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1
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Zhai H, Zheng T, Fan L. Unveiling the STAT3-ACC1 axis: a key driver of lipid metabolism and tumor progression in non-small cell lung cancer. J Cancer 2024; 15:2340-2353. [PMID: 38495496 PMCID: PMC10937262 DOI: 10.7150/jca.93890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 02/19/2024] [Indexed: 03/19/2024] Open
Abstract
Background and Objective: Lung cancer is a prevalent global malignancy, and investigating the metabolic reprogramming of tumor cells has significant therapeutic implications. This study aims to explore the molecular mechanism driving the progression of non-small cell lung cancer (NSCLC), with a specific emphasis on the STAT3-ACC1-FAS axis involved in fatty acid synthesis. Methods: The levels of Signal transducer and activator of transcription 3 (STAT3) and acetyl-CoA carboxylase 1 (ACC1) were determined in mouse NSCLC specimens and cell lines using Western blot and qPCR methods. Various assays such as CCK-8, colony formation, EDU, wound-healing, and transwell migration were employed to assess cancer cell proliferation, migration, and invasion. Additionally, a nude mouse xenograft model was utilized for in vivo tumor growth analysis. The interaction between STAT3 and ACC1 was examined through chromatin immunoprecipitation and dual-luciferase assays. Results: The study observed upregulation of STAT3 and ACC1 in NSCLC tissues. Notably, the suppression of STAT3 and ACC1 inhibited the in vitro progression and lipid synthesis of NSCLC cells. Furthermore, STAT3 enhanced lipid synthesis by upregulating ACC1 expression. Mechanistic assays revealed that this process occurred through direct activation of ACC1 transcription by STAT3. STAT3 played a vital role in regulating lipid metabolism and supporting NSCLC progression. Conclusion: The findings of this study underscore the significance of the STAT3-ACC1-FAS axis in NSCLC. The activation of ACC1 through STAT3-mediated transcription serves as a crucial mechanism for stimulating the progression of NSCLC tumors and promoting lipid synthesis. Consequently, targeting the STAT3-ACC1 axis may present a promising avenue for the diagnosis and treatment of NSCLC patients.
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Affiliation(s)
- Hong Zhai
- Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai200072, China
| | - Tiansheng Zheng
- Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai200072, China
| | - Lihong Fan
- Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai200072, China
- Department of Integrated Traditional Chinese and Western Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
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2
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Longhi E, Carminati L, Carlessi E, Belotti D, Taraboletti G. Thrombospondin-1 in drug activity and tumor response to therapies. Semin Cell Dev Biol 2024; 155:45-51. [PMID: 37414720 DOI: 10.1016/j.semcdb.2023.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 06/26/2023] [Indexed: 07/08/2023]
Abstract
Thrombospondins (TSPs) have numerous different roles in cancer, regulating the behavior of cancer cells and non-neoplastic cells, and defining the responses of tumor cells to environmental changes, thorough their ability to orchestrate cellular and molecular interactions in the tumor microenvironment (TME). As a result of these activities, TSPs can also control drug delivery and activity, tumor response and resistance to therapies, with different outcomes depending on the nature of TSP-interacting cell types, receptors, and ligands, in a highly context-dependent manner. This review, focusing primarily on TSP-1, discusses the effects of TSPs on tumor response to chemotherapy, antiangiogenic, low-dose metronomic chemotherapy, immunotherapy, and radiotherapy, by analyzing TSP activity on different cell compartments - tumor cells, vascular endothelial cells and immune cells. We review evidence of the value of TSPs, specifically TSP-1 and TSP-2, as biomarkers of prognosis and tumor response to therapy. Finally, we examine possible approaches to develop TSP-based compounds as therapeutic tools to potentiate the efficacy of anticancer therapy.
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Affiliation(s)
- Elisa Longhi
- Laboratory of Tumor Microenvironment, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Stezzano 87, Bergamo 24126, Italy
| | - Laura Carminati
- Laboratory of Tumor Microenvironment, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Stezzano 87, Bergamo 24126, Italy
| | - Elena Carlessi
- Laboratory of Tumor Microenvironment, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Stezzano 87, Bergamo 24126, Italy
| | - Dorina Belotti
- Laboratory of Tumor Microenvironment, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Stezzano 87, Bergamo 24126, Italy.
| | - Giulia Taraboletti
- Laboratory of Tumor Microenvironment, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Stezzano 87, Bergamo 24126, Italy.
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3
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Lambrescu IM, Gaina GF, Ceafalan LC, Hinescu ME. Inside anticancer therapy resistance and metastasis. Focus on CD36. J Cancer 2024; 15:1675-1686. [PMID: 38370376 PMCID: PMC10869978 DOI: 10.7150/jca.90457] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 11/28/2023] [Indexed: 02/20/2024] Open
Abstract
Despite recent advances in targeted cancer therapies, drug resistance remains an important setback in tumor control. Understanding the complex mechanisms involved in both innate and acquired drug resistance represents the first step in discovering novel therapeutic agents. Because of its importance in tumorigenesis, progression, and metastasis, lipid metabolism is increasingly garnering attention. CD36 is a membrane receptor at the top of the signaling cascade that transports lipids. Its expression has been repeatedly presented as an unfavorable prognostic factor for various tumor types, raising the question: could CD36 be a critical factor in cancer treatment resistance? In our review, we set out to explore the most prominent studies on the implication of CD36 in resistance to platinum-based drugs and other adjuvant cancer therapies in solid and haematological neoplasia. Moreover, we provide an overview of the latest anti-CD36 cancer therapies, thus opening new perspectives for future personalized medicine.
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Affiliation(s)
- Ioana M. Lambrescu
- Cell Biology, Neurosciences, and Experimental Myology Laboratory, Victor Babeș Institute of Pathology, 050096 Bucharest, Romania
- Department of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Gisela F. Gaina
- Cell Biology, Neurosciences, and Experimental Myology Laboratory, Victor Babeș Institute of Pathology, 050096 Bucharest, Romania
- Department of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Laura C. Ceafalan
- Cell Biology, Neurosciences, and Experimental Myology Laboratory, Victor Babeș Institute of Pathology, 050096 Bucharest, Romania
- Department of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Mihail E. Hinescu
- Department of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- National Institute of Pathology "Victor Babes," 050096 Bucharest, Romania
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4
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Xia L, Zhou Z, Chen X, Luo W, Ding L, Xie H, Zhuang W, Ni K, Li G. Ligand-dependent CD36 functions in cancer progression, metastasis, immune response, and drug resistance. Biomed Pharmacother 2023; 168:115834. [PMID: 37931517 DOI: 10.1016/j.biopha.2023.115834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 10/27/2023] [Accepted: 11/01/2023] [Indexed: 11/08/2023] Open
Abstract
CD36, a multifunctional glycoprotein, has been shown to play critical roles in tumor initiation, progression, metastasis, immune response, and drug resistance. CD36 serves as a receptor for a wide range of ligands, including lipid-related ligands (e.g., long-chain fatty acid (LCFA), oxidized low-density lipoprotein (oxLDL), and oxidized phospholipids), as well as protein-related ligands (e.g., thrombospondins, amyloid proteins, collagens I and IV). CD36 is overexpressed in various cancers and may act as an independent prognostic marker. While it was initially identified as a mediator of anti-angiogenesis through its interaction with thrombospondin-1 (TSP1), recent research has highlighted its role in promoting tumor growth, metastasis, drug resistance, and immune suppression. The varied impact of CD36 on cancer is likely ligand-dependent. Therefore, we focus specifically on the ligand-dependent role of CD36 in cancer to provide a critical review of recent advances, perspectives, and challenges.
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Affiliation(s)
- Liqun Xia
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Zhenwei Zhou
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xianjiong Chen
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wenqin Luo
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lifeng Ding
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haiyun Xie
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Zhuang
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Urology, The Second Affiliated Hospital of Fujian Medical University, Fujian, China
| | - Kangxin Ni
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Gonghui Li
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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5
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Ali A, Gao M, Iskantar A, Wang H, Karlsson-Parra A, Yu D, Jin C. Proinflammatory allogeneic dendritic cells enhance the therapeutic efficacy of systemic anti-4-1BB treatment. Front Immunol 2023; 14:1146413. [PMID: 37654492 PMCID: PMC10466132 DOI: 10.3389/fimmu.2023.1146413] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 07/26/2023] [Indexed: 09/02/2023] Open
Abstract
As an immune adjuvant, proinflammatory allogeneic dendritic cells (AlloDCs) have demonstrated promising immune-priming effects in several preclinical and clinical studies. The effector cells, including NK cells and T cells are widely acknowledged as pivotal factors in the effectiveness of cancer immunotherapy due to their ability to selectively identify and eradicate malignant cells. 4-1BB, as a costimulatory receptor, plays a significant role in the stimulation of effector cell activation. This study evaluated the anti-tumor effects when combining intratumoral administration of the immune-adjuvant AlloDCs with systemic α4-1BB treatment directly acting on effector cells. In both the CT-26 murine colon carcinoma model and B16 murine melanoma model, AlloDCs demonstrated a significant enhancement in the therapeutic efficacy of α4-1BB antibody. This enhancement was observed through the delayed growth of tumors and prolonged survival. Analysis of the tumor microenvironment (TME) in the combined-treatment group revealed an immune-inflamed TME characterized by increased infiltration of activated endogenous DCs and IFNγ+ CD8+ T cells, showing reduced signs of exhaustion. Furthermore, there was an augmented presence of tissue-resident memory (TRM) CD8+ T cells (CD103+CD49a+CD69+). The combination treatment also led to increased infiltration of CD39+CD103+ tumor-specific CD8+ T cells and neoantigen-specific T cells into the tumor. Additionally, the combined treatment resulted in a less immunosuppressive TME, indicated by decreased infiltration of myeloid-derived suppressor cells and Tregs. These findings suggest that the combination of intratumoral AlloDCs administration with systemic agonistic α4-1BB treatment can generate a synergistic anti-tumor response, thereby warranting further investigation through clinical studies.
