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Huang X, Chen W, Wang Y, Shytikov D, Wang Y, Zhu W, Chen R, He Y, Yang Y, Guo W. Canonical and noncanonical NOTCH signaling in the nongenetic resistance of cancer: distinct and concerted control. Front Med 2025; 19:23-52. [PMID: 39745621 DOI: 10.1007/s11684-024-1107-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 09/18/2024] [Indexed: 02/27/2025]
Abstract
Therapeutic resistance in cancer is responsible for numerous cancer deaths in clinical practice. While target mutations are well recognized as the basis of genetic resistance to targeted therapy, nontarget mutation resistance (or nongenetic resistance) remains poorly characterized. Despite its complex and unintegrated mechanisms in the literature, nongenetic resistance is considered from our perspective to be a collective response of innate or acquired resistant subpopulations in heterogeneous tumors to therapy. These subpopulations, e.g., cancer stem-like cells, cancer cells with epithelial-to-mesenchymal transition, and drug-tolerant persisters, are protected by their resistance traits at cellular and molecular levels. This review summarizes recent advances in the research on resistant populations and their resistance traits. NOTCH signaling, as a central regulator of nongenetic resistance, is discussed with a special focus on its canonical maintenance of resistant cancer cells and noncanonical regulation of their resistance traits. This novel view of canonical and noncanonical NOTCH signaling pathways is translated into our proposal of reshaping therapeutic strategies targeting NOTCH signaling in resistant cancer cells. We hope that this review will lead researchers to study the canonical and noncanonical arms of NOTCH signaling as an integrated resistant mechanism, thus promoting the development of innovative therapeutic strategies.
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Affiliation(s)
- Xianzhe Huang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Wenwei Chen
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yanyan Wang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Dmytro Shytikov
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yanwen Wang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Wangyi Zhu
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Ruyi Chen
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yuwei He
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yanjia Yang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Wei Guo
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China.
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
- Biomedical and Health Translational Research Center of Zhejiang Province, Jiaxing, 314400, China.
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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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Fu M, He J, Zhu D, Zhang Q, Jiang Z, Yang G. Promising therapeutic targets for tumor treatment: Cleaved activation of receptors in the nucleus. Drug Discov Today 2024; 29:104192. [PMID: 39332484 DOI: 10.1016/j.drudis.2024.104192] [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: 08/04/2024] [Revised: 09/11/2024] [Accepted: 09/21/2024] [Indexed: 09/29/2024]
Abstract
A new fate of cell surface receptors, cleaved activation in the nucleus, is summarized. The intracellular domain (ICD) of cell surface receptors, cleaved by enzymes like γ-secretase, translocates to the nucleus to form transcriptional complexes participating in the onset and development of tumors. The fate is clinically significant, as inhibitors of cleavage enzymes have shown effectiveness in treating advanced tumors by reducing tumorigenic ICDs. Additionally, the construction of synthetic receptors also conforms with the fate mechanism. This review details each step of cleaved activation in the nucleus, elucidates tumorigenic mechanisms, explores application in antitumor therapy, and scrutinizes possible limitations.
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Affiliation(s)
- Mengdie Fu
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, 310006, China
| | - Jin He
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, 310006, China
| | - Danji Zhu
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, 310006, China
| | - Qinmeng Zhang
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, 310006, China
| | - Zhiwei Jiang
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, 310006, China.
| | - Guoli Yang
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, 310006, China.
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4
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Lu Y, Cao Y, Guo X, Gao Y, Chen X, Zhang Z, Ge Z, Chu D. Notch-Targeted Therapeutic in Colorectal Cancer by Notch1 Attenuation Via Tumor Microenvironment-Responsive Cascade DNA Delivery. Adv Healthc Mater 2024; 13:e2400797. [PMID: 38726796 DOI: 10.1002/adhm.202400797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/08/2024] [Indexed: 06/04/2024]
Abstract
The Notch signaling is a key molecular pathway that regulates cell fate and development. Aberrant Notch signaling can lead to carcinogenesis and progression of malignant tumors. However, current therapies targeting Notch pathway lack specificity and induce high toxicity. In this report, a tumor microenvironment-responsive and injectable hydrogel is designed to load plasmid DNA complexes as a cascade gene delivery system to achieve precise Notch-targeted gene therapy of colorectal cancer (CRC). The hydrogels are prepared through cross-linking between phenylboric acid groups containing poly(oligo(ethylene glycol)methacrylate) (POEGMA) and epigallocatechin gallate (EGCG), used to load the complexes between plasmid DNA encoding short hairpin RNAs of Notch1 (shNotch1) and fluorinated polyamidoamine (PAMAM-F) (PAMAM-F/shNotch1). In response to low pH and H2O2 in tumor microenvironment, the hydrogel can be dissociated and release the complexes for precise delivery of shNotch1 into tumor cells and inhibit Notch1 activity to suppress malignant biological behaviors of CRC. In the subcutaneous tumor model of CRC, PAMAM-F/shNotch1-loaded hydrogels can accurately attenuate Notch1 activity and significantly inhibit tumor growth without affecting Notch signal in adjacent normal tissues. Therefore, this therapeutic system can precisely inhibit Notch1 signal in CRC with high responsiveness and low toxicity, providing a promising Notch-targeted gene therapeutic for human malignancy.
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Affiliation(s)
- Yan Lu
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Yufei Cao
- School of Chemistry, Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Xiaowen Guo
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Yijie Gao
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Xue Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Zixi Zhang
- Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Zhishen Ge
- School of Chemistry, Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China
| | - Dake Chu
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
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Sinha S, Hembram KC, Chatterjee S. Targeting signaling pathways in cancer stem cells: A potential approach for developing novel anti-cancer therapeutics. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 385:157-209. [PMID: 38663959 DOI: 10.1016/bs.ircmb.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Abstract
Cancer stem cells (CSCs) have emerged as prime players in the intricate landscape of cancer development, progression, and resistance to traditional treatments. These unique cellular subpopulations own the remarkable capability of self-renewal and differentiation, giving rise to the diverse cellular makeup of tumors and fostering their recurrence following conventional therapies. In the quest for developing more effective cancer therapeutics, the focus has now shifted toward targeting the signaling pathways that govern CSCs behavior. This chapter underscores the significance of these signaling pathways in CSC biology and their potential as pivotal targets for the development of novel chemotherapy approaches. We delve into several key signaling pathways essential for maintaining the defining characteristics of CSCs, including the Wnt, Hedgehog, Notch, JAK-STAT, NF-κB pathways, among others, shedding light on their potential crosstalk. Furthermore, we highlight the latest advancements in CSC-targeted therapies, spanning from promising preclinical models to ongoing clinical trials. A comprehensive understanding of the intricate molecular aspects of CSC signaling pathways and their manipulation holds the prospective to revolutionize cancer treatment paradigms. This, in turn, could lead to more efficacious and personalized therapies with the ultimate goal of eradicating CSCs and enhancing overall patient outcomes. The exploration of CSC signaling pathways represents a key step towards a brighter future in the battle against cancer.
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Affiliation(s)
- Saptarshi Sinha
- National Institute of Biomedical Genomics, Kalyani, West Bengal, India
| | | | - Subhajit Chatterjee
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD, United States.
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Bardhan M, Dey D, Suresh V, Javed B, Venur VA, Joe N, Kalidindi R, Ozair A, Khan M, Mahtani R, Lo S, Odia Y, Ahluwalia MS. An overview of the therapeutic strategies for neoplastic meningitis due to breast cancer: when and why? Expert Rev Neurother 2024; 24:77-103. [PMID: 38145503 DOI: 10.1080/14737175.2023.2293223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/06/2023] [Indexed: 12/27/2023]
Abstract
INTRODUCTION Neoplastic meningitis (NM), also known as leptomeningeal carcinomatosis, is characterized by the infiltration of tumor cells into the meninges, and poses a significant therapeutic challenge owing to its aggressive nature and limited treatment options. Breast cancer is a common cause of NM among solid tumors, further highlighting the urgent need to explore effective therapeutic strategies. This review aims to provide insights into the evolving landscape of NM therapy in breast cancer by collating existing research, evaluating current treatments, and identifying potential emerging therapeutic options. AREAS COVERED This review explores the clinical features, therapeutic strategies, recent advances, and challenges of managing NM in patients with breast cancer. Its management includes multimodal strategies, including systemic and intrathecal chemotherapy, radiation therapy, and supportive care. This review also emphasizes targeted drug options and optimal drug concentrations, and discusses emerging therapies. Additionally, it highlights the variability in treatment outcomes and the potential of combination regimens to effectively manage NM in breast cancer. EXPERT OPINION Challenges in treating NM include debates over clinical trial end points and the management of adverse effects. Drug resistance and low response rates are significant hurdles, particularly inHER2-negative breast cancer. The development of more precise and cost-effective medications with improved selectivity is crucial. Additionally, global efforts are needed for infrastructure development and cancer control considering the diverse nature of the disease.
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Affiliation(s)
- Mainak Bardhan
- Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
| | | | - Vinay Suresh
- King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Binish Javed
- Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, New Delhi, India
| | - Vyshak Alva Venur
- Seattle Cancer Care Alliance, Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA
| | - Neha Joe
- St John's Medical College Hospital, Bengaluru, India
| | | | - Ahmad Ozair
- Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | | | - Reshma Mahtani
- Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
| | - Simon Lo
- Department of Radiation Oncology, University of Washington School of Medicine, Seattle, WA, USA
| | - Yazmin Odia
- Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
| | - Manmeet S Ahluwalia
- Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
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7
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Cao J, Zhang Z, Zhou L, Luo M, Li L, Li B, Nice EC, He W, Zheng S, Huang C. Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy. MedComm (Beijing) 2023; 4:e427. [PMID: 38045829 PMCID: PMC10693315 DOI: 10.1002/mco2.427] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 12/05/2023] Open
Abstract
Emerging evidence indicates that cancer cells can mimic characteristics of embryonic development, promoting their development and progression. Cancer cells share features with embryonic development, characterized by robust proliferation and differentiation regulated by signaling pathways such as Wnt, Notch, hedgehog, and Hippo signaling. In certain phase, these cells also mimic embryonic diapause and fertilized egg implantation to evade treatments or immune elimination and promote metastasis. Additionally, the upregulation of ATP-binding cassette (ABC) transporters, including multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and breast cancer-resistant protein (BCRP), in drug-resistant cancer cells, analogous to their role in placental development, may facilitate chemotherapy efflux, further resulting in treatment resistance. In this review, we concentrate on the underlying mechanisms that contribute to tumor development and progression from the perspective of embryonic development, encompassing the dysregulation of developmental signaling pathways, the emergence of dormant cancer cells, immune microenvironment remodeling, and the hyperactivation of ABC transporters. Furthermore, we synthesize and emphasize the connections between cancer hallmarks and embryonic development, offering novel insights for the development of innovative cancer treatment strategies.
