targetted skin cancer therapy. Biosci Rep 2018; 38:BSR20180511. [PMID: 30166456 PMCID: PMC6167501 DOI: 10.1042/bsr20180511] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 08/14/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
Although most melanoma cases may be treated by surgical intervention upon early diagnosis, a significant portion of patients can still be refractory, presenting low survival rates within 5 years after the discovery of the illness. As a hallmark, melanomas are highly prone to evolve into metastatic sites. Moreover, melanoma tumors are highly resistant to most available drug therapies and their incidence have increased over the years, therefore leading to public health concerns about the development of novel therapies. Therefore, researches are getting deeper in unveiling the mechanisms by which melanoma initiation can be triggered and sustained. In this context, important progress has been achieved regarding the roles and the impact of cellular signaling pathways in melanoma. This knowledge has provided tools for the development of therapies based on the intervention of signal(s) promoted by these cascades. In this review, we summarize the importance of major signaling pathways (mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)-Akt, Wnt, nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB), Janus kinase (JAK)-signal transducer and activator of transcription (STAT), transforming growth factor β (TGF-β) and Notch) in skin homeostasis and melanoma progression. Available and developing melanoma therapies interfering with these signaling cascades are further discussed.
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Mir O, Azaro A, Merchan J, Chugh R, Trent J, Rodon J, Ohnmacht U, Diener JT, Smith C, Yuen E, Oakley GJ, Le Cesne A, Soria JC, Benhadji KA, Massard C. Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours. Eur J Cancer 2018; 103:88-97. [PMID: 30218977 DOI: 10.1016/j.ejca.2018.08.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 08/08/2018] [Accepted: 08/16/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND LY3039478 is an orally bioavailable selective Notch inhibitor. This phase 1a/b trial evaluated the safety, pharmacokinetics and antitumour activity of LY3039478 in patients with soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST). METHODS This multipart, phase 1 trial enrolled patients with refractory advanced/metastatic STS and GIST, measurable disease, Eastern Cooperative Oncology Group ≤1 and baseline tumour tissue. Eligible patients received LY3039478 50mg/75 mg three times per week, for 28-day cycle until disease progression. Safety assessments were based on Common Terminology Criteria for Adverse Events, V4.0. Tumour responses were assessed using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) and Choi criteria. Primary objectives were to confirm the recommended phase 2 dose of LY3039478 and document the antitumour activity. Secondary objectives were safety and toxicity, pharmacokinetics (PK), progression-free survival (PFS) and overall survival (OS). RESULTS Sixty-nine patients were enrolled and received LY3039478 (27 males, 42 females; median age 58, range 31-78). 16/37 (43%) patients with evaluable samples were positive for Notch 1 immunohistochemistry. Per RECIST 1.1, in leiomyosarcoma (LMS) group (n = 29), ten (36%) had stable disease (SD) and one (4%) had unconfirmed partial response (PR). In GIST group (n = 13), four (31%) had SD. Among other STS subtypes (n = 27), one patient with angiosarcoma had unconfirmed PR, six (21%) had SD. Median PFS was 1.9 months (95% confidence interval:1.6-3.3) for LMS, 1.9 months (0.3-6.1) for GIST and 1.7 months (1.4-2.2) for other STS groups. Median OS was 7.4 months (4.3-non-evaluable [NE]) for LMS, 16.5 months (3.9-16.5) for GIST and 5.6 months (3.4-NE) for other STS groups. Most common adverse events were diarrhoea, nausea, vomiting and decreased appetite. CONCLUSION LY3039478 suggested a modest clinical activity in patients with STS and GIST and had a manageable safety profile.
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Affiliation(s)
- Olivier Mir
- Institut Gustave Roussy Cancer Campus, Drug Development Department, Villejuif Cedex, France
| | - Analia Azaro
- Molecular Therapeutics Research Unit, Department of Medical Oncology, Vall D'Hebron University Hospital, and Pharmacology Department, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Jaime Merchan
- University of Miami, Sylvester Comprehensive Cancer Center, United States
| | | | - Jonathan Trent
- University of Miami, Sylvester Comprehensive Cancer Center, United States
| | | | | | | | | | | | | | - Axel Le Cesne
- Institut Gustave Roussy Cancer Campus, Drug Development Department, Villejuif Cedex, France
| | - Jean-Charles Soria
- Institut Gustave Roussy Cancer Campus, Drug Development Department, Villejuif Cedex, France
| | | | - Christophe Massard
- Institut Gustave Roussy Cancer Campus, Drug Development Department, Villejuif Cedex, France.