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Affiliation(s)
- Arwa Ali
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Menghan Gao
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Alexandros Iskantar
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Hai Wang
- Chinese Academy of Science (CAS) Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | | | - Di Yu
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Chuan Jin
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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6
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Hasan G, Hassan MI, Sohal SS, Shamsi A, Alam M. Therapeutic Targeting of Regulated Signaling Pathways of Non-Small Cell Lung Carcinoma. ACS OMEGA 2023; 8:26685-26698. [PMID: 37546685 PMCID: PMC10398694 DOI: 10.1021/acsomega.3c02424] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 06/15/2023] [Indexed: 08/08/2023]
Abstract
Non-small cell lung carcinoma (NSCLC) is the most common cancer globally. Phytochemicals and small molecule inhibitors significantly prevent varying types of cancers, including NSCLC. These therapeutic molecules serve as important sources for new drugs that interfere with cellular proliferation, apoptosis, metastasis, and angiogenesis by regulating signaling pathways. These molecules affect several cellular signaling cascades, including p53, NF-κB, STAT3, RAS, MAPK/ERK, Wnt, and AKT/PI3K, and are thus implicated in the therapeutic management of cancers. This review aims to describe the bioactive compounds and small-molecule inhibitors, their anticancer action, and targeting cellular signaling cascades in NSCLC. We highlighted the therapeutic potential of Epigallocatechin gallate (EGCG), Perifosine, ABT-737, Thymoquinine, Quercetin, Venetoclax, Gefitinib, and Genistein. These compounds are implicated in the therapeutic management of NSCLC. This review further offers deeper mechanistic insights into different signaling pathways that could be targeted for NSCLC therapy by phytochemicals and small-molecule inhibitors.
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Affiliation(s)
- Gulam
Mustafa Hasan
- Department
of Biochemistry, College of Medicine, Prince
Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia
| | - Md. Imtaiyaz Hassan
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Sukhwinder Singh Sohal
- Respiratory
Translational Research Group, Department of Laboratory Medicine, School
of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston 7001, Tasmania, Australia
| | - Anas Shamsi
- Centre
of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman 346, United Arab
Emirates
| | - Manzar Alam
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
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7
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El-Tanani M, Nsairat H, Aljabali AA, Serrano-Aroca Á, Mishra V, Mishra Y, Naikoo GA, Alshaer W, Tambuwala MM. Role of mammalian target of rapamycin (mTOR) signalling in oncogenesis. Life Sci 2023; 323:121662. [PMID: 37028545 DOI: 10.1016/j.lfs.2023.121662] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/07/2023] [Accepted: 03/31/2023] [Indexed: 04/09/2023]
Abstract
The signalling system known as mammalian target of rapamycin (mTOR) is believed to be required for several biological activities involving cell proliferation. The serine-threonine kinase identified as mTOR recognises PI3K-AKT stress signals. It is well established in the scientific literature that the deregulation of the mTOR pathway plays a crucial role in cancer growth and advancement. This review focuses on the normal functions of mTOR as well as its abnormal roles in cancer development.
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Affiliation(s)
- Mohamed El-Tanani
- Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan; Institute of Cancer Therapeutics, University of Bradford, Bradford, West Yorkshire BD7 1DP, United Kingdom.
| | - Hamdi Nsairat
- Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan
| | - Alaa A Aljabali
- Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid 21163, Jordan.
| | - Ángel Serrano-Aroca
- Biomaterials and Bioengineering Laboratory, Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, c/Guillem de Castro 94, 46001, Valencia, Spain.
| | - Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, 144411, Punjab, India
| | - Yachana Mishra
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, 144411, Punjab, India
| | - Gowhar A Naikoo
- Department of Mathematics and Sciences, College of Arts and Applied Sciences, Dhofar University, Salalah, PC 211, Oman.
| | - Walhan Alshaer
- Cell Therapy Center, the University of Jordan, Amman 11942, Jordan
| | - Murtaza M Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln LN6 7TS, United Kingdom.
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8
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Matsumura K, Hayashi H, Uemura N, Ogata Y, Zhao L, Sato H, Shiraishi Y, Kuroki H, Kitamura F, Kaida T, Higashi T, Nakagawa S, Mima K, Imai K, Yamashita YI, Baba H. Thrombospondin-1 overexpression stimulates loss of Smad4 and accelerates malignant behavior via TGF-β signal activation in pancreatic ductal adenocarcinoma. Transl Oncol 2022; 26:101533. [PMID: 36115074 PMCID: PMC9483797 DOI: 10.1016/j.tranon.2022.101533] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/03/2022] [Accepted: 09/05/2022] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and cancer-associated fibroblasts (CAFs) provide a favorable tumor microenvironment. Smad4 is known as tumor suppressor in several types of cancers including PDAC, and loss of Smad4 triggers accelerated cell invasiveness and metastatic potential. The thrombospondin-1 (TSP-1) can act as a major activator of latent transforming growth factor-β (TGF-β) in vivo. However, the roles of TSP-1 and the mediator of Smad4 loss and TGF-β signal activation during PDAC progression have not yet been addressed. The aim is to elucidate the biological role of TSP-1 in PDAC progression. METHODS AND RESULTS High substrate stiffness stimulated TSP-1 expression in CAFs, and TSP-1 knockdown inhibited cell proliferation with suppressed profibrogenic and activated stroma-related gene expressions in CAFs. Paracrine TSP-1 treatment for PDAC cells promoted cell proliferation and epithelial mesenchymal transition (EMT) with activated TGF-β signals such as phosphorylated Akt and Smad2/3 expressions. Surprisingly, knockdown of DPC4 (Smad4 gene) induced TSP-1 overexpression with TGF-β signal activation in PDAC cells. Interestingly, TSP-1 overexpression also induced downregulation of Smad4 expression and enhanced cell proliferation in vitro and in vivo. Treatment with LSKL peptide, which antagonizes TSP-1-mediated latent TGF-β activation, attenuated cell proliferation, migration and chemoresistance with enhanced apoptosis in PDAC cells. CONCLUSIONS TSP-1 derived from CAFs stimulates loss of Smad4 expression in cancer cells and accelerates malignant behavior by TGF-β signal activation in PDAC. TSP-1 could be a novel therapeutic target, not only for CAFs in stiff stroma, but also for cancer cells in the PDAC microenvironment.
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Affiliation(s)
- Kazuki Matsumura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Norio Uemura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Yoko Ogata
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Liu Zhao
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hiroki Sato
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Yuta Shiraishi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hideyuki Kuroki
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Fumimasa Kitamura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Takayoshi Kaida
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Takaaki Higashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Shigeki Nakagawa
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Kosuke Mima
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Katsunori Imai
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Yo-Ichi Yamashita
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
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Weina T, Ying L, Yiwen W, Huan-Huan Q. What we have learnt from Drosophila model organism: the coordination between insulin signaling pathway and tumor cells. Heliyon 2022; 8:e09957. [PMID: 35874083 PMCID: PMC9304707 DOI: 10.1016/j.heliyon.2022.e09957] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/25/2022] [Accepted: 07/11/2022] [Indexed: 02/08/2023] Open
Abstract
Cancer development is related to a variety of signaling pathways which mediate various cellular processes including growth, survival, division and competition of cells, as well as cell-cell interaction. The insulin signaling pathway interacts with different pathways and plays a core role in the regulations of all these processes. In this study, we reviewed recent studies on the relationship between the insulin signaling pathway and tumors using the Drosophila melanogaster model. We found that on one hand, the insulin pathway is normally hyperactive in tumor cells, which promotes tumor growth, and on the other hand, tumor cells can suppress the growth of healthy tissues via inhibition of their insulin pathway. Moreover, systematic disruption in glucose homeostasis also facilitates cancer development by different mechanisms. The studies on how the insulin network regulates the behaviors of cancer cells may help to discover new therapeutic treatments for cancer.