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Affiliation(s)
- Jiangjun Cao
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Zhe Zhang
- Zhejiang Provincial Key Laboratory of Pancreatic Diseasethe First Affiliated HospitalSchool of MedicineZhejiang UniversityZhejiangChina
| | - Li Zhou
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education)Department of Infectious Diseasesthe Second Affiliated HospitalInstitute for Viral Hepatitis, Chongqing Medical UniversityChongqingChina
| | - Maochao Luo
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Lei Li
- Department of anorectal surgeryHospital of Chengdu University of Traditional Chinese Medicine and Chengdu University of Traditional Chinese MedicineChengduChina
| | - Bowen Li
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Edouard C. Nice
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVICAustralia
| | - Weifeng He
- State Key Laboratory of TraumaBurn and Combined InjuryInstitute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University)ChongqingChina
| | - Shaojiang Zheng
- Hainan Cancer Medical Center of The First Affiliated Hospital, the Hainan Branch of National Clinical Research Center for Cancer, Hainan Engineering Research Center for Biological Sample Resources of Major DiseasesHainan Medical UniversityHaikouChina
- Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, Hainan Women and Children's Medical Center, Key Laboratory of Emergency and Trauma of Ministry of EducationHainan Medical UniversityHaikouChina
| | - Canhua Huang
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
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8
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Song C, Zhang J, Xu C, Gao M, Li N, Geng Q. The critical role of γ-secretase and its inhibitors in cancer and cancer therapeutics. Int J Biol Sci 2023; 19:5089-5103. [PMID: 37928268 PMCID: PMC10620818 DOI: 10.7150/ijbs.87334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 07/22/2023] [Indexed: 11/07/2023] Open
Abstract
As a multi-substrate transmembrane protease, γ-secretase exists widely in various cells. It controls multiple important cellular activities through substrate cleavage. γ-secretase inhibitors (GSIs) play a role in cancer inhibition by blocking Notch cleavage, and are considered as potential therapeutic strategies for cancer. Currently, GSIs have encouraging performance in preclinical models, yet this success does not translate well in clinical trials. In recent years, a number of breakthrough discoveries have shown us the promise of targeting γ-secretase for the treatment of cancer. Here, we integrate a large amount of data from γ-secretase and its inhibitors and cancer in nearly 30 years, comb and discuss the close connection between γ-secretase and cancer, as well as the potential and problems of current GSIs in cancer treatment. We analyze the possible reasons for the failure performance of current GSIs in clinical trials, and make recommendations for future research areas.
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Affiliation(s)
- Congkuan Song
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jinjin Zhang
- Department of Emergency, Taihe Hospital, Shiyan, China
| | - Chenzhen Xu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Minglang Gao
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ning Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
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9
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Reisenauer KN, Aroujo J, Tao Y, Ranganathan S, Romo D, Taube JH. Therapeutic vulnerabilities of cancer stem cells and effects of natural products. Nat Prod Rep 2023; 40:1432-1456. [PMID: 37103550 PMCID: PMC10524555 DOI: 10.1039/d3np00002h] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/28/2023]
Abstract
Covering: 1995 to 2022Tumors possess both genetic and phenotypic heterogeneity leading to the survival of subpopulations post-treatment. The term cancer stem cells (CSCs) describes a subpopulation that is resistant to many types of chemotherapy and which also possess enhanced migratory and anchorage-independent growth capabilities. These cells are enriched in residual tumor material post-treatment and can serve as the seed for future tumor re-growth, at both primary and metastatic sites. Elimination of CSCs is a key goal in enhancing cancer treatment and may be aided by application of natural products in conjunction with conventional treatments. In this review, we highlight molecular features of CSCs and discuss synthesis, structure-activity relationships, derivatization, and effects of six natural products with anti-CSC activity.
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Affiliation(s)
| | - Jaquelin Aroujo
- Department of Chemistry and Biochemistry, Baylor Univesrity, Waco, TX, USA
| | - Yongfeng Tao
- Department of Chemistry and Biochemistry, Baylor Univesrity, Waco, TX, USA
| | | | - Daniel Romo
- Department of Chemistry and Biochemistry, Baylor Univesrity, Waco, TX, USA
| | - Joseph H Taube
- Department of Biology, Baylor University, Waco, TX, USA.
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
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10
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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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11
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Identification, Culture and Targeting of Cancer Stem Cells. Life (Basel) 2022; 12:life12020184. [PMID: 35207472 PMCID: PMC8879966 DOI: 10.3390/life12020184] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
Chemoresistance, tumor progression, and metastasis are features that are frequently seen in cancer that have been associated with cancer stem cells (CSCs). These cells are a promising target in the future of cancer therapy but remain largely unknown. Deregulation of pathways that govern stemness in non-tumorigenic stem cells (SCs), such as Notch, Wnt, and Hedgehog pathways, has been described in CSC pathogenesis, but it is necessary to conduct further studies to discover potential new therapeutic targets. In addition, some markers for the identification and characterization of CSCs have been suggested, but the search for specific CSC markers in many cancer types is still under development. In addition, methods for CSC cultivation are also under development, with great heterogeneity existing in the protocols used. This review focuses on the most recent aspects of the identification, characterization, cultivation, and targeting of human CSCs, highlighting the advances achieved in the clinical implementation of therapies targeting CSCs and remarking those potential areas where more research is still required.
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12
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Reddy AV, Hill CS, Sehgal S, Ding D, Hacker-Prietz A, He J, Zheng L, Herman JM, Meyer J, Narang AK. Impact of somatic mutations on clinical and pathologic outcomes in borderline resectable and locally advanced pancreatic cancer treated with neoadjuvant chemotherapy and stereotactic body radiotherapy followed by surgical resection. Radiat Oncol J 2021; 39:304-314. [PMID: 34986552 PMCID: PMC8743453 DOI: 10.3857/roj.2021.00815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/08/2021] [Accepted: 10/14/2021] [Indexed: 01/05/2023] Open
Abstract
PURPOSE The purpose of this study was to determine if somatic mutations are associated with clinical and pathologic outcomes in patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) who were treated with neoadjuvant chemotherapy and stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS Patients treated with neoadjuvant chemotherapy and SBRT followed by surgical resection from August 2016 to January 2019 and who underwent next generation sequencing of their primary tumor were included in the study. Next-generation sequencing was performed either in-house with a Solid Tumor Panel or with FoundationOne CDx. Univariate (UVA) and multivariable analyses (MVA) were performed to determine associations between somatic mutations and pathologic and clinical outcomes. RESULTS Thirty-five patients were included in the study. Chemotherapy consisted of modified FOLFIRINOX, gemcitabine and nab-paclitaxel, or gemcitabine and capecitabine. Patients were treated with SBRT in 33 Gy in 5 fractions. On UVA and MVA, tumors with KRAS G12V mutation demonstrated better pathologic tumor regression grade (TRG) to neoadjuvant therapy when compared to tumors with other KRAS mutations (odds ratio = 0.087; 95% confidence interval [CI], 0.009-0.860; p = 0.036). On UVA and MVA, mutations in NOTCH1/2 were associated with worse overall survival (hazard ratio [HR] = 4.15; 95% CI, 1.57-10.95; p = 0.004) and progression-free survival (HR = 3.61; 95% CI, 1.41-9.28; p = 0.008). On UVA, only mutations in NOTCH1/2 were associated with inferior distant metastasis-free survival (HR = 3.38; 95% CI, 1.25-9.16; p = 0.017). CONCLUSION In BRPC and LAPC, the KRAS G12V mutation was associated with better TRG following chemotherapy and SBRT. Additionally, NOTCH1/2 mutations were associated with worse overall survival, distant metastasis-free survival, and progression-free survival.