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Gómez-Galeno JE, Hurtado C, Cheng J, Yardimci C, Mercola M, Cashman JR. b-Annulated 1,4-dihydropyridines as Notch inhibitors. Bioorg Med Chem Lett 2018; 28:3363-3367. [PMID: 30201292 DOI: 10.1016/j.bmcl.2018.09.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 08/19/2018] [Accepted: 09/03/2018] [Indexed: 12/31/2022]
Abstract
The Notch signaling pathway is involved in cell proliferation and differentiation, and has been recognized as an active pathway in regenerating tissue and cancerous cells. Notch signaling inhibition is considered a viable approach to the treatment of a variety of conditions including colorectal cancer, pancreatic cancer, breast cancer and metastatic melanoma. The discovery that the b-annulated dihydropyridine FLI-06 (1) is an inhibitor of the Notch pathway with an EC50 ≈ 2.5 μM prompted us to screen a library of related analogs. After structure activity studies were conducted, racemic compound 7 was identified with an EC50 = 0.36 μM. Synthesis of individual enantiomers provided (+)-7 enantiomer with an EC50 = 0.13 μM, or about 20-fold the potency of 1.
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Affiliation(s)
- Jorge E Gómez-Galeno
- Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121-2804, United States.
| | - Cecilia Hurtado
- Cardiovascular Institute and Department of Medicine, Stanford University, 300 Pasteur Drive, MC-5501, Stanford, CA 94305, United States
| | - Jiongjia Cheng
- Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121-2804, United States
| | - Ceren Yardimci
- Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121-2804, United States
| | - Mark Mercola
- Cardiovascular Institute and Department of Medicine, Stanford University, 300 Pasteur Drive, MC-5501, Stanford, CA 94305, United States
| | - John R Cashman
- Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121-2804, United States
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Cook N, Basu B, Smith DM, Gopinathan A, Evans J, Steward WP, Palmer D, Propper D, Venugopal B, Hategan M, Anthoney DA, Hampson LV, Nebozhyn M, Tuveson D, Farmer-Hall H, Turner H, McLeod R, Halford S, Jodrell D. A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma. Br J Cancer 2018; 118:793-801. [PMID: 29438372 PMCID: PMC5877439 DOI: 10.1038/bjc.2017.495] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 12/18/2017] [Accepted: 12/20/2017] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. METHODS A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m-2, was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D). Secondary and tertiary objectives included tumour response, plasma and tumour MK-0752 concentration, and inhibition of the Notch pathway in hair follicles and tumour. RESULTS Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response. CONCLUSIONS Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.
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Affiliation(s)
- Natalie Cook
- Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0RE, UK
| | - Bristi Basu
- Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0RE, UK
| | - Donna-Michelle Smith
- Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK
| | - Aarthi Gopinathan
- Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK
| | - Jeffry Evans
- Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow G12 0YN, United Kingdom
| | - William P Steward
- Department of Oncology, University of Leicester, Leicester LE2 7LX, UK
| | - Daniel Palmer
- Clatterbridge Cancer Centre, Clatterbridge Road, Bebington, Wirral CH63 4JY, UK
| | - David Propper
- Bart’s Cancer Institute, Queen Mary University of London EC1M 6BQ, London, UK
| | - Balaji Venugopal
- Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK
| | - Mirela Hategan
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0RE, UK
| | - D Alan Anthoney
- St James Institute of Oncology, University of Leeds & Leeds Teaching Hospitals Trust, Leeds LS9 7TF, UK
| | - Lisa V Hampson
- Department of Mathematics and Statistics, Fylde College, Lancaster University, Lancaster LA1 4YF, UK
| | | | - David Tuveson
- Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724, USA
| | - Hayley Farmer-Hall
- Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK
| | - Helen Turner
- Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK
| | - Robert McLeod
- Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK
| | - Sarah Halford
- Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK
| | - Duncan Jodrell
- Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0RE, UK
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