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Affiliation(s)
- Tang Weina
- School of Pharmaceutical Science and Technology, Tianjin University, 300072, Tianjin, China
| | - Li Ying
- School of Pharmaceutical Science and Technology, Tianjin University, 300072, Tianjin, China
| | - Wang Yiwen
- School of Pharmaceutical Science and Technology, Tianjin University, 300072, Tianjin, China
| | - Qiao Huan-Huan
- Academy of Medical Engineering and Translational Medicine, Tianjin University, 300072, Tianjin, China
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10
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Fatty acid translocase: a culprit of lipid metabolism dysfunction in disease. IMMUNOMETABOLISM 2022; 4:e00001. [PMID: 35991116 PMCID: PMC9380421 DOI: 10.1097/in9.0000000000000001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 05/09/2022] [Indexed: 11/25/2022]
Abstract
Dysregulation of lipid deposition into and mobilization from white adipose tissue (WAT) underlies various diseases. Long-chain fatty acids (LCFA) and cholesterol trafficking in and out of adipocytes is a process relying on transporters shuttling lipids from the plasma membrane (PM) to lipid droplets (LD). CD36 is the fatty acid translocase (FAT) that transports LCFA and cholesterol across the PM. Interactions of CD36 with proteins PHB1, ANX2, and CAV1 mediate intercellular lipid transport between adipocytes, hematopoietic, epithelial, and endothelial cells. Intracellularly, the FAT complex has been found to regulate LCFA trafficking between the PM and LD. This process is regulated by CD36 glycosylation and S-acylation, as well as by post-translational modifications of PHB1 and ANX2, which determine both protein–protein interactions and the cellular localization of the complex. Changes in extracellular and intracellular LCFA levels have been found to induce the post-translational modifications and the function of the FAT complex in lipid uptake and mobilization. The role of the CD36/PHB1/ANX2 complex may span beyond lipid trafficking. The requirement of PHB1 for mitochondrial oxidative metabolism in brown adipocytes has been revealed. Cancer cells which take advantage of lipids mobilized by adipocytes and oxidized in leukocytes are indirectly affected by the function of FAT complex in other tissues. The direct importance of CD36 interaction with PHB1/and ANX2 in cancer cells remains to be established. This review highlights the multifaceted roles of the FAT complex in systemic lipid trafficking and discuss it as a potential target in metabolic disease and cancer.
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11
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Xu Z, Chu M. Advances in Immunosuppressive Agents Based on Signal Pathway. Front Pharmacol 2022; 13:917162. [PMID: 35694243 PMCID: PMC9178660 DOI: 10.3389/fphar.2022.917162] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 05/02/2022] [Indexed: 12/13/2022] Open
Abstract
Immune abnormality involves in various diseases, such as infection, allergic diseases, autoimmune diseases, as well as transplantation. Several signal pathways have been demonstrated to play a central role in the immune response, including JAK/STAT, NF-κB, PI3K/AKT-mTOR, MAPK, and Keap1/Nrf2/ARE pathway, in which multiple targets have been used to develop immunosuppressive agents. In recent years, varieties of immunosuppressive agents have been approved for clinical use, such as the JAK inhibitor tofacitinib and the mTOR inhibitor everolimus, which have shown good therapeutic effects. Additionally, many immunosuppressive agents are still in clinical trials or preclinical studies. In this review, we classified the immunosuppressive agents according to the immunopharmacological mechanisms, and summarized the phase of immunosuppressive agents.
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Affiliation(s)
- Zhiqing Xu
- Department of Immunology, National Health Commission (NHC) Key Laboratory of Medical Immunology (Peking University), School of Basic Medical Sciences, Peking University, Beijing, China
- Department of Pharmacology, Jilin University, Changchun, China
| | - Ming Chu
- Department of Immunology, National Health Commission (NHC) Key Laboratory of Medical Immunology (Peking University), School of Basic Medical Sciences, Peking University, Beijing, China
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12
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Rodrigues ACBDC, Costa RGA, Silva SLR, Dias IRSB, Dias RB, Bezerra DP. Cell signaling pathways as molecular targets to eliminate AML stem cells. Crit Rev Oncol Hematol 2021; 160:103277. [PMID: 33716201 DOI: 10.1016/j.critrevonc.2021.103277] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 01/25/2021] [Accepted: 02/27/2021] [Indexed: 02/08/2023] Open
Abstract
Acute myeloid leukemia (AML) remains the most lethal of leukemias and a small population of cells called leukemic stem cells (LSCs) has been associated with disease relapses. Some cell signaling pathways play an important role in AML survival, proliferation and self-renewal properties and are abnormally activated or suppressed in LSCs. This includes the NF-κB, Wnt/β-catenin, Hedgehog, Notch, EGFR, JAK/STAT, PI3K/AKT/mTOR, TGF/SMAD and PPAR pathways. This review aimed to discuss these pathways as molecular targets for eliminating AML LSCs. Herein, inhibitors/activators of these pathways were summarized as a potential new anti-AML therapy capable of eliminating LSCs to guide future researches. The clinical use of cell signaling pathways data can be useful to enhance the anti-AML therapy.
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Affiliation(s)
| | - Rafaela G A Costa
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Suellen L R Silva
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Ingrid R S B Dias
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Rosane B Dias
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Daniel P Bezerra
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil.
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13
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Matsushita Y, Nakagawa H, Koike K. Lipid Metabolism in Oncology: Why It Matters, How to Research, and How to Treat. Cancers (Basel) 2021; 13:474. [PMID: 33530546 PMCID: PMC7865757 DOI: 10.3390/cancers13030474] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/20/2021] [Accepted: 01/22/2021] [Indexed: 12/11/2022] Open
Abstract
Lipids in our body, which are mainly composed of fatty acids, triacylglycerides, sphingolipids, phospholipids, and cholesterol, play important roles at the cellular level. In addition to being energy sources and structural components of biological membranes, several types of lipids serve as signaling molecules or secondary messengers. Metabolic reprogramming has been recognized as a hallmark of cancer, but changes in lipid metabolism in cancer have received less attention compared to glucose or glutamine metabolism. However, recent innovations in mass spectrometry- and chromatography-based lipidomics technologies have increased our understanding of the role of lipids in cancer. Changes in lipid metabolism, so-called "lipid metabolic reprogramming", can affect cellular functions including the cell cycle, proliferation, growth, and differentiation, leading to carcinogenesis. Moreover, interactions between cancer cells and adjacent immune cells through altered lipid metabolism are known to support tumor growth and progression. Characterization of cancer-specific lipid metabolism can be used to identify novel metabolic targets for cancer treatment, and indeed, several clinical trials are currently underway. Thus, we discuss the latest findings on the roles of lipid metabolism in cancer biology and introduce current advances in lipidomics technologies, focusing on their applications in cancer research.
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Affiliation(s)
| | - Hayato Nakagawa
- Department of Gastroenterology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; (Y.M.); (K.K.)
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14
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Bułakowska A, Sławiński J, Siedlecka-Kroplewska K, Stasiłojć G, Serocki M, Heldt M. Novel N-(aryl/heteroaryl)-2-chlorobenzenesulfonamide derivatives: Synthesis and anticancer activity evaluation. Bioorg Chem 2020; 104:104309. [PMID: 33011532 DOI: 10.1016/j.bioorg.2020.104309] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/19/2020] [Accepted: 09/20/2020] [Indexed: 12/27/2022]
Abstract
A new series of N-(aryl/heteroaryl)-2-chlorobenzenesulfonamide derivatives 4-21 have been synthesized, and evaluated at the National Cancer Institute (USA) for their in vitro activities against a panel of 60 different human cancer cell lines. Among them, compounds 16, 20 and 21 exhibited remarkable cytotoxic activity against numerous human cancer cell lines. We found that sulfonamide derivative 21 appeared to be more selective than compounds 16 and 20. In comparison to compounds 16 and 20 it showed higher cytotoxic activity against A549 non-small cell lung adenocarcinoma and HCT-116 colon carcinoma cells and was less toxic to HEK-293 human embryonic kidney cells and HaCaT immortalized human keratinocytes. Treatment of A549 and HCT-116 cells with compound 21 resulted in the G0/G1-cell cycle arrest with a concomitant increase in p53 and p21 protein levels. Moreover, compound 21 led to ATP depletion and disruption of the mitochondrial membrane potential in both studied cell lines. Our results suggest that 2,4-dichloro-N-(quinolin-8-yl and/or 1H-indazol-7-yl)benzenesulfonamides serve as novel promising anticancer agents.
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Affiliation(s)
- Anita Bułakowska
- Department of Organic Chemistry, Medical University of Gdańsk, Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
| | - Jarosław Sławiński
- Department of Organic Chemistry, Medical University of Gdańsk, Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
| | | | - Grzegorz Stasiłojć
- Department of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology UG-MUG, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Marcin Serocki
- Department of Pharmaceutical Technology and Biochemistry, Gdańsk University of Technology, G. Narutowicza 11/12, 80-233 Gdańsk, Poland
| | - Mateusz Heldt
- Department of Pharmaceutical Technology and Biochemistry, Gdańsk University of Technology, G. Narutowicza 11/12, 80-233 Gdańsk, Poland
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15
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Xu T, Sun D, Chen Y, Ouyang L. Targeting mTOR for fighting diseases: A revisited review of mTOR inhibitors. Eur J Med Chem 2020; 199:112391. [DOI: 10.1016/j.ejmech.2020.112391] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/24/2020] [Accepted: 04/24/2020] [Indexed: 02/07/2023]
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16
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Ramchandani D, Mittal V. Thrombospondin in Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1272:133-147. [PMID: 32845506 DOI: 10.1007/978-3-030-48457-6_8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Thrombospondins (TSPs) are multifaceted proteins that contribute to physiologic as well as pathologic conditions. Due to their multiple receptor-binding domains, TSPs display both oncogenic and tumor-suppressive qualities and are thus essential components of the extracellular matrix. Known for their antiangiogenic capacity, TSPs are an important component of the tumor microenvironment. The N- and C-terminal domains of TSP are, respectively, involved in cell adhesion and spreading, an important feature of wound healing as well as cancer cell migration. Previously known for the activation of TGF-β to promote tumor growth and inflammation, TSP-1 has recently been found to be transcriptionally induced by TGF-β, implying the presence of a possible feedback loop. TSP-1 is an endogenous inhibitor of T cells and also mediates its immunosuppressive effects via induction of Tregs. Given the diverse roles of TSPs in the tumor microenvironment, many therapeutic strategies have utilized TSP-mimetic peptides or antibody blockade as anti-metastatic approaches. This chapter discusses the diverse structural domains, functional implications, and anti-metastatic therapies in the context of the role of TSP in the tumor microenvironment.