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Affiliation(s)
- Abhinav V. Reddy
- Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Colin S. Hill
- Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shuchi Sehgal
- Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ding Ding
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Amy Hacker-Prietz
- Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jin He
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lei Zheng
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Joseph M. Herman
- Department of Radiation Oncology, Northwell Health Cancer Institute, New Hyde Park, NY, USA
| | - Jeffrey Meyer
- Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Amol K. Narang
- Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Zhdanovskaya N, Firrincieli M, Lazzari S, Pace E, Scribani Rossi P, Felli MP, Talora C, Screpanti I, Palermo R. Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives. Cancers (Basel) 2021; 13:cancers13205106. [PMID: 34680255 PMCID: PMC8533696 DOI: 10.3390/cancers13205106] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/03/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary The Notch signaling pathway regulates cell proliferation, apoptosis, stem cell self-renewal, and differentiation in a context-dependent fashion both during embryonic development and in adult tissue homeostasis. Consistent with its pleiotropic physiological role, unproper activation of the signaling promotes or counteracts tumor pathogenesis and therapy response in distinct tissues. In the last twenty years, a wide number of studies have highlighted the anti-cancer potential of Notch-modulating agents as single treatment and in combination with the existent therapies. However, most of these strategies have failed in the clinical exploration due to dose-limiting toxicity and low efficacy, encouraging the development of novel agents and the design of more appropriate combinations between Notch signaling inhibitors and chemotherapeutic drugs with improved safety and effectiveness for distinct types of cancer. Abstract Notch signaling guides cell fate decisions by affecting proliferation, apoptosis, stem cell self-renewal, and differentiation depending on cell and tissue context. Given its multifaceted function during tissue development, both overactivation and loss of Notch signaling have been linked to tumorigenesis in ways that are either oncogenic or oncosuppressive, but always context-dependent. Notch signaling is critical for several mechanisms of chemoresistance including cancer stem cell maintenance, epithelial-mesenchymal transition, tumor-stroma interaction, and malignant neovascularization that makes its targeting an appealing strategy against tumor growth and recurrence. During the last decades, numerous Notch-interfering agents have been developed, and the abundant preclinical evidence has been transformed in orphan drug approval for few rare diseases. However, the majority of Notch-dependent malignancies remain untargeted, even if the application of Notch inhibitors alone or in combination with common chemotherapeutic drugs is being evaluated in clinical trials. The modest clinical success of current Notch-targeting strategies is mostly due to their limited efficacy and severe on-target toxicity in Notch-controlled healthy tissues. Here, we review the available preclinical and clinical evidence on combinatorial treatment between different Notch signaling inhibitors and existent chemotherapeutic drugs, providing a comprehensive picture of molecular mechanisms explaining the potential or lacking success of these combinations.
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Affiliation(s)
- Nadezda Zhdanovskaya
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Mariarosaria Firrincieli
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Center for Life Nano Science, Istituto Italiano di Tecnologia, 00161 Rome, Italy
| | - Sara Lazzari
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Eleonora Pace
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Pietro Scribani Rossi
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Maria Pia Felli
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
| | - Claudio Talora
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Isabella Screpanti
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Correspondence: (I.S.); (R.P.)
| | - Rocco Palermo
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Center for Life Nano Science, Istituto Italiano di Tecnologia, 00161 Rome, Italy
- Correspondence: (I.S.); (R.P.)
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14
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MYH9 is crucial for stem cell-like properties in non-small cell lung cancer by activating mTOR signaling. Cell Death Discov 2021; 7:282. [PMID: 34635641 PMCID: PMC8505404 DOI: 10.1038/s41420-021-00681-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/09/2021] [Accepted: 09/24/2021] [Indexed: 12/12/2022] Open
Abstract
The fatality rate of non-small cell lung cancer (NSCLC) has been high due to the existence of cancer stem cells (CSCs). Non-muscle myosin heavy chain 9 (MYH9) can promote the progression of various tumors, but its effect on the stem cell-like characteristics of lung cancer cells (LCCs) has not been clarified. Our research found that the stemness characteristics of LCCs were significantly enhanced by the overexpression of MYH9, and the knockout of MYH9 had the opposite effects. The in vivo with inhibitor blebbistatin further confirmed the effect of MYH9 on the stem cell-like behavior of LCCs. Furthermore, western blotting showed that the expression level of CSCs markers (CD44, SOX2, Nanog, CD133, and OCT4) was also regulated by MYH9. Mechanistic studies have shown that MYH9 regulates stem cell-like features of LCCs by regulating the mTOR signaling pathway, which was supported by sphere formation experiments after LCCs were treated with inhibitors Rapamycin and CHIR-99021. Importantly, high expression of MYH9 in lung cancer is positively correlated with poor clinical prognosis and is an independent risk factor for patients with NSCLC.
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15
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Dardare J, Witz A, Merlin JL, Bochnakian A, Toussaint P, Gilson P, Harlé A. Epithelial to Mesenchymal Transition in Patients with Pancreatic Ductal Adenocarcinoma: State-of-the-Art and Therapeutic Opportunities. Pharmaceuticals (Basel) 2021; 14:740. [PMID: 34451837 PMCID: PMC8399337 DOI: 10.3390/ph14080740] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the malignancies with the worst prognosis despite a decade of efforts. Up to eighty percent of patients are managed at late stages with metastatic disease, in part due to a lack of diagnosis. The effectiveness of PDAC therapies is challenged by the early and widespread metastasis. Epithelial to mesenchymal transition (EMT) is a major driver of cancer progression and metastasis. This process allows cancer cells to gain invasive properties by switching their phenotype from epithelial to mesenchymal. The importance of EMT has been largely described in PDAC, and its importance is notably highlighted by the two major subtypes found in PDAC: the classical epithelial and the quasi-mesenchymal subtypes. Quasi-mesenchymal subtypes have been associated with a poorer prognosis. EMT has also been associated with resistance to treatments such as chemotherapy and immunotherapy. EMT is associated with several key molecular markers both epithelial and mesenchymal. Those markers might be helpful as a biomarker in PDAC diagnosis. EMT might becoming a key new target of interest for the treatment PDAC. In this review, we describe the role of EMT in PDAC, its contribution in diagnosis, in the orientation and treatment follow-up. We also discuss the putative role of EMT as a new therapeutic target in the management of PDAC.
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Affiliation(s)
- Julie Dardare
- Université de Lorraine, CNRS UMR7039 CRAN, Service de Biopathologie, Institut de Cancérologie de Lorraine, 54519 Vandoeuvre-lès-Nancy, France; (A.W.); (J.-L.M.); (A.B.); (P.T.); (P.G.); (A.H.)
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16
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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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17
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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: 69] [Impact Index Per Article: 17.3] [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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18
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Perez-Fidalgo JA, Ortega B, Simon S, Samartzis EP, Boussios S. NOTCH signalling in ovarian cancer angiogenesis. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1705. [PMID: 33490217 PMCID: PMC7812236 DOI: 10.21037/atm-20-4497] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The Notch signalling pathway is involved in the new vessel formation process by regulating tip and stalk cells, which are key cells in the sprout formation. This process is essential in both normal ovary and cancer angiogenesis and is regulated by Notch-VEGF crosstalk. Furthermore, Notch has been linked in ovary with stem cell maintenance and epithelial mesenchymal transition processes. Dysregulation of the Notch pathway is frequent in ovarian cancer (OC) and it has been associated with impaired survival and advanced stages or lymph node involvement. Notch also plays a role in chemoresistance to platinum. In this context, this pathway has emerged as an attractive target for precision medicine in OC. Two main targets of this pathway concentrate the clinical development of compounds blocking Notch: gamma secretase and Delta-like ligand 4. Most of the clinical trials including OC patients have been developed in phase I or phase Ib. Despite being in an early phase, both of these compounds, navicixizumab or demcizumab, two monoclonal antibodies targeting Dll4, showed promising efficacy data in platinum-resistant OC patients in recent studies. This review will focus on the mechanisms of the Notch pathway with special interest in angiogenesis regulation and the implication of Notch as a potential therapeutic target in OC.
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Affiliation(s)
- Jose Alejandro Perez-Fidalgo
- Department of Medical Oncology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, CIBERONC, Valencia, Spain
| | - Belen Ortega
- Department of Medical Oncology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, CIBERONC, Valencia, Spain
| | - Soraya Simon
- Department of Medical Oncology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, CIBERONC, Valencia, Spain
| | | | - Stergios Boussios
- King's College London, School of Medicine, Guy's Campus, London, UK.,Medway NHS Foundation Trust, Gillingham, Kent, UK.,AELIA Organization, 9th Km Thessaloniki-Thermi, Thessaloniki, Greece
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Gharaibeh L, Elmadany N, Alwosaibai K, Alshaer W. Notch1 in Cancer Therapy: Possible Clinical Implications and Challenges. Mol Pharmacol 2020; 98:559-576. [PMID: 32913140 DOI: 10.1124/molpharm.120.000006] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 08/10/2020] [Indexed: 12/19/2022] Open
Abstract
The Notch family consists of four highly conserved transmembrane receptors. The release of the active intracellular domain requires the enzymatic activity of γ-secretase. Notch is involved in embryonic development and in many physiologic processes of normal cells, in which it regulates growth, apoptosis, and differentiation. Notch1, a member of the Notch family, is implicated in many types of cancer, including breast cancer (especially triple-negative breast cancer), leukemias, brain tumors, and many others. Notch1 is tightly connected to many signaling pathways that are therapeutically involved in tumorigenesis. Together, they impact apoptosis, proliferation, chemosensitivity, immune response, and the population of cancer stem cells. Notch1 inhibition can be achieved through various and diverse methods, the most common of which are the γ-secretase inhibitors, which produce a pan-Notch inhibition, or the use of Notch1 short interference RNA or Notch1 monoclonal antibodies, which produce a more specific blockade. Downregulation of Notch1 can be used alone or in combination with chemotherapy, which can achieve a synergistic effect and a decrease in chemoresistance. Targeting Notch1 in cancers that harbor high expression levels of Notch1 offers an addition to therapeutic strategies recruited for managing cancer. Considering available evidence, Notch1 offers a legitimate target that might be incorporated in future strategies for combating cancer. In this review, the possible clinical applications of Notch1 inhibition and the obstacles that hinder its clinical application are discussed. SIGNIFICANCE STATEMENT: Notch1 plays an important role in different types of cancer. Numerous approaches of Notch1 inhibition possess potential benefits in the management of various clinical aspects of cancer. The application of different Notch1 inhibition modalities faces many challenges.
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Affiliation(s)
- L Gharaibeh
- Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan (L.G); Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.E.); Research Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia (K.A.); and Cell Therapy Center, The University of Jordan, Amman, Jordan (W.A.)
| | - N Elmadany
- Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan (L.G); Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.E.); Research Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia (K.A.); and Cell Therapy Center, The University of Jordan, Amman, Jordan (W.A.)
| | - K Alwosaibai
- Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan (L.G); Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.E.); Research Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia (K.A.); and Cell Therapy Center, The University of Jordan, Amman, Jordan (W.A.)
| | - W Alshaer
- Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan (L.G); Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.E.); Research Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia (K.A.); and Cell Therapy Center, The University of Jordan, Amman, Jordan (W.A.)
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20
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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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21
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Kong D, Hughes CJ, Ford HL. Cellular Plasticity in Breast Cancer Progression and Therapy. Front Mol Biosci 2020; 7:72. [PMID: 32391382 PMCID: PMC7194153 DOI: 10.3389/fmolb.2020.00072] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/31/2020] [Indexed: 12/24/2022] Open
Abstract
With the exception of non-melanoma skin cancer, breast cancer is the most frequently diagnosed malignant disease among women, with the majority of mortality being attributable to metastatic disease. Thus, even with improved early screening and more targeted treatments which may enable better detection and control of early disease progression, metastatic disease remains a significant problem. While targeted therapies exist for breast cancer patients with particular subtypes of the disease (Her2+ and ER/PR+), even in these subtypes the therapies are often not efficacious once the patient's tumor metastasizes. Increases in stemness or epithelial-to-mesenchymal transition (EMT) in primary breast cancer cells lead to enhanced plasticity, enabling tumor progression, therapeutic resistance, and distant metastatic spread. Numerous signaling pathways, including MAPK, PI3K, STAT3, Wnt, Hedgehog, and Notch, amongst others, play a critical role in maintaining cell plasticity in breast cancer. Understanding the cellular and molecular mechanisms that regulate breast cancer cell plasticity is essential for understanding the biology of breast cancer progression and for developing novel and more effective therapeutic strategies for targeting metastatic disease. In this review we summarize relevant literature on mechanisms associated with breast cancer plasticity, tumor progression, and drug resistance.
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Affiliation(s)
- Deguang Kong
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Connor J. Hughes
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Pharmacology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Heide L. Ford
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Pharmacology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, Zhang G, Wang X, Dong Z, Chen F, Cui H. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther 2020; 5:8. [PMID: 32296030 PMCID: PMC7005297 DOI: 10.1038/s41392-020-0110-5] [Citation(s) in RCA: 1173] [Impact Index Per Article: 234.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 12/15/2019] [Accepted: 12/19/2019] [Indexed: 12/18/2022] Open
Abstract
Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.
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Affiliation(s)
- Liqun Yang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Pengfei Shi
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Gaichao Zhao
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Jie Xu
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Wen Peng
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Jiayi Zhang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Guanghui Zhang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Xiaowen Wang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Fei Chen
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, 48201, USA
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China.
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China.
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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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Qian XQ, Tang SS, Shen YM, Chen LL, Cheng XD, Wan XY. Notch1 Affects Chemo-resistance Through Regulating Epithelial-Mesenchymal Transition (EMT) in Epithelial Ovarian cancer cells. Int J Med Sci 2020; 17:1215-1223. [PMID: 32547317 PMCID: PMC7294924 DOI: 10.7150/ijms.44683] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 04/27/2020] [Indexed: 01/14/2023] Open
Abstract
Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, chemo-resistance is the main cause for treatment failure. Our previous studies have found that SKOV3 could promote immune escape and tumor progression via Notch1 pathway. Therefore, Notch1 is suspected to be involved in chemo-resistance. The current study is to investigate the possible mechanisms of platinum-resistance in epithelial ovarian cancer mediated by Notch1. Methods: The expressions of Notch1, Snail, MMP-2, N-cadherin, Vimentin and E-cadherin were detected by Western-blot. A stable high expression or low expression of Notch1 in ovarian cancer cells was established by using lentiviral gene engineering. The cell migration and invasion ability were observed by scratch test and transwell test. Cell apoptosis rate and cell cycle were analyzed by flow cytometry. Results: The expression levels of Notch1, Snail, MMP-2, N-cadherin and Vimentin in ovarian cancer were high, while the expression levels of E-cadherin were low.Notch1 promoted the expression of Snail, vimentin, N-cadherin and MMP2 protein, but inhibiting the expression of E-cadherin, promoting cell migration and invasion. Notch1 affected apoptosis of cells through Epithelial-Mesenchymal Transition (EMT), increasing the proportion of cells in S phase and G2 phase, thus affecting drug resistance. Conclusion: Notch1 affects EOC cells chemo-resistance by regulating EMT. This may provide a new target for the treatment of ovarian cancer.
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Affiliation(s)
- Xue-Qian Qian
- Women's Reproductive Health Key Laboratory of Zhejiang Province; Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, and Hangzhou, China
| | - Sang-Sang Tang
- Women's Reproductive Health Key Laboratory of Zhejiang Province; Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, and Hangzhou, China
| | - Yuan-Ming Shen
- Women's Reproductive Health Key Laboratory of Zhejiang Province; Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, and Hangzhou, China
| | - Li-Li Chen
- Women's Reproductive Health Key Laboratory of Zhejiang Province; Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, and Hangzhou, China
| | - Xiao-Dong Cheng
- Women's Reproductive Health Key Laboratory of Zhejiang Province; Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, and Hangzhou, China
| | - Xiao-Yun Wan
- Women's Reproductive Health Key Laboratory of Zhejiang Province; Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, and Hangzhou, China
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Clara JA, Monge C, Yang Y, Takebe N. Targeting signalling pathways and the immune microenvironment of cancer stem cells - a clinical update. Nat Rev Clin Oncol 2019; 17:204-232. [PMID: 31792354 DOI: 10.1038/s41571-019-0293-2] [Citation(s) in RCA: 487] [Impact Index Per Article: 81.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/14/2019] [Indexed: 02/06/2023]
Abstract
Cancer stem cells (CSCs) have important roles in tumour development, relapse and metastasis; the intrinsic self-renewal characteristics and tumorigenic properties of these cells provide them with unique capabilities to resist diverse forms of anticancer therapy, seed recurrent tumours, and disseminate to and colonize distant tissues. The findings of several studies indicate that CSCs originate from non-malignant stem or progenitor cells. Accordingly, inhibition of developmental signalling pathways that are crucial for stem and progenitor cell homeostasis and function, such as the Notch, WNT, Hedgehog and Hippo signalling cascades, continues to be pursued across multiple cancer types as a strategy for targeting the CSCs hypothesized to drive cancer progression - with some success in certain malignancies. In addition, with the renaissance of anticancer immunotherapy, a better understanding of the interplay between CSCs and the tumour immune microenvironment might be the key to unlocking a new era of oncological treatments associated with a reduced propensity for the development of resistance and with enhanced antimetastatic activity, thus ultimately resulting in improved patient outcomes. Herein, we provide an update on the progress to date in the clinical development of therapeutics targeting the Notch, WNT, Hedgehog and Hippo pathways. We also discuss the interactions between CSCs and the immune system, including the potential immunological effects of agents targeting CSC-associated developmental signalling pathways, and provide an overview of the emerging approaches to CSC-targeted immunotherapy.
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Affiliation(s)
- Joseph A Clara
- National Heart Lung and Blood Institute, NIH, Bethesda, MD, USA
| | - Cecilia Monge
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Yingzi Yang
- Department of Developmental Biology, Harvard School of Dental Medicine, Dana-Farber/Harvard Cancer Center, Boston, MA, USA
| | - Naoko Takebe
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA.
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26
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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: 58] [Impact Index Per Article: 9.7] [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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27
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Rice MA, Hsu EC, Aslan M, Ghoochani A, Su A, Stoyanova T. Loss of Notch1 Activity Inhibits Prostate Cancer Growth and Metastasis and Sensitizes Prostate Cancer Cells to Antiandrogen Therapies. Mol Cancer Ther 2019; 18:1230-1242. [PMID: 31028097 DOI: 10.1158/1535-7163.mct-18-0804] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 10/29/2018] [Accepted: 04/24/2019] [Indexed: 02/07/2023]
Abstract
Prostate cancer remains among the leading causes of cancer-related deaths in men. Patients with aggressive disease typically undergo hormone deprivation therapy. Although treatment is initially very successful, these men commonly progress to lethal, castration-resistant prostate cancer (CRPC) in 2 to 3 years. Standard therapies for CRPC include second-generation antiandrogens, which prolong patient lifespan by only several months. It is imperative to advance our understanding of the mechanisms leading to resistance to identify new therapies for aggressive prostate cancer. This study identifies Notch1 as a therapeutic target in prostate cancer. Loss of NOTCH1 in aggressive prostate cancer cells decreases proliferation, invasion, and tumorsphere formation. Therapeutic inhibition of Notch1 activity with gamma secretase inhibitors RO4929097 or DAPT in prostate cancer cells further results in decreased proliferative abilities. Loss of NOTCH1 and treatment of immunocompromised mice bearing prostate cancer xenografts with RO4929097 display significantly impaired tumor growth. Loss of NOTCH1 additionally decreased metastatic potential of prostate cancer cells in invasion assays in vitro as well as in vivo experiments. Moreover, treatment with gamma secretase inhibitors or NOTCH1 gene deletion synergized with antiandrogen therapies, enzalutamide or abiraterone, to decrease the growth of prostate cancer cells. Combination of gamma secretase inhibitors with abiraterone significantly inhibited cell migration and invasion, while combination with enzalutamide reversed enzalutamide-induced migration and invasion. These collective findings suggest loss of NOTCH1 delays growth of CRPC and inhibits metastasis, and inhibition of Notch1 activation in conjunction with second-generation antiandrogen therapies could delay growth and progression of prostate cancer.
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Affiliation(s)
- Meghan A Rice
- Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Palo Alto, California
| | - En-Chi Hsu
- Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Palo Alto, California
| | - Merve Aslan
- Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Palo Alto, California
| | - Ali Ghoochani
- Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Palo Alto, California
| | - Austin Su
- Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Palo Alto, California
| | - Tanya Stoyanova
- Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Palo Alto, California.