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Affiliation(s)
- Divya Ramchandani
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA
| | - Vivek Mittal
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA.
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17
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Chimeric antigen receptor modified T cell (CAR-T) co-expressed with ICOSL-41BB promote CAR-T proliferation and tumor rejection. Biomed Pharmacother 2019; 118:109333. [PMID: 31545280 DOI: 10.1016/j.biopha.2019.109333] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 07/26/2019] [Accepted: 08/05/2019] [Indexed: 01/14/2023] Open
Abstract
T cells edited by chimeric antigen receptors (CAR) have shown great potential in the treatment of tumors, especially malignant blood tumors. However, there remain many obstacles in the CAR-T therapy against solid tumors, such as the expansion of CAR-T cells ex vivo and the exhaustion of CAR-T cells in vivo. In order to solve these problems, we described a novel CAR which is targeting GPC3 by expressing CD28 co-stimulation domain and CD3z ITAM (G328z), meanwhile co-expressing ICOSL extracellular and transmembrane region fused with 41BB cytoplasmic domain (G328z-ICOSL-41BB). Compared with G328z, G328z-ICOSL-41BB fusion protein significantly reinforced the expansion ability of CAR-T cells ex vivo, and prolonged the survival time of mice with hepatocellular carcinoma. We now demonstrate that the enhancement of CAR-T cell activity is dependent on the enhanced PI3K signaling pathway and up-regulated expression of Bcl2 to inhibit apoptosis and promote proliferation of CAR-T cells. Besides, the CAR with ICOSL-41BB fusion protein have been strengthened significantly in comparison with fusing ICOSL protein only, which might be caused by the fact that ICOSL-41BB not only supplies ICOS signal for other cells, but also provides 41BB signal for itself. Consequently, CARs with ICOSL-41BB fusion protein could increase the therapeutic efficacy against solid tumors in vivo compared with the G328z CAR, which might further assist the development of potent and durable T cell therapeutics.
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18
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Wang J, Li Y. CD36 tango in cancer: signaling pathways and functions. Theranostics 2019; 9:4893-4908. [PMID: 31410189 PMCID: PMC6691380 DOI: 10.7150/thno.36037] [Citation(s) in RCA: 230] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 06/12/2019] [Indexed: 12/22/2022] Open
Abstract
CD36, a scavenger receptor expressed in multiple cell types, mediates lipid uptake, immunological recognition, inflammation, molecular adhesion, and apoptosis. CD36 is a transmembrane glycoprotein that contains several posttranslational modification sites and binds to diverse ligands, including apoptotic cells, thrombospondin-1 (TSP-1), and fatty acids (FAs). Beyond fueling tumor metastasis and therapy resistance by enhancing lipid uptake and FA oxidation, CD36 attenuates angiogenesis by binding to TSP-1 and thereby inducing apoptosis or blocking the vascular endothelial growth factor receptor 2 pathway in tumor microvascular endothelial cells. Moreover, CD36-driven lipid metabolic reprogramming and functions in tumor-associated immune cells lead to tumor immune tolerance and cancer development. Notable advances have been made in demonstrating the regulatory networks that govern distinct physiological properties of CD36, and this has identified targeting CD36 as a potential strategy for cancer treatment. Here, we provide an overview on the structure, regulation, ligands, functions, and clinical trials of CD36 in cancer.
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19
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Rehan M. Anticancer compound XL765 as PI3K/mTOR dual inhibitor: A structural insight into the inhibitory mechanism using computational approaches. PLoS One 2019; 14:e0219180. [PMID: 31247018 PMCID: PMC6597235 DOI: 10.1371/journal.pone.0219180] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 06/18/2019] [Indexed: 12/16/2022] Open
Abstract
The PI3K-AKT-mTOR pathway is often a commonly disrupted pathway in human cancer and, therefore, it is widely exploited for cancer therapy. The inhibitors for the important proteins of the pathway including PI3K and mTOR have been increasingly designed. The dual inhibitors targeting PI3K and mTOR both have proven to be more effective than those targeting single protein only. An orally-active compound XL765 is well established as PI3K/mTOR dual inhibitor and have shown in vitro and in vivo anticancer activity against a variety of cancer types and is undergoing clinical trials. The present study explored the exact binding pose and the the interactive forces holding XL765 within the active sites of PI3Kγ and mTOR using molecular docking analyses. The XL765 interacting residues of both the proteins were delineated and the degree of participation in binding was estimated by various methods. In the process, among the interacting residues of PI3Kγ, the Lys-890 and the Met-953 were recognized as the key residues involved in XL765 binding. While, in mTOR case, the Trp-2239 was recognized as the key residue playing role in the XL765 binding. In order to explore the better inhibitors, the study also generated combinatorial chemical library by modifying the scaffold considered from XL765. The virtual screening of the generated compound library led to identification of six novel promising compounds proposed as PI3K/mTOR dual inhibitors. Thus, the present work will through light on the drug inhibitory mechanism of XL765 for PI3K and mTOR, and will also assist in designing novel efficacious drug candidates.
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Affiliation(s)
- Mohd Rehan
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
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20
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Buchan SL, Dou L, Remer M, Booth SG, Dunn SN, Lai C, Semmrich M, Teige I, Mårtensson L, Penfold CA, Chan HTC, Willoughby JE, Mockridge CI, Dahal LN, Cleary KLS, James S, Rogel A, Kannisto P, Jernetz M, Williams EL, Healy E, Verbeek JS, Johnson PWM, Frendéus B, Cragg MS, Glennie MJ, Gray JC, Al-Shamkhani A, Beers SA. Antibodies to Costimulatory Receptor 4-1BB Enhance Anti-tumor Immunity via T Regulatory Cell Depletion and Promotion of CD8 T Cell Effector Function. Immunity 2018; 49:958-970.e7. [PMID: 30446386 DOI: 10.1016/j.immuni.2018.09.014] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 07/12/2018] [Accepted: 09/20/2018] [Indexed: 12/11/2022]
Abstract
The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell-dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4-1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection. These distinct mechanisms were competitive and dependent on antibody isotype and FcγR availability. Administration of anti-4-1BB IgG2a, which preferentially depletes Treg cells, followed by either agonistic anti-4-1BB IgG1 or anti-PD-1 mAb augmented anti-tumor responses in multiple solid tumor models. An antibody engineered to optimize both FcγR-dependent Treg cell depleting capacity and FcγR-independent agonism delivered enhanced anti-tumor therapy. These insights into the effector mechanisms of anti-4-1BB mAbs lay the groundwork for translation into the clinic.
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Affiliation(s)
- Sarah L Buchan
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Lang Dou
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Marcus Remer
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Steven G Booth
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Stuart N Dunn
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Chester Lai
- Department of Dermatopharmacology, University of Southampton, Faculty of Medicine, Southampton SO16 6YD, UK; Department of Dermatology, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - Monika Semmrich
- BioInvent International AB, Sölvegatan 41, 22370 Lund, Sweden
| | - Ingrid Teige
- BioInvent International AB, Sölvegatan 41, 22370 Lund, Sweden
| | | | - Christine A Penfold
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - H T Claude Chan
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Jane E Willoughby
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - C Ian Mockridge
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Lekh N Dahal
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Kirstie L S Cleary
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Sonya James
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Anne Rogel
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Päivi Kannisto
- Department of Obstetrics and Gynecology, Lund University Hospital, Lund, Sweden
| | - Mats Jernetz
- Department of Obstetrics and Gynecology, Lund University Hospital, Lund, Sweden
| | - Emily L Williams
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Eugene Healy
- Department of Dermatopharmacology, University of Southampton, Faculty of Medicine, Southampton SO16 6YD, UK; Department of Dermatology, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - J Sjef Verbeek
- Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands
| | - Peter W M Johnson
- Cancer Research UK Southampton Centre, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Björn Frendéus
- BioInvent International AB, Sölvegatan 41, 22370 Lund, Sweden
| | - Mark S Cragg
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Martin J Glennie
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK
| | - Juliet C Gray
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK.
| | - Aymen Al-Shamkhani
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK.
| | - Stephen A Beers
- Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Southampton SO16 6YD, UK.