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28
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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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Venkatesh V, Nataraj R, Thangaraj GS, Karthikeyan M, Gnanasekaran A, Kaginelli SB, Kuppanna G, Kallappa CG, Basalingappa KM. Targeting Notch signalling pathway of cancer stem cells. Stem Cell Investig 2018; 5:5. [PMID: 29682512 DOI: 10.21037/sci.2018.02.02] [Citation(s) in RCA: 203] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 01/16/2018] [Indexed: 12/18/2022]
Abstract
Cancer stem cells (CSCs) have been defined as cells within tumor that possess the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. CSCs have been increasingly identified in blood cancer, prostate, ovarian, lung, melanoma, pancreatic, colon, brain and many more malignancies. CSCs have slow growth rate and are resistant to chemotherapy and radiotherapy that lead to the failure of traditional current therapy. Eradicating the CSCs and recurrence, is promising aspect for the cure of cancer. The CSCs like any other stem cells activate the signal transduction pathways that involve the development and tissue homeostasis, which include Notch signaling pathway. The new treatment targets these pathway that control stem-cell replication, survival and differentiation that are under development. Notch inhibitors either single or in combination with chemotherapy drugs have been developed to treat cancer and its recurrence. This approach of targeting signaling pathway of CSCs represents a promising future direction for the therapeutic strategy to cure cancer.
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Affiliation(s)
- Vandana Venkatesh
- Division of Biochemistry, Faculty of Life Sciences, JSS Academy of Higher Education and Research, (Deemed to be University), Mysuru, India
| | - Raghu Nataraj
- Division of Molecular Biology, Faculty of Life Sciences, JSS Academy of Higher Education and Research, (Deemed to be University), Mysuru, India
| | - Gopenath S Thangaraj
- Division of Biotechnology, Faculty of Life Sciences, JSS Academy of Higher Education and Research, (Deemed to be University), Mysuru, India
| | - Murugesan Karthikeyan
- Senior Lecturer, Department of Microbiology, Faculty of Medicine, Quest International University Perak, Malaysia
| | - Ashok Gnanasekaran
- Senior Lecturer, Department of Microbiology, Faculty of Medicine, Quest International University Perak, Malaysia
| | - Shanmukhappa B Kaginelli
- Division of Medical Physics, Faculty of Life Sciences, JSS Academy of Higher Education and Research, (Deemed to be University), Mysuru, India
| | - Gobianand Kuppanna
- Department of Microbiology, Vivekanandha College of Arts and Sciences for Women, Elayampalayam, Tiruchengode. Tamil Nadu, India
| | | | - Kanthesh M Basalingappa
- Division of Biochemistry, Faculty of Life Sciences, JSS Academy of Higher Education and Research, (Deemed to be University), Mysuru, India
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30
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Phi LTH, Sari IN, Yang YG, Lee SH, Jun N, Kim KS, Lee YK, Kwon HY. Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment. Stem Cells Int 2018; 2018:5416923. [PMID: 29681949 PMCID: PMC5850899 DOI: 10.1155/2018/5416923] [Citation(s) in RCA: 614] [Impact Index Per Article: 87.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 01/11/2018] [Indexed: 12/14/2022] Open
Abstract
Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are suggested to be responsible for drug resistance and cancer relapse due in part to their ability to self-renew themselves and differentiate into heterogeneous lineages of cancer cells. Thus, it is important to understand the characteristics and mechanisms by which CSCs display resistance to therapeutic agents. In this review, we highlight the key features and mechanisms that regulate CSC function in drug resistance as well as recent breakthroughs of therapeutic approaches for targeting CSCs. This promises new insights of CSCs in drug resistance and provides better therapeutic rationales to accompany novel anticancer therapeutics.
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Affiliation(s)
- Lan Thi Hanh Phi
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Ita Novita Sari
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Ying-Gui Yang
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Sang-Hyun Lee
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Nayoung Jun
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Kwang Seock Kim
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Yun Kyung Lee
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Hyog Young Kwon
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
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31
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Locatelli MA, Aftimos P, Dees EC, LoRusso PM, Pegram MD, Awada A, Huang B, Cesari R, Jiang Y, Shaik MN, Kern KA, Curigliano G. Phase I study of the gamma secretase inhibitor PF-03084014 in combination with docetaxel in patients with advanced triple-negative breast cancer. Oncotarget 2018; 8:2320-2328. [PMID: 27906684 PMCID: PMC5356802 DOI: 10.18632/oncotarget.13727] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 11/22/2016] [Indexed: 12/13/2022] Open
Abstract
Background The NOTCH signaling pathway may be involved in the survival of stem cell-like tumor-initiating cells and contribute to tumor growth. In this phase Ib, open-label, multicenter study (NCT01876251), we evaluated PF-03084014, a selective gamma-secretase inhibitor in patients with advanced triple-negative breast cancer. Methods The dose-finding part was based on a 2×3 matrix design using the modified toxicity probability interval method. Oral PF-03084014 was administered twice daily continuously in combination with intravenous docetaxel given on day 1 of each 21-day cycle. Primary endpoint was first-cycle dose-limiting toxicity (DLT) for the dose-finding part and 6-month progression-free survival (PFS) for the expansion cohort treated at the maximum tolerated dose (MTD). Secondary endpoints included safety, objective response, and pharmacokinetics of the combination. Results and Conclusions The MTD was estimated to be PF-03084014 100 mg twice daily / docetaxel 75 mg/m2. At this dose level, combination treatment was generally well tolerated (one DLT, grade 3 diarrhea, among eight DLT-evaluable patients). The most common all-grade, treatment-related adverse events reported in all patients (N = 29) were neutropenia (90%), fatigue (79%), nausea (72%), leukopenia (69%), diarrhea (59%), alopecia (55%), anemia (55%), and vomiting (48%). No effect was observed on the pharmacokinetics of docetaxel when administered in combination with PF-03084014. Four (16%) of 25 response-evaluable patients achieved a confirmed partial response; nine (36%) patients had stable disease, including five patients with unconfirmed partial response. In the expansion cohort, median PFS was 4.1 (95% CI 1.3-8.1) months (6-month PFS rate 17.1% [95% CI 0.8-52.6%]).
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Affiliation(s)
- Marzia A Locatelli
- Division of Experimental Therapeutics, European Institute of Oncology, Milan, Italy
| | - Philippe Aftimos
- Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - E Claire Dees
- Department of Hematology and Oncology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
| | - Patricia M LoRusso
- Medical Oncology, Karmanos Cancer Institute, Detroit, MI, USA.,Yale Cancer Center, New Haven, CT, USA
| | - Mark D Pegram
- Breast Cancer Research Program, Stanford Cancer Institute, Stanford, CA, USA
| | - Ahmad Awada
- Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Bo Huang
- Pfizer Oncology, Groton, CT, USA
| | | | | | | | | | - Giuseppe Curigliano
- Division of Experimental Therapeutics, European Institute of Oncology, Milan, Italy
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Capodanno Y, Buishand FO, Pang LY, Kirpensteijn J, Mol JA, Argyle DJ. Notch pathway inhibition targets chemoresistant insulinoma cancer stem cells. Endocr Relat Cancer 2018; 25:131-144. [PMID: 29175872 DOI: 10.1530/erc-17-0415] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 11/24/2017] [Indexed: 12/12/2022]
Abstract
Insulinomas (INS) are the most common neuroendocrine pancreatic tumours in humans and dogs. The long-term prognosis for malignant INS is still poor due to a low success rate of the current treatment modalities, particularly chemotherapy. A better understanding of the molecular processes underlying the development and progression of INS is required to develop novel targeted therapies. Cancer stem cells (CSCs) are thought to be critical for the engraftment and chemoresistance of many tumours, including INS. This study was aimed to characterise and target INS CSCs in order to develop novel targeted therapies. Highly invasive and tumourigenic human and canine INS CSC-like cells were successfully isolated. These cells expressed stem cell markers (OCT4, SOX9, SOX2, CD133 and CD34), exhibited greater resistance to 5-fluorouracil (5-FU) and demonstrated a more invasive and tumourigenic phenotype in vivo compared to bulk INS cells. Here, we demonstrated that Notch-signalling-related genes (NOTCH2 and HES1) were overexpressed in INS CSC-like cells. Protein analysis showed an active NOTCH2-HES1 signalling in INS cell lines, especially in cells resistant to 5-FU. Inhibition of the Notch pathway, using a gamma secretase inhibitor (GSI), enhanced the sensitivity of INS CSC-like cells to 5-FU. When used in combination GSI and 5-FU, the clonogenicity in vitro and the tumourigenicity in vivo of INS CSC-like cells were significantly reduced. These findings suggested that the combined strategy of Notch signalling inhibition and 5-FU synergistically attenuated enriched INS CSC populations, providing a rationale for future therapeutic exploitation.
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Affiliation(s)
- Y Capodanno
- Royal (Dick) School of Veterinary Studies and The Roslin InstituteUniversity of Edinburgh, Midlothian, UK
| | - F O Buishand
- Department of Clinical Sciences of Companion AnimalsFaculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - L Y Pang
- Royal (Dick) School of Veterinary Studies and The Roslin InstituteUniversity of Edinburgh, Midlothian, UK
| | | | - J A Mol
- Department of Clinical Sciences of Companion AnimalsFaculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - D J Argyle
- Royal (Dick) School of Veterinary Studies and The Roslin InstituteUniversity of Edinburgh, Midlothian, UK
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Notch signaling: its roles and therapeutic potential in hematological malignancies. Oncotarget 2018; 7:29804-23. [PMID: 26934331 PMCID: PMC5045435 DOI: 10.18632/oncotarget.7772] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 02/11/2016] [Indexed: 01/07/2023] Open
Abstract
Notch is a highly conserved signaling system that allows neighboring cells to communicate, thereby controlling their differentiation, proliferation and apoptosis, with the outcome of its activation being highly dependent on signal strength and cell type. As such, there is growing evidence that disturbances in physiological Notch signaling contribute to cancer development and growth through various mechanisms. Notch was first reported to contribute to tumorigenesis in the early 90s, through identification of the involvement of the Notch1 gene in the chromosomal translocation t(7;9)(q34;q34.3), found in a small subset of T-cell acute lymphoblastic leukemia. Since then, Notch mutations and aberrant Notch signaling have been reported in numerous other precursor and mature hematological malignancies, of both myeloid and lymphoid origin, as well as many epithelial tumor types. Of note, Notch has been reported to have both oncogenic and tumor suppressor roles, dependent on the cancer cell type. In this review, we will first give a general description of the Notch signaling pathway, and its physiologic role in hematopoiesis. Next, we will review the role of aberrant Notch signaling in several hematological malignancies. Finally, we will discuss current and potential future therapeutic approaches targeting this pathway.
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Nilendu P, Kumar A, Kumar A, Pal JK, Sharma NK. Breast cancer stem cells as last soldiers eluding therapeutic burn: A hard nut to crack. Int J Cancer 2018; 142:7-17. [PMID: 28722143 DOI: 10.1002/ijc.30898] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 07/13/2017] [Indexed: 12/26/2022]
Abstract
Cancer stem cells (CSCs) are found in many cancer types, including breast carcinoma. Breast cancer stem cells (BCSCs) are considered as seed of cancer formation and they are associated with metastasis and genotoxic drug resistance. Several studies highlighted the presence of BCSCs in tumor microenvironment and they are accentuated with several carcinoma events including metastasis and resistance to genotoxic drugs and they also rebound after genotoxic burn. Stemness properties of a small population of cells in carcinoma have provided clues regarding the role of tumor microenvironment in tumor pathophysiology. Hence, insights in cancer stem cell biology with respect to molecular signaling, genetics and epigenetic behavior of CSCs have been used to modulate tumor drug resistance due to genotoxic drugs and signaling protein inhibitors. This review summarizes major scientific breakthroughs in understanding the contribution of BCSCs towards tumor's capability to endure destruction inflicted by molecular as well as genotoxic drugs.
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Affiliation(s)
- Pritish Nilendu
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India
| | - Ajay Kumar
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India
| | - Azad Kumar
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India
| | - Jayanta K Pal
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India
| | - Nilesh Kumar Sharma
- Cancer and Translational Research Lab, Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India
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Dobranowski P, Ban F, Contreras-Sanz A, Cherkasov A, Black PC. Perspectives on the discovery of NOTCH2-specific inhibitors. Chem Biol Drug Des 2017; 91:691-706. [PMID: 29078041 DOI: 10.1111/cbdd.13132] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 09/18/2017] [Accepted: 10/02/2017] [Indexed: 12/17/2022]
Abstract
The Notch pathway is a cell-cell communication system where membrane-bound ligands interact with the extracellular region of Notch receptors to induce intracellular, downstream effects on gene expression. Aberrant Notch signaling promotes tumorigenesis, and the Notch pathway has tremendous potential for novel targeting strategies in cancer treatment. While γ-secretase inhibitors as Notch-inhibiting agents are already promising in clinical trials, they are highly non-specific with adverse side-effects. One of the underlying challenges is that two of the four known human Notch paralogs, NOTCH1 and 2, share very high structural similarity but play opposing roles in some tumorigenesis pathways. This perspective explores the feasibility of developing Notch-specific small molecule inhibitors targeting the anti-NOTCH2 antibody-binding epitopes or the "S2-Leu-plug-binding site" using a computer-aided drug discovery approach.
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Affiliation(s)
- Peter Dobranowski
- Department of Pediatrics, British Columbia Children's Hospital Research, Vancouver, British Columbia, Canada.,University of British Columbia, Vancouver, British Columbia, Canada
| | - Fuqiang Ban
- University of British Columbia, Vancouver, British Columbia, Canada.,Department of Urologic Sciences, Faculty of Medicine, Vancouver Prostate Centre, Vancouver, British Columbia, Canada
| | - Alberto Contreras-Sanz
- University of British Columbia, Vancouver, British Columbia, Canada.,Department of Urologic Sciences, Faculty of Medicine, Vancouver Prostate Centre, Vancouver, British Columbia, Canada
| | - Artem Cherkasov
- University of British Columbia, Vancouver, British Columbia, Canada.,Department of Urologic Sciences, Faculty of Medicine, Vancouver Prostate Centre, Vancouver, British Columbia, Canada
| | - Peter C Black
- University of British Columbia, Vancouver, British Columbia, Canada.,Department of Urologic Sciences, Faculty of Medicine, Vancouver Prostate Centre, Vancouver, British Columbia, Canada
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Abstract
Cancer stem cells can generate tumors from only a small number of cells, whereas differentiated cancer cells cannot. The prominent feature of cancer stem cells is its ability to self-renew and differentiate into multiple types of cancer cells. Cancer stem cells have several distinct tumorigenic abilities, including stem cell signal transduction, tumorigenicity, metastasis, and resistance to anticancer drugs, which are regulated by genetic or epigenetic changes. Like normal adult stem cells involved in various developmental processes and tissue homeostasis, cancer stem cells maintain their self-renewal capacity by activating multiple stem cell signaling pathways and inhibiting differentiation signaling pathways during cancer initiation and progression. Recently, many studies have focused on targeting cancer stem cells to eradicate malignancies by regulating stem cell signaling pathways, and products of some of these strategies are in preclinical and clinical trials. In this review, we describe the crucial features of cancer stem cells related to tumor relapse and drug resistance, as well as the new therapeutic strategy to target cancer stem cells named "differentiation therapy."
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Affiliation(s)
- Xiong Jin
- 1 Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
- 2 Institute of Animal Molecular Biotechnology, Korea University, Seoul, Republic of Korea
| | - Xun Jin
- 3 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- 4 Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- 5 Institute of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hyunggee Kim
- 1 Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
- 2 Institute of Animal Molecular Biotechnology, Korea University, Seoul, Republic of Korea
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Notch inhibitors and their role in the treatment of triple negative breast cancer: promises and failures. Curr Opin Oncol 2017; 29:411-427. [DOI: 10.1097/cco.0000000000000406] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Ruess DA, Görgülü K, Wörmann SM, Algül H. Pharmacotherapeutic Management of Pancreatic Ductal Adenocarcinoma: Current and Emerging Concepts. Drugs Aging 2017; 34:331-357. [PMID: 28349415 DOI: 10.1007/s40266-017-0453-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma is a devastating malignancy, which is the result of late diagnosis, aggressive disease, and a lack of effective treatment options. Thus, pancreatic ductal adenocarcinoma is projected to become the second leading cause of cancer-related death by 2030. This review summarizes recent developments of oncological therapy in the palliative setting of metastatic pancreatic ductal adenocarcinoma. It further compiles novel targets and therapeutic approaches as well as promising treatment combinations, which are presently in preclinical evaluation, covering several aspects of the hallmarks of cancer. Finally, challenges to the implementation of an individualized therapy approach in the context of precision medicine are discussed.
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Affiliation(s)
- Dietrich A Ruess
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.
| | - Kivanc Görgülü
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Sonja M Wörmann
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Hana Algül
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.
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Kummar S, O'Sullivan Coyne G, Do KT, Turkbey B, Meltzer PS, Polley E, Choyke PL, Meehan R, Vilimas R, Horneffer Y, Juwara L, Lih A, Choudhary A, Mitchell SA, Helman LJ, Doroshow JH, Chen AP. Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis). J Clin Oncol 2017; 35:1561-1569. [PMID: 28350521 PMCID: PMC5455706 DOI: 10.1200/jco.2016.71.1994] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the γ-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment.
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Affiliation(s)
- Shivaani Kummar
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Geraldine O'Sullivan Coyne
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Khanh T. Do
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Baris Turkbey
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Paul S. Meltzer
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Eric Polley
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Peter L. Choyke
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Robert Meehan
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Rasa Vilimas
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Yvonne Horneffer
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Lamin Juwara
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Ann Lih
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Amul Choudhary
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Sandra A. Mitchell
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Lee J. Helman
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - James H. Doroshow
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Alice P. Chen
- Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD
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Liu Z, Sanders AJ, Liang G, Song E, Jiang WG, Gong C. Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment. Mol Cancer Ther 2017; 16:775-786. [PMID: 28468863 DOI: 10.1158/1535-7163.mct-16-0576] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 12/29/2016] [Accepted: 12/29/2016] [Indexed: 11/16/2022]
Affiliation(s)
- Zihao Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Andrew J Sanders
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
| | - Gehao Liang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Erwei Song
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wen G Jiang
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
| | - Chang Gong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
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Eyre TA, Schuh A. An update for Richter syndrome - new directions and developments. Br J Haematol 2017; 178:508-520. [DOI: 10.1111/bjh.14700] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Toby A. Eyre
- Department of Haematology; Cancer and Haematology Centre; Oxford University Hospitals NHS Trust; Oxford UK
- Early Phase Clinical Trial Unit; Oxford University Hospitals NHS Foundation Trust; Churchill Hospital; Oxford UK
| | - Anna Schuh
- Department of Haematology; Cancer and Haematology Centre; Oxford University Hospitals NHS Trust; Oxford UK
- Early Phase Clinical Trial Unit; Oxford University Hospitals NHS Foundation Trust; Churchill Hospital; Oxford UK
- NIHR BRC Oxford Molecular Diagnostic Centre; Oxford University Hospitals NHS Foundation Trust; Oxford UK
- Department of Oncology; University of Oxford; Oxford UK
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42
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Xie Q, Cheng Z, Chen X, Lobe CG, Liu J. The role of Notch signalling in ovarian angiogenesis. J Ovarian Res 2017; 10:13. [PMID: 28284219 PMCID: PMC5346233 DOI: 10.1186/s13048-017-0308-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2016] [Accepted: 03/01/2017] [Indexed: 12/19/2022] Open
Abstract
In adults, the ovary is characterized with extensive angiogenesis and regular intervals of rapid growth. Ovarian function is dependent on the network of angiogenic vessels which enable the follicle and/or corpus luteum to receive oxygen, nutrients and hormonal support. Abnormal angiogenesis is involved in the induction and development of pathological ovary, such as polycystic ovary syndrome and ovarian cancer. Notch signalling pathway is one of the primary regulators of angiogenesis and a therapeutic target for ovarian diseases. Here, we will review literatures on the expression pattern of Notch pathway components in the ovary and on the role of Notch signalling pathway on ovarian angiogenesis.