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21
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Carballo GB, Honorato JR, de Lopes GPF, Spohr TCLDSE. A highlight on Sonic hedgehog pathway. Cell Commun Signal 2018; 16:11. [PMID: 29558958 PMCID: PMC5861627 DOI: 10.1186/s12964-018-0220-7] [Citation(s) in RCA: 304] [Impact Index Per Article: 43.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 02/16/2018] [Indexed: 12/25/2022] Open
Abstract
Hedgehog (Hh) signaling pathway plays an essential role during vertebrate embryonic development and tumorigenesis. It is already known that Sonic hedgehog (Shh) pathway is important for the evolution of radio and chemo-resistance of several types of tumors. Most of the brain tumors are resistant to chemotherapeutic drugs, consequently, they have a poor prognosis. So, a better knowledge of the Shh pathway opens an opportunity for targeted therapies against brain tumors considering a multi-factorial molecular overview. Therefore, emerging studies are being conducted in order to find new inhibitors for Shh signaling pathway, which could be safely used in clinical trials. Shh can signal through a canonical and non-canonical way, and it also has important points of interaction with other pathways during brain tumorigenesis. So, a better knowledge of Shh signaling pathway opens an avenue of possibilities for the treatment of not only for brain tumors but also for other types of cancers. In this review, we will also highlight some clinical trials that use the Shh pathway as a target for treating brain cancer.
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Affiliation(s)
- Gabriela Basile Carballo
- Laboratorio de Biomedicina do Cérebro, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Secretaria de Estado de Saúde, Rua do Rezende 156, Centro, Rio de Janeiro, CEP: 20230-024, Brazil.,Programa de Pós-Gradução em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jéssica Ribeiro Honorato
- Laboratorio de Biomedicina do Cérebro, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Secretaria de Estado de Saúde, Rua do Rezende 156, Centro, Rio de Janeiro, CEP: 20230-024, Brazil.,Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Pesquisa em Hemato-Oncologia Molecular, Coordenação de Pesquisa, Instituto Nacional de Câncer (INCA), RJ, Brazil.,Programa de Pós-Gradução em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Giselle Pinto Farias de Lopes
- Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Pesquisa em Hemato-Oncologia Molecular, Coordenação de Pesquisa, Instituto Nacional de Câncer (INCA), RJ, Brazil
| | - Tania Cristina Leite de Sampaio E Spohr
- Laboratorio de Biomedicina do Cérebro, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Secretaria de Estado de Saúde, Rua do Rezende 156, Centro, Rio de Janeiro, CEP: 20230-024, Brazil.
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22
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Guduru SKR, Arya P. Synthesis and biological evaluation of rapamycin-derived, next generation small molecules. MEDCHEMCOMM 2018; 9:27-43. [PMID: 30108899 PMCID: PMC6072512 DOI: 10.1039/c7md00474e] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Accepted: 11/21/2017] [Indexed: 12/20/2022]
Abstract
Over the years, rapamycin has attracted serious attention due to its remarkable biological properties and as a potent inhibitor of the mammalian target of rapamycin (mTOR) protein through its binding with FKBP-12. Several efficient strategies that utilize synthetic and biosynthetic approaches have been utilized to develop small molecule rapamycin analogs or for synthesizing hybrid compounds containing a partial rapamycin structure to improve pharmacokinetic properties. Herein, we report selected case studies related to the synthesis of rapamycin-derived compounds and hybrid molecules to explore their biological properties.
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Affiliation(s)
- Shiva Krishna Reddy Guduru
- Center for Drug Discovery , Department of Pharmacology and Chemical Biology , Baylor College of Medicine , One Baylor Plaza , Houston , Texas 77030 , USA . ; ; Tel: +1 713 798 8794
- Department of Pharmacology and Chemical Biology , Baylor College of Medicine , One Baylor Plaza , Houston , Texas 77030 , USA
| | - Prabhat Arya
- Chemistry and Chemical Biology , Dr. Reddy's Institute of Life Sciences (DRILS) , University of Hyderabad Campus , Hyderabad 500046 , India
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23
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Boegemann M, Aydin AM, Bagrodia A, Krabbe LM. Prospects and progress of immunotherapy for bladder cancer. Expert Opin Biol Ther 2017; 17:1417-1431. [PMID: 28832261 DOI: 10.1080/14712598.2017.1366445] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION With recent advances in immunooncology and the introduction of checkpoint inhibitors into clinical practice for many cancers, the treatment landscape of urothelial carcinoma has changed dramatically and will continue to change further. Currently, a number of compounds and combinations are under investigation in numerous clinical trials and various clinical scenarios for bladder cancer. Areas covered: In this review, the authors provide an overview of the history and rationale for immunotherapy in bladder cancer. They also provide the currently available data evaluating checkpoint inhibitors for bladder cancer, and discuss ongoing trials and future perspectives for urothelial carcinoma treatment. Expert opinion: The introduction of checkpoint inhibitors into the management of bladder cancer marks a significant milestone for this disease. Checkpoint inhibitors have the potential to impact patients across multiple disease states from non-muscle-invasive disease to metastatic tumors refractory to conventional treatment. That being said, validated biomarkers, including genetic signatures, to accurately predict response, and the establishment of optimal sequencing and combination of these immunotherapeutic agents with chemo/radiotherapy are urgently needed.
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Affiliation(s)
- Martin Boegemann
- a Department of Urology , University of Muenster Medical Center , Muenster , Germany
| | - Ahmet Murat Aydin
- b Department of Urology , The University of Texas Southwestern Medical Center , Dallas , TX , USA.,c Department of Urology, School of Medicine , Hacettepe University , Ankara , Turkey
| | - Aditya Bagrodia
- b Department of Urology , The University of Texas Southwestern Medical Center , Dallas , TX , USA
| | - Laura-Maria Krabbe
- a Department of Urology , University of Muenster Medical Center , Muenster , Germany.,b Department of Urology , The University of Texas Southwestern Medical Center , Dallas , TX , USA
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24
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Huang T, Sun L, Yuan X, Qiu H. Thrombospondin-1 is a multifaceted player in tumor progression. Oncotarget 2017; 8:84546-84558. [PMID: 29137447 PMCID: PMC5663619 DOI: 10.18632/oncotarget.19165] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 06/28/2017] [Indexed: 01/21/2023] Open
Abstract
Thrombospondins are a family of extracellular matrix (ECM) proteins. Thrombospondin-1 (TSP1) was the first member to be identified and is a main player in tumor microenvironment. The diverse functions of TSP1 depend on the interactions between its structural domains and multiple cell surface molecules. TSP1 acts as an angiogenesis inhibitor by stimulating endothelial cell apoptosis, inhibiting endothelial cell migration and proliferation, and regulating vascular endothelial growth factor bioavailability and activity. In addition to angiogenesis modulation, TSP1 also affects tumor cell adhesion, invasion, migration, proliferation, apoptosis and tumor immunity. This review discusses the multifaceted and sometimes opposite effects of TSP1 on tumor progression depending on the molecular and cellular composition of the microenvironment. Clinical implications of TSP1-related compounds are also discussed.
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Affiliation(s)
- Tingting Huang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Li Sun
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Hong Qiu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
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Yang J, Farren MR, Ahn D, Bekaii-Saab T, Lesinski GB. Signaling pathways as therapeutic targets in biliary tract cancer. Expert Opin Ther Targets 2017; 21:485-498. [PMID: 28282502 DOI: 10.1080/14728222.2017.1306055] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The incidence of biliary tract cancer (BTC) is increasing, and the disease is frequently diagnosed during advanced stages, leading to poor overall survival. Limited treatment options are currently available and novel therapeutic approaches are needed. A number of completed clinical trials have evaluated the role of chemotherapy for BTC, demonstrating a marginal benefit. Thus, there is increased interest in applying targeted therapies for this disease. Areas covered: This review article summarizes the role of chemotherapeutic regimens for the treatment of BTC, and highlights key signal transduction pathways of interest for targeted inhibition. Of particular interest are the MEK or MAP2K (mitogen-activated protein kinase kinase), phosphatidylinositol-3 kinase (PI3K) and signal transducer and activator of transcription-3 (STAT3) pathways. We discuss the available data on several promising inhibitors of these pathways, both in the pre-clinical and clinical settings. Expert opinion: Future treatment strategies should address targeting of MEK, PI3K and STAT3 for BTC, with a focus on combined therapeutic approaches.
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Affiliation(s)
- Jennifer Yang
- a Molecular Cellular and Developmental Biology Graduate Program , The Ohio State University , Columbus , OH , USA
| | - Matthew R Farren
- b Department of Hematology and Medical Oncology , The Winship Cancer Institute of Emory University , Atlanta , GA , USA
| | - Daniel Ahn
- c Division of Medical Oncology, Department of Medicine , Mayo Clinic , Phoenix , AZ , USA
| | - Tanios Bekaii-Saab
- c Division of Medical Oncology, Department of Medicine , Mayo Clinic , Phoenix , AZ , USA
| | - Gregory B Lesinski
- b Department of Hematology and Medical Oncology , The Winship Cancer Institute of Emory University , Atlanta , GA , USA
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Martin-Liberal J, Ochoa de Olza M, Hierro C, Gros A, Rodon J, Tabernero J. The expanding role of immunotherapy. Cancer Treat Rev 2017; 54:74-86. [PMID: 28231560 DOI: 10.1016/j.ctrv.2017.01.008] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 01/25/2017] [Accepted: 01/28/2017] [Indexed: 12/17/2022]
Abstract
The use of agents able to modulate the immune system to induce or potentiate its anti-tumour activity is not a new strategy in oncology. However, the development of new agents such as immune checkpoint inhibitors has achieved unprecedented efficacy results in a wide variety of tumours, dramatically changing the landscape of cancer treatment in recent years. Ipilimumab, nivolumab, pembrolizumab or atezolizumab are now standard of care options in several malignancies and new indications are being approved on a regular basis in different tumours. Moreover, there are many other novel immunotherapy strategies that are currently being assessed in clinical trials. Agonists of co-stimulatory signals, adoptive cell therapies, vaccines, virotherapy and others have raised interest as therapeutic options against cancer. In addition, many of these novel approaches are being developed both in monotherapy and as part of combinatory regimes in order to synergize their activity. The results from those studies will help to define the expanding role of immunotherapy in cancer treatment in a forthcoming future.