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Affiliation(s)
- Qi Xie
- Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, People's Republic of China
| | - Zuowang Cheng
- Taishan Medical College, Taian, People's Republic of China
| | - Xiaocui Chen
- Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, People's Republic of China
| | - Corrinne G Lobe
- Molecular and Cellular Biology Division, Sunnybrook Health Science Centre, University of Toronto, Toronto, ON, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Ju Liu
- Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, People's Republic of China.
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43
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Mani SKK, Zhang H, Diab A, Pascuzzi PE, Lefrançois L, Fares N, Bancel B, Merle P, Andrisani O. EpCAM-regulated intramembrane proteolysis induces a cancer stem cell-like gene signature in hepatitis B virus-infected hepatocytes. J Hepatol 2016; 65:888-898. [PMID: 27238755 PMCID: PMC5289705 DOI: 10.1016/j.jhep.2016.05.022] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 05/02/2016] [Accepted: 05/17/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hepatocytes in which the hepatitis B virus (HBV) is replicating exhibit loss of the chromatin modifying polycomb repressive complex 2 (PRC2), resulting in re-expression of specific, cellular PRC2-repressed genes. Epithelial cell adhesion molecule (EpCAM) is a PRC2-repressed gene, normally expressed in hepatic progenitors, but re-expressed in hepatic cancer stem cells (hCSCs). Herein, we investigated the functional significance of EpCAM re-expression in HBV-mediated hepatocarcinogenesis. METHODS Employing molecular approaches (transfections, fluorescence-activated cell sorting, immunoblotting, qRT-PCR), we investigated the role of EpCAM-regulated intramembrane proteolysis (RIP) in HBV replicating cells in vitro, and in liver tumors from HBV X/c-myc mice and chronically HBV infected patients. RESULTS EpCAM undergoes RIP in HBV replicating cells, activating canonical Wnt signaling. Transfection of Wnt-responsive plasmid expressing green fluorescent protein (GFP) identified a GFP + population of HBV replicating cells. These GFP+/Wnt+ cells exhibited cisplatin- and sorafenib-resistant growth resembling hCSCs, and increased expression of pluripotency genes NANOG, OCT4, SOX2, and hCSC markers BAMBI, CD44 and CD133. These genes are referred as EpCAM RIP and Wnt-induced hCSC-like gene signature. Interestingly, this gene signature is also overexpressed in liver tumors of X/c-myc bitransgenic mice. Clinically, a group of HBV-associated hepatocellular carcinomas was identified, exhibiting elevated expression of the hCSC-like gene signature and associated with reduced overall survival post-surgical resection. CONCLUSIONS The hCSC-like gene signature offers promise as prognostic tool for classifying subtypes of HBV-induced HCCs. Since EpCAM RIP and Wnt signaling drive expression of this hCSC-like signature, inhibition of these pathways can be explored as therapeutic strategy for this subtype of HBV-associated HCCs. LAY SUMMARY In this study, we provide evidence for a molecular mechanism by which chronic infection by the hepatitis B virus results in the development of poor prognosis liver cancer. Based on this mechanism our results suggest possible therapeutic interventions.
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Affiliation(s)
- Saravana Kumar Kailasam Mani
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, United States; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States
| | - Hao Zhang
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, United States; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States
| | - Ahmed Diab
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, United States; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States
| | - Pete E Pascuzzi
- Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States; Purdue University Libraries, Purdue University, West Lafayette, IN 47907, United States
| | - Lydie Lefrançois
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052 - CNRS 5286, Lyon Cedex 03, France
| | - Nadim Fares
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052 - CNRS 5286, Lyon Cedex 03, France
| | - Brigitte Bancel
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052 - CNRS 5286, Lyon Cedex 03, France
| | - Philippe Merle
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052 - CNRS 5286, Lyon Cedex 03, France
| | - Ourania Andrisani
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, United States; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States.
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44
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Greene LM, Nathwani SM, Zisterer DM. Inhibition of γ-secretase activity synergistically enhances tumour necrosis factor-related apoptosis-inducing ligand induced apoptosis in T-cell acute lymphoblastic leukemia cells via upregulation of death receptor 5. Oncol Lett 2016; 12:2900-2905. [PMID: 27698877 DOI: 10.3892/ol.2016.5011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 05/26/2016] [Indexed: 12/20/2022] Open
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive hematopoietic malignancy prone to relapse and drug resistance. Half of all T-ALL patients exhibit mutations in Notch1, which leads to aberrant Notch1 associated signaling cascades. Notch1 activation is mediated by the γ-secretase cleavage of the Notch1 receptor into the active intracellular domain of Notch1 (NCID). Clinical trials of γ-secretase small molecule inhibitors (GSIs) as single agents for the treatment of T-ALL have been unsuccessful. The present study demonstrated, using immunofluorescence and western blotting, that blocking γ-secretase activity in T-ALL cells with N-[(3,5-difluorophenyl) acetyl]-L-alanyl-2-phenyl] glycine-1,1-dimethylethyl ester (DAPT) downregulated NCID and upregulated the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5). Upregulation of DR5 restored the sensitivity of T-ALL cells to TRAIL. Combination index revealed that the combined treatment of DAPT and TRAIL synergistically enhanced apoptosis compared with treatment with either drug alone. TRAIL combined with the clinically evaluated γ-secretase inhibitor 3-[(1r, 4s)-4-(4-chlorophenylsulfonyl)-4-(2, 5-difluorophenyl) cyclohexyl] propanoic acid (MK-0752) also significantly enhanced TRAIL-induced cell death compared with either drug alone. DAPT/TRAIL apoptotic synergy was dependent on the extrinsic apoptotic pathway and was associated with a decrease in BH3 interacting-domain death agonist and x-linked inhibitor of apoptosis. In conclusion, γ-secretase inhibition represents a potential therapeutic strategy to overcome TRAIL resistance for the treatment of T-ALL.
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Affiliation(s)
- Lisa M Greene
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Republic of Ireland
| | - Seema M Nathwani
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Republic of Ireland
| | - Daniela M Zisterer
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Republic of Ireland
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45
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Carnero A, Garcia-Mayea Y, Mir C, Lorente J, Rubio IT, LLeonart ME. The cancer stem-cell signaling network and resistance to therapy. Cancer Treat Rev 2016; 49:25-36. [PMID: 27434881 DOI: 10.1016/j.ctrv.2016.07.001] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 07/01/2016] [Accepted: 07/02/2016] [Indexed: 12/13/2022]
Abstract
The study of cancer stem cells (CSCs) has shown that tumors are driven by a subpopulation of self-renewing CSCs that retain the capacity to engender the various differentiated cell populations that form tumors. The characterization of CSCs has indicated that CSCs are remarkably resistant to conventional radio- and chemo-therapy. Clinically, the remaining populations of CSC are responsible for metastasis and recurrence in patients with cancer, which can lead to the disease becoming chronic and incurable. Therefore, the elimination of CSCs is an important goal of cancer treatments. Furthermore, CSCs are subject to strong regulation by the surrounding microenvironment, which also impacts tumor responses. In this review, we discuss the mechanisms by which pathways that are defective in CSCs influence ultimately therapeutic and clinical outcomes.
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Affiliation(s)
- A Carnero
- Instituto de Biomedicina de Sevilla (IBIS/HUVR/CSIC/Universidad de Sevilla), Molecular Biology of Cancer Group, Oncohematology and Genetic Department, Campus HUVR, Edificio IBIS, Avda. Manuel Siurot s/n. 41013, Sevilla, Spain
| | - Y Garcia-Mayea
- Vall d'Hebron Institut de Recerca (VHIR), Hospital Vall d'Hebron, Translational Research in Cancer Stem Cell Group, Pathology Department, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - C Mir
- Vall d'Hebron Institut de Recerca (VHIR), Hospital Vall d'Hebron, Translational Research in Cancer Stem Cell Group, Pathology Department, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - J Lorente
- Vall d'Hebron Institut de Recerca (VHIR), Hospital Vall d'Hebron, Translational Research in Cancer Stem Cell Group, Pathology Department, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - I T Rubio
- Vall d'Hebron Institut de Oncologia (VHIO), Hospital Vall d'Hebron, Breast Surgical Oncology Unit, Breast Cancer Center, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - M E LLeonart
- Vall d'Hebron Institut de Recerca (VHIR), Hospital Vall d'Hebron, Translational Research in Cancer Stem Cell Group, Pathology Department, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain.
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46
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Xu R, Shimizu F, Hovinga K, Beal K, Karimi S, Droms L, Peck KK, Gutin P, Iorgulescu JB, Kaley T, DeAngelis L, Pentsova E, Nolan C, Grommes C, Chan T, Bobrow D, Hormigo A, Cross JR, Wu N, Takebe N, Panageas K, Ivy P, Supko JG, Tabar V, Omuro A. Molecular and Clinical Effects of Notch Inhibition in Glioma Patients: A Phase 0/I Trial. Clin Cancer Res 2016; 22:4786-4796. [PMID: 27154916 DOI: 10.1158/1078-0432.ccr-16-0048] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 04/09/2016] [Indexed: 12/31/2022]
Abstract
PURPOSE High-grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO4929097 has emerged as a potential therapeutic option based on modulation of the cancer-initiating cell (CIS) population and a presumed antiangiogenic role. EXPERIMENTAL DESIGN In this phase 0/I trial, 21 patients with newly diagnosed glioblastoma or anaplastic astrocytoma received RO4929097 combined with temozolomide and radiotherapy. In addition to establishing the MTD, the study design enabled exploratory studies evaluating tumor and brain drug penetration and neuroimaging parameters. We also determined functional effects on the Notch pathway and targeting of CISs through analysis of tumor tissue sampled from areas with and without blood-brain barrier disruption. Finally, recurrent tumors were also sampled and assessed for Notch pathway responses while on treatment. RESULTS Treatment was well tolerated and no dose-limiting toxicities were observed. IHC of treated tumors showed a significant decrease in proliferation and in the expression of the Notch intracellular domain (NICD) by tumor cells and blood vessels. Patient-specific organotypic tumor explants cultures revealed a specific decrease in the CD133+ CIS population upon treatment. Perfusion MRI demonstrated a significant decrease in relative plasma volume after drug exposure. Gene expression data in recurrent tumors suggested low Notch signaling activity, the upregulation of key mesenchymal genes, and an increase in VEGF-dependent angiogenic factors. CONCLUSIONS The addition of RO4929097 to temozolomide and radiotherapy was well tolerated; the drug has a variable blood-brain barrier penetration. Evidence of target modulation was observed, but recurrence occurred, associated with alterations in angiogenesis signaling pathways. Clin Cancer Res; 22(19); 4786-96. ©2016 AACR.