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Affiliation(s)
- Juan Martin-Liberal
- Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain.
| | - María Ochoa de Olza
- Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Cinta Hierro
- Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Alena Gros
- Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Jordi Rodon
- Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Josep Tabernero
- Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain
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Han J, Chen Y, Yang C, Liu T, Wang M, Xu H, Zhang L, Zheng C, Song Y, Zhu J. Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor. Eur J Med Chem 2016; 122:684-701. [DOI: 10.1016/j.ejmech.2016.06.030] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Revised: 06/16/2016] [Accepted: 06/17/2016] [Indexed: 01/01/2023]
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The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol 2016; 13:273-90. [PMID: 26977780 DOI: 10.1038/nrclinonc.2016.25] [Citation(s) in RCA: 781] [Impact Index Per Article: 86.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In the past decade, advances in the use of monoclonal antibodies (mAbs) and adoptive cellular therapy to treat cancer by modulating the immune response have led to unprecedented responses in patients with advanced-stage tumours that would otherwise have been fatal. To date, three immune-checkpoint-blocking mAbs have been approved in the USA for the treatment of patients with several types of cancer, and more patients will benefit from immunomodulatory mAb therapy in the months and years ahead. Concurrently, the adoptive transfer of genetically modified lymphocytes to treat patients with haematological malignancies has yielded dramatic results, and we anticipate that this approach will rapidly become the standard of care for an increasing number of patients. In this Review, we highlight the latest advances in immunotherapy and discuss the role that it will have in the future of cancer treatment, including settings for which testing combination strategies and 'armoured' CAR T cells are recommended.
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Ghasemzadeh A, Bivalacqua TJ, Hahn NM, Drake CG. New Strategies in Bladder Cancer: A Second Coming for Immunotherapy. Clin Cancer Res 2016; 22:793-801. [PMID: 26683632 PMCID: PMC4825862 DOI: 10.1158/1078-0432.ccr-15-1135] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 11/24/2015] [Indexed: 12/21/2022]
Abstract
Urothelial bladder cancer (UBC) remains one of the most common and deadly cancers worldwide, and platinum-based chemotherapy, which has been the standard-of-care in metastatic bladder cancer, has had limited success in improving outcomes for patients. The recent development and translation of therapeutic strategies aimed at harnessing the immune system have led to durable and prolonged survival for patients with several different cancers, including UBC. In this review, we discuss new findings in bladder cancer immunotherapy, including recent successes with immune checkpoint blockade. We also discuss therapeutic cancer vaccines and highlight several additional immunotherapy modalities in early stages of development.
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Affiliation(s)
- Ali Ghasemzadeh
- Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Trinity J Bivalacqua
- Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Surgery, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. The Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Noah M Hahn
- Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. The Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Charles G Drake
- Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. The Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
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Jeanne A, Schneider C, Martiny L, Dedieu S. Original insights on thrombospondin-1-related antireceptor strategies in cancer. Front Pharmacol 2015; 6:252. [PMID: 26578962 PMCID: PMC4625054 DOI: 10.3389/fphar.2015.00252] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 10/15/2015] [Indexed: 01/04/2023] Open
Abstract
Thrombospondin-1 (TSP-1) is a large matricellular glycoprotein known to be overexpressed within tumor stroma in several cancer types. While mainly considered as an endogenous angiogenesis inhibitor, TSP-1 exhibits multifaceted functionalities in a tumor context depending both on TSP-1 concentration as well as differential receptor expression by cancer cells and on tumor-associated stromal cells. Besides, the complex modular structure of TSP-1 along with the wide variety of its soluble ligands and membrane receptors considerably increases the complexity of therapeutically targeting interactions involving TSP-1 ligation of cell-surface receptors. Despite the pleiotropic nature of TSP-1, many different antireceptor strategies have been developed giving promising results in preclinical models. However, transition to clinical trials often led to nuanced outcomes mainly due to frequent severe adverse effects. In this review, we will first expose the intricate and even sometimes opposite effects of TSP-1-related signaling on tumor progression by paying particular attention to modulation of angiogenesis and tumor immunity. Then, we will provide an overview of current developments and prospects by focusing particularly on the cell-surface molecules CD47 and CD36 that function as TSP-1 receptors; including antibody-based approaches, therapeutic gene modulation and the use of peptidomimetics. Finally, we will discuss original approaches specifically targeting TSP-1 domains, as well as innovative combination strategies with a view to producing an overall anticancer response.
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Affiliation(s)
- Albin Jeanne
- Laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne Reims, France ; CNRS, Matrice Extracellulaire et Dynamique Cellulaire, UMR 7369 Reims, France ; SATT Nord Lille, France
| | - Christophe Schneider
- Laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne Reims, France ; CNRS, Matrice Extracellulaire et Dynamique Cellulaire, UMR 7369 Reims, France
| | - Laurent Martiny
- Laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne Reims, France ; CNRS, Matrice Extracellulaire et Dynamique Cellulaire, UMR 7369 Reims, France
| | - Stéphane Dedieu
- Laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne Reims, France ; CNRS, Matrice Extracellulaire et Dynamique Cellulaire, UMR 7369 Reims, France
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Khedri M, Rafatpanah H, Abnous K, Ramezani P, Ramezani M. Cancer immunotherapy via nucleic acid aptamers. Int Immunopharmacol 2015; 29:926-936. [PMID: 26603636 DOI: 10.1016/j.intimp.2015.10.013] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Revised: 10/09/2015] [Accepted: 10/13/2015] [Indexed: 02/07/2023]
Abstract
Over the past decade, immune therapy has become a standard treatment for a variety of cancers. Monoclonal antibodies, immune adjuvants and vaccines against oncogenic viruses are now well-established cancer therapies. Immune modulation is a principal element of supportive care for many high-dose chemotherapy regimens. Aptamers are short nucleic acids that bind to defined targets with high affinity and specificity. The first aptamers have been selected around two decades ago by an in vitro process named SELEX (systematic evolution of ligands by exponential enrichment). Since then, numerous aptamers with specificities for a variety of targets from small molecules to proteins or even whole cells have been selected. Targeting immunomodulatory ligands in the progressive tumor lesions of the patients would be prophylactic or therapeutic and may reduce drug-associated toxicities. A new class of inhibitory and agonistic ligands composed of short oligonucleotide (ODN) aptamers was developed recently that exhibited bioactivities comparable or superior to that of antibodies. This paper addressed progress in cancer immunotherapy with nucleic acid aptamers and highlighted recent developments either in immune system targeting or in immunotherapy methods involved aptamers. We discussed aptamer limitations when used as therapeutic agents for cancer treatment and suggested ways to overcome those limitations.
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Affiliation(s)
- Mostafa Khedri
- Department of Immunology, Immunology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Houshang Rafatpanah
- Department of Immunology, Immunology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Khalil Abnous
- Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Pouria Ramezani
- Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Ramezani
- Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Jackson SR, Yuan J, Teague RM. Targeting CD8+ T-cell tolerance for cancer immunotherapy. Immunotherapy 2015; 6:833-52. [PMID: 25290416 DOI: 10.2217/imt.14.51] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
In the final issue of Science in 2013, the American Association of Science recognized progress in the field of cancer immunotherapy as the 'Breakthrough of the Year.' The achievements were actually twofold, owing to the early success of genetically engineered chimeric antigen receptors (CAR) and to the mounting clinical triumphs achieved with checkpoint blockade antibodies. While fundamentally very different, the common thread of these independent strategies is the ability to prevent or overcome mechanisms of CD8(+) T-cell tolerance for improved tumor immunity. Here we discuss how circumventing T-cell tolerance has provided experimental insights that have guided the field of clinical cancer immunotherapy to a place where real breakthroughs can finally be claimed.
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Affiliation(s)
- Stephanie R Jackson
- Saint Louis University School of Medicine, Department of Molecular Microbiology & Immunology, 1100 South Grand Blvd, St Louis, MO 63104, USA
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Digging a hole under Hedgehog: downstream inhibition as an emerging anticancer strategy. Biochim Biophys Acta Rev Cancer 2015; 1856:62-72. [PMID: 26080084 DOI: 10.1016/j.bbcan.2015.06.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 05/04/2015] [Accepted: 06/11/2015] [Indexed: 12/25/2022]
Abstract
Hedgehog signaling is a key regulator of development and stem cell fate and its aberrant activation is a leading cause of a number of tumors. Activating germline or somatic mutations of genes encoding Hh pathway components are found in Basal Cell Carcinoma (BCC) and Medulloblastoma (MB). Ligand-dependent Hedgehog hyperactivation, due to autocrine or paracrine mechanisms, is also observed in a large number of malignancies of the breast, colon, skin, bladder, pancreas and other tissues. The key tumorigenic role of Hedgehog has prompted effort aimed at identifying inhibitors of this signaling. To date, only the antagonists of the membrane transducer Smo have been approved for therapy or are under clinical trials in patients with BCC and MB linked to Ptch or Smo mutations. Despite the good initial response, patients treated with Smo antagonists have eventually developed resistance due to the occurrence of compensating mechanisms. Furthermore, Smo antagonists are not effective in tumors where the Hedgehog hyperactivation is due to mutations of pathway components downstream of Smo, or in case of non-canonical, Smo-independent activation of the Gli transcription factors. For all these reasons, the research of Hh inhibitors acting downstream of Smo is becoming an area of intensive investigation. In this review we illustrate the progresses made in the identification of effective Hedgehog inhibitors and their application in cancer, with a special emphasis on the newly identified downstream inhibitors. We describe in detail the Gli inhibitors and illustrate their mode of action and applications in experimental and/or clinical settings.
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Sanmamed MF, Pastor F, Rodriguez A, Perez-Gracia JL, Rodriguez-Ruiz ME, Jure-Kunkel M, Melero I. Agonists of Co-stimulation in Cancer Immunotherapy Directed Against CD137, OX40, GITR, CD27, CD28, and ICOS. Semin Oncol 2015; 42:640-55. [PMID: 26320067 DOI: 10.1053/j.seminoncol.2015.05.014] [Citation(s) in RCA: 161] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
T and natural killer (NK) lymphocytes are considered the main effector players in the immune response against tumors. Full activation of T and NK lymphocytes requires the coordinated participation of several surface receptors that meet their cognate ligands through structured transient cell-to-cell interactions known as immune synapses. In the case of T cells, the main route of stimulation is driven by antigens as recognized in the form of short polypeptides associated with major histocompatibility complex (MHC) antigen-presenting molecules. However, the functional outcome of T-cell stimulation towards clonal expansion and effector function acquisition is contingent on the contact of additional surface receptor-ligand pairs and on the actions of cytokines in the milieu. While some of those interactions are inhibitory, others are activating and are collectively termed co-stimulatory receptors. The best studied belong to either the immunoglobulin superfamily or the tumor necrosis factor-receptor (TNFR) family. Co-stimulatory receptors include surface moieties that are constitutively expressed on resting lymphocytes such as CD28 or CD27 and others whose expression is induced upon recent previous antigen priming, ie, CD137, GITR, OX40, and ICOS. Ligation of these glycoproteins with agonist antibodies actively conveys activating signals to the lymphocyte. Those signals, acting through a potentiation of the cellular immune response, give rise to anti-tumor effects in mouse models. Anti-CD137 antibodies are undergoing clinical trials with evidence of clinical activity and anti-OX40 monoclonal antibodies (mAbs) induce interesting immunomodulation effects in humans. Antibodies anti-CD27 and GITR have recently entered clinical trials. The inherent dangers of these immunomodulation strategies are the precipitation of excessive systemic inflammation or/and invigorating silent autoimmunity. Agonist antibodies, recombinant forms of the natural ligands, and polynucleotide-based aptamers constitute the pharmacologic tools to manipulate such receptors. Preclinical data suggest that the greatest potential of these agents is achieved in combined treatment strategies.
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Affiliation(s)
- Miguel F Sanmamed
- Department of Immunobiology, Yale School of Medicine, New Haven, CT.
| | - Fernando Pastor
- Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | - Alfonso Rodriguez
- Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | | | | | | | - Ignacio Melero
- Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain; Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
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Mizugaki H, Yamamoto N, Fujiwara Y, Nokihara H, Yamada Y, Tamura T. Current Status of Single-Agent Phase I Trials in Japan: Toward Globalization. J Clin Oncol 2015; 33:2051-61. [PMID: 25918301 DOI: 10.1200/jco.2014.58.4953] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE In Japan, phase I trials, except first-in-human trials, are usually initiated from approximately 50% of the maximum-tolerated dose (MTD) or maximum administered dose (MAD) determined during the initial phase I trials in North America and Europe (the West). However, the key findings of phase I trials in Japan and the West, such as dose-limiting toxicity (DLT) profiles and MTD or MAD levels, have not been compared. PATIENTS AND METHODS We retrospectively analyzed data for patients enrolled onto single-agent phase I trials at the National Cancer Center Hospital between 1995 and 2012. DLT profiles, MTDs, and MADs of single-agent phase I trials in Japan were compared with those from trials in the West that were obtained from the literature. RESULTS A total of 777 patients were enrolled onto 54 single-agent phase I trials, including five first-in-human trials. DLTs were observed in 11.1% of the patients. Importantly, 66.4% of the DLTs were observed within a dose range (80% to 120%) similar to those reported for the trials in the West. The majority of MTDs or MADs could be considered similar between patients, and 80.3% of the drugs had similar MTDs or MADs in the West. CONCLUSION The toxicity profiles of single-agent phase I agents determined from trials conducted in Japan were comparable to those obtained from trials in the West. We believe that phase I trials in Japan could be conducted over timelines similar to those in the West, allowing for global or parallel phase I clinical trials.
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Huang J, Lyu H, Wang J, Liu B. MicroRNA regulation and therapeutic targeting of survivin in cancer. Am J Cancer Res 2014; 5:20-31. [PMID: 25628918 PMCID: PMC4300714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 11/18/2014] [Indexed: 06/04/2023] Open
Abstract
Survivin, the smallest member of IAP (inhibitor of apoptosis) family, is a dual functional protein acting as a critical apoptosis inhibitor and key cell cycle regulator. Survivin is usually expressed in embryonic tissues during development and undetectable in most terminally differentiated tissues. Numerous studies demonstrate that survivin is selectively upregulated in almost all types of human malignancies and its overexpression positively correlates with poor prognosis, tumor recurrence, and therapeutic resistance. This differential expression of survivin in tumors and normal tissues draws a great interest to develop survivin-targeted therapy for cancer treatment. Nonetheless, the molecular mechanisms controlling survivin expression in malignant tumor cells have not been fully understood. While aberrant activation of receptor tyrosine kinases (RTKs) and the downstream signaling, such as PI-3K/Akt, MEK/MAPK, mTOR, and STAT pathways, have frequently been shown to upregulate survivin, recent data suggest that a class of noncoding RNAs, microRNAs (miRNAs) also play an important role in survivin dysregulation in human cancers. Here, we focus on survivin expression-regulated by specific miRNAs binding to the 3'-UTR of survivin mRNA, and summarize the latest advances on survivin-targeted therapy in clinical trials and the therapeutic potential of survivin-targeting miRNAs in cancer.
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Affiliation(s)
- Jingcao Huang
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical CampusAurora, CO, USA
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin, China
| | - Hui Lyu
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical CampusAurora, CO, USA
| | - Jianxiang Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin, China
| | - Bolin Liu
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical CampusAurora, CO, USA
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Yan Y, Chen G, Wei H, Huang RYC, Mo J, Rempel DL, Tymiak AA, Gross ML. Fast photochemical oxidation of proteins (FPOP) maps the epitope of EGFR binding to adnectin. JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY 2014; 25:2084-92. [PMID: 25267085 PMCID: PMC4224620 DOI: 10.1007/s13361-014-0993-x] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 08/15/2014] [Accepted: 08/21/2014] [Indexed: 05/11/2023]
Abstract
Epitope mapping is an important tool for the development of monoclonal antibodies, mAbs, as therapeutic drugs. Recently, a class of therapeutic mAb alternatives, adnectins, has been developed as targeted biologics. They are derived from the 10th type III domain of human fibronectin ((10)Fn3). A common approach to map the epitope binding of these therapeutic proteins to their binding partners is X-ray crystallography. Although the crystal structure is known for Adnectin 1 binding to human epidermal growth factor receptor (EGFR), we seek to determine complementary binding in solution and to test the efficacy of footprinting for this purpose. As a relatively new tool in structural biology and complementary to X-ray crystallography, protein footprinting coupled with mass spectrometry is promising for protein-protein interaction studies. We report here the use of fast photochemical oxidation of proteins (FPOP) coupled with MS to map the epitope of EGFR-Adnectin 1 at both the peptide and amino-acid residue levels. The data correlate well with the previously determined epitopes from the crystal structure and are consistent with HDX MS data, which are presented in an accompanying paper. The FPOP-determined binding interface involves various amino-acid and peptide regions near the N terminus of EGFR. The outcome adds credibility to oxidative labeling by FPOP for epitope mapping and motivates more applications in the therapeutic protein area as a stand-alone method or in conjunction with X-ray crystallography, NMR, site-directed mutagenesis, and other orthogonal methods.
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Affiliation(s)
- Yuetian Yan
- Center for Biomedical and Bioorganic Mass Spectrometry, Department of Chemistry, Washington University in St. Louis, St. Louis, MO, 63130-4899, USA
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Nwabo Kamdje AH, Seke Etet PF, Vecchio L, Muller JM, Krampera M, Lukong KE. Signaling pathways in breast cancer: therapeutic targeting of the microenvironment. Cell Signal 2014; 26:2843-2856. [PMID: 25093804 DOI: 10.1016/j.cellsig.2014.07.034] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Accepted: 07/28/2014] [Indexed: 02/08/2023]
Abstract
Breast cancer is the most common cancer in women worldwide. Understanding the biology of this malignant disease is a prerequisite for selecting an appropriate treatment. Cell cycle alterations are seen in many cancers, including breast cancer. Newly popular targeted agents in breast cancer include cyclin dependent kinase inhibitors (CDKIs) which are agents inhibiting the function of cyclin dependent kinases (CDKs) and agents targeting proto-oncogenic signaling pathways like Notch, Wnt, and SHH (Sonic hedgehog). CDKIs are categorized as selective and non-selective inhibitors of CDK. CDKIs have been tried as monotherapy and combination therapy. The CDKI Palbocyclib is now a promising therapeutic in breast cancer. This drug recently entered phase III trial for estrogen receptor (ER) positive breast cancer after showing encouraging results in progression free survival in a phase II trials. The tumor microenvironment is now recognized as a significant factor in cancer treatment response. The tumor microenvironment is increasingly considered as a target for combination therapy of breast cancer. Recent findings in the signaling pathways in breast cancer are herein summarized and discussed. Furthermore, the therapeutic targeting of the microenvironment in breast cancer is also considered.
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Affiliation(s)
- Armel Herve Nwabo Kamdje
- Department of Biomedical Sciences, Faculty of Sciences, University of Ngaoundéré, P.O. Box 454, Ngaoundéré, Cameroon.
| | - Paul Faustin Seke Etet
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Lorella Vecchio
- Laboratory of Cytometry, Institute of Molecular Genetics, CNR, University of Pavia, 27100 Pavia, Italy
| | - Jean Marc Muller
- Université de Poitiers, Faculté des Sciences, Pôle Biologie-Santé Bât B36, 1, rue Georges Bonnet-BP633, 86022-Poitiers cedex, France
| | - Mauro Krampera
- Department of Medicine, Section of Hematology, Stem Cell Research Laboratory, University of Verona, Verona, Italy
| | - Kiven Erique Lukong
- Department of Biochemistry, College of Medicine, Room 4D30.5 Health Sciences Bldg, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK. S7N 5E5, Canada
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mTOR Signaling in Protein Translation Regulation: Implications in Cancer Genesis and Therapeutic Interventions. Mol Biol Int 2014; 2014:686984. [PMID: 25505994 PMCID: PMC4258317 DOI: 10.1155/2014/686984] [Citation(s) in RCA: 128] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 10/06/2014] [Indexed: 12/29/2022] Open
Abstract
mTOR is a central nutrient sensor that signals a cell to grow and proliferate. Through distinct protein complexes it regulates different levels of available cellular energy substrates required for cell growth. One of the important functions of the complex is to maintain available amino acid pool by regulating protein translation. Dysregulation of mTOR pathway leads to aberrant protein translation which manifests into various pathological states. Our review focuses on the role mTOR signaling plays in protein translation and its physiological role. It also throws some light on available data that show translation dysregulation as a cause of pathological complexities like cancer and the available drugs that target the pathway for cancer treatment.
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Mathew E, Zhang Y, Holtz AM, Kane KT, Song JY, Allen BL, Pasca di Magliano M. Dosage-dependent regulation of pancreatic cancer growth and angiogenesis by hedgehog signaling. Cell Rep 2014; 9:484-94. [PMID: 25310976 DOI: 10.1016/j.celrep.2014.09.010] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 07/18/2014] [Accepted: 09/07/2014] [Indexed: 02/04/2023] Open
Abstract
Pancreatic cancer, a hypovascular and highly desmoplastic cancer, is characterized by tumor expression of Hedgehog (HH) ligands that signal to fibroblasts in the surrounding stroma that in turn promote tumor survival and growth. However, the mechanisms and consequences of stromal HH pathway activation are not well understood. Here, we show that the HH coreceptors GAS1, BOC, and CDON are expressed in cancer-associated fibroblasts. Deletion of two coreceptors (Gas1 and Boc) in fibroblasts reduces HH responsiveness. Strikingly, these fibroblasts promote greater tumor growth in vivo that correlates with increased tumor-associated vascularity. In contrast, deletion of all three coreceptors (Gas1, Boc, and Cdon) results in the near complete abrogation of HH signaling and a corresponding failure to promote tumorigenesis and angiogenesis. Collectively, these data identify a role for HH dosage in pancreatic cancer promotion and may explain the clinical failure of HH pathway blockade as a therapeutic approach in pancreatic cancer.
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Affiliation(s)
- Esha Mathew
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yaqing Zhang
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Alexander M Holtz
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - Kevin T Kane
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jane Y Song
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Benjamin L Allen
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Marina Pasca di Magliano
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109, USA; Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
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Abstract
Optimal T cell response is dependent not only on T cell receptor activation, but also on additional signaling from coreceptors. The main coreceptors include B7 and tumor necrosis factor family members. They exert costimulatory or coinhibitory effects, and their balance determines the fate of T cell response. In normal conditions, costimulators facilitate the development of protective immune response, whereas coinhibitors dampen inflammation to avoid organ/tissue damage from excessive immune reaction. In the tumor microenvironment, the balance is garbled: inhibitory pathways predominate, and T cell response is impaired. The importance of cosignaling in the tumor immune response has been experimentally and clinically demonstrated. New therapeutic strategies targeting T cell cosignaling, especially coinhibitory molecules, are under active experimental and clinical investigation. This review summarizes the functions of main T cell cosignaling axes and discusses their clinical application.
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Jeong WJ, Cha PH, Choi KY. Strategies to overcome resistance to epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer. World J Gastroenterol 2014; 20:9862-9871. [PMID: 25110417 PMCID: PMC4123368 DOI: 10.3748/wjg.v20.i29.9862] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/14/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Administration of monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) such as cetuximab and panitumumab in combination with conventional chemotherapy substantially prolongs survival of patients with metastatic colorectal cancer (mCRC). However, the efficacy of these mAbs is limited due to genetic variation among patients, in particular K-ras mutations. The discovery of K-ras mutation as a predictor of non-responsiveness to EGFR mAb therapy has caused a major change in the treatment of mCRC. Drugs that inhibit transformation caused by oncogenic alterations of Ras and its downstream components such as BRAF, MEK and AKT seem to be promising cancer therapeutics as single agents or when given with EGFR inhibitors. Although multiple therapeutic strategies to overcome EGFR mAb-resistance are under investigation, our understanding of their mode of action is limited. Rational drug development based on stringent preclinical data, biomarker validation, and proper selection of patients is of paramount importance in the treatment of mCRC. In this review, we will discuss diverse approaches to overcome the problem of resistance to existing anti-EGFR therapies and potential future directions for cancer therapies related to the mutational status of genes associated with EGFR-Ras-ERK and PI3K signalings.
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Kinoshita K, Aono Y, Azuma M, Kishi J, Takezaki A, Kishi M, Makino H, Okazaki H, Uehara H, Izumi K, Sone S, Nishioka Y. Antifibrotic effects of focal adhesion kinase inhibitor in bleomycin-induced pulmonary fibrosis in mice. Am J Respir Cell Mol Biol 2014; 49:536-43. [PMID: 23642017 DOI: 10.1165/rcmb.2012-0277oc] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in various biological functions, including cell survival, proliferation, migration, and adhesion. FAK is an essential factor for transforming growth factor β to induce myofibroblast differentiation. In the present study, we investigated whether the targeted inhibition of FAK by using a specific inhibitor, TAE226, has the potential to regulate pulmonary fibrosis. TAE226 showed inhibitory activity of autophosphorylation of FAK at tyrosine 397 in lung fibroblasts. The addition of TAE226 inhibited the proliferation of lung fibroblasts in response to various growth factors, including platelet-derived growth factor and insulin-like growth factor I, in vitro. TAE226 strongly suppressed the production of type I collagen by lung fibroblasts. Furthermore, treatment of fibroblasts with TAE226 reduced the expression of α-smooth muscle actin induced by transforming growth factor β, indicating the inhibition of differentiation of fibroblasts to myofibroblasts. Administration of TAE226 ameliorated the pulmonary fibrosis induced by bleomycin in mice even when used late in the treatment. The number of proliferating mesenchymal cells was reduced in the lungs of TAE226-treated mice. These data suggest that FAK signal plays a significant role in the progression of pulmonary fibrosis and that it can become a promising target for therapeutic approaches to pulmonary fibrosis.
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Chumsri S, Schech A, Chakkabat C, Sabnis G, Brodie A. Advances in mechanisms of resistance to aromatase inhibitors. Expert Rev Anticancer Ther 2014; 14:381-93. [PMID: 24559291 DOI: 10.1586/14737140.2014.882233] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Clinically, there are two distinct types of aromatase inhibitor (AI) resistance, namely acquired and innate resistance. Because the underlying mechanisms of these two types of resistance may not be mutually exclusive, strategies to tackle these resistances may not be effective when used interchangeably. Activation of growth factor receptor pathways is the hallmark of acquired AI resistance. These pathways can be targeted either at the cell surface receptor level or their downstream signaling cascades. Currently, everolimus in combination with exemestane represents a new standard of care for patients progressing on non-steroidal AIs. HDAC inhibitors have also shown promising results For innate resistance, the combination of fulvestrant and AI in the front line setting represents a new treatment option, particularly for patients who present with de novo metastatic disease. A Phase III trial is currently ongoing to evaluate the benefit of CDK 4/6 inhibitor, palbociclib, in the first line setting in combination with AI.
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Affiliation(