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Affiliation(s)
- Ran Xu
- Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Neurosurgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Fumiko Shimizu
- Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Koos Hovinga
- Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kathryn Beal
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sasan Karimi
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Leif Droms
- Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kyung K Peck
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Philip Gutin
- Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - J Bryan Iorgulescu
- Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Thomas Kaley
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Lisa DeAngelis
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Elena Pentsova
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Craig Nolan
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Christian Grommes
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Timothy Chan
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Dylan Bobrow
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Adilia Hormigo
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Justin R Cross
- The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nian Wu
- Analytical Pharmacology Core, Memorial Sloan Kettering Cancer Center, New York, New York. LipoSeuticals Inc, Princeton, New Jersey
| | - Naoko Takebe
- Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland
| | - Katherine Panageas
- Epidemiology and Statistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Percy Ivy
- National Cancer Institute, Cancer Therapy Evaluation Program, Bethesda, Maryland
| | - Jeffrey G Supko
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Viviane Tabar
- Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
| | - Antonio Omuro
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York
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NOTCH1 inhibition enhances the efficacy of conventional chemotherapeutic agents by targeting head neck cancer stem cell. Sci Rep 2016; 6:24704. [PMID: 27108536 PMCID: PMC4842967 DOI: 10.1038/srep24704] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 03/08/2016] [Indexed: 12/18/2022] Open
Abstract
Cancer stem cells (CSCs) are considered responsible for tumor initiation and chemoresistance. This study was aimed to investigate the possibility of targeting head neck squamous cell carcinoma (HNSCC) by NOTCH1 pathway inhibition and explore the synergistic effect of combining NOTCH inhibition with conventional chemotherapy. NOTCH1/HES1 elevation was found in human HNSCC, especially in tissue post chemotherapy and lymph node metastasis, which is correlated with CSCs markers. NOTCH1 inhibitor DAPT (GSI-IX) significantly reduces CSCs population and tumor self-renewal ability in vitro and in vivo. Flow cytometry analysis showed that NOTCH1 inhibition reduces CSCs frequency either alone or in combination with chemotherapeutic agents, namely, cisplatin, docetaxel, and 5-fluorouracil. The combined strategy of NOTCH1 blockade and chemotherapy synergistically attenuated chemotherapy-enriched CSC population, promising a potential therapeutic exploitation in future clinical trial.
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48
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Seow HF, Yip WK, Fifis T. Advances in targeted and immunobased therapies for colorectal cancer in the genomic era. Onco Targets Ther 2016; 9:1899-920. [PMID: 27099521 PMCID: PMC4821380 DOI: 10.2147/ott.s95101] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Targeted therapies require information on specific defective signaling pathways or mutations. Advances in genomic technologies and cell biology have led to identification of new therapeutic targets associated with signal-transduction pathways. Survival times of patients with colorectal cancer (CRC) can be extended with combinations of conventional cytotoxic agents and targeted therapies. Targeting EGFR- and VEGFR-signaling systems has been the major focus for treatment of metastatic CRC. However, there are still limitations in their clinical application, and new and better drug combinations are needed. This review provides information on EGFR and VEGF inhibitors, new therapeutic agents in the pipeline targeting EGFR and VEGFR pathways, and those targeting other signal-transduction pathways, such as MET, IGF1R, MEK, PI3K, Wnt, Notch, Hedgehog, and death-receptor signaling pathways for treatment of metastatic CRC. Additionally, multitargeted approaches in combination therapies targeting negative-feedback loops, compensatory networks, and cross talk between pathways are highlighted. Then, immunobased strategies to enhance antitumor immunity using specific monoclonal antibodies, such as the immune-checkpoint inhibitors anti-CTLA4 and anti-PD1, as well as the challenges that need to be overcome for increased efficacy of targeted therapies, including drug resistance, predictive markers of response, tumor subtypes, and cancer stem cells, are covered. The review concludes with a brief insight into the applications of next-generation sequencing, expression profiling for tumor subtyping, and the exciting progress made in in silico predictive analysis in the development of a prescription strategy for cancer therapy.
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Affiliation(s)
- Heng Fong Seow
- Immunology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Wai Kien Yip
- Immunology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Theodora Fifis
- Department of Surgery, University of Melbourne, Melbourne, Australia
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49
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Pisklakova A, Grigson E, Ozerova M, Chen F, Sullivan DM, Nefedova Y. Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment. Cancer Biol Ther 2016; 17:477-85. [PMID: 26934342 DOI: 10.1080/15384047.2016.1156261] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Multiple myeloma (MM), a blood cancer characterized by the uncontrolled proliferation of plasma cells, remains incurable by current therapy. Notch signaling has been implicated in the growth and chemoresistance of various cancer types including MM, and therefore we hypothesized that targeting the Notch pathway could be beneficial for the treatment of this disease. Here, we report an anti-tumor effect of Notch/γ-secretase inhibitor RO4929097 in a pre-clinical model of MM. We demonstrate that this effect was associated with decreased angiogenesis and significant down-regulation of TGF-β1. In addition, we also show that treatment with RO4929097 results in decreased number and functional activity of osteoclasts. Taken together, our data indicate that targeting Notch may be considered as a new strategy to be tested for MM therapy.
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Affiliation(s)
| | - Eileen Grigson
- a H. Lee Moffitt Cancer Center and Research Institute , Tampa , FL , USA.,b The Wistar Institute , Philadelphia , PA , USA
| | - Maria Ozerova
- a H. Lee Moffitt Cancer Center and Research Institute , Tampa , FL , USA
| | - Feng Chen
- a H. Lee Moffitt Cancer Center and Research Institute , Tampa , FL , USA
| | - Daniel M Sullivan
- a H. Lee Moffitt Cancer Center and Research Institute , Tampa , FL , USA
| | - Yulia Nefedova
- a H. Lee Moffitt Cancer Center and Research Institute , Tampa , FL , USA.,b The Wistar Institute , Philadelphia , PA , USA
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50
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Natsumeda M, Maitani K, Liu Y, Miyahara H, Kaur H, Chu Q, Zhang H, Kahlert UD, Eberhart CG. Targeting Notch Signaling and Autophagy Increases Cytotoxicity in Glioblastoma Neurospheres. Brain Pathol 2016; 26:713-723. [PMID: 26613556 DOI: 10.1111/bpa.12343] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 11/25/2015] [Indexed: 01/04/2023] Open
Abstract
Glioblastomas are highly aggressive tumors that contain treatment resistant stem-like cells. Therapies targeting developmental pathways such as Notch eliminate many neoplastic glioma cells, including those with stem cell features, but their efficacy can be limited by various mechanisms. One potential avenue for chemotherapeutic resistance is the induction of autophagy, but little is known how it might modulate the response to Notch inhibitors. We used the γ-secretase inhibitor MRK003 to block Notch pathway activity in glioblastoma neurospheres and assessed its effects on autophagy. A dramatic, several fold increase of LC3B-II/LC3B-I autophagy marker was noted on western blots, along with the emergence of punctate LC3B immunostaining in cultured cells. By combining the late stage autophagy inhibitor chloroquine (CQ) with MRK003, a significant induction in apoptosis and reduction in growth was noted as compared to Notch inhibition alone. A similar beneficial effect on inhibition of cloogenicity in soft agar was seen using the combination treatment. These results demonstrated that pharmacological Notch blockade can induce protective autophagy in glioma neurospheres, resulting in chemoresistance, which can be abrogated by combination treatment with autophagy inhibitors.
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Affiliation(s)
- Manabu Natsumeda
- Department of Pathology, Division of Neuropathology, Johns Hopkins Hospital, Baltimore, MD.,Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan
| | - Kosuke Maitani
- Department of Pathology, Division of Neuropathology, Johns Hopkins Hospital, Baltimore, MD
| | - Yang Liu
- Department of Pathology, Division of Neuropathology, Johns Hopkins Hospital, Baltimore, MD
| | - Hiroaki Miyahara
- Department of Pathology, Division of Neuropathology, Johns Hopkins Hospital, Baltimore, MD
| | - Harpreet Kaur
- Department of Pathology, Division of Neuropathology, Johns Hopkins Hospital, Baltimore, MD
| | - Qian Chu
- Department of Pathology, Division of Neuropathology, Johns Hopkins Hospital, Baltimore, MD.,Department of Oncology, Tongji Hospital, Wuhan, China
| | - Hongyan Zhang
- Department of Pathology, Division of Neuropathology, Johns Hopkins Hospital, Baltimore, MD
| | - Ulf D Kahlert
- Department of Pathology, Division of Neuropathology, Johns Hopkins Hospital, Baltimore, MD.,Department of Neurosurgery, University Medical Center Düsseldorf, Düsseldorf, Germany
| | - Charles G Eberhart
- Department of Pathology, Division of Neuropathology, Johns Hopkins Hospital, Baltimore, MD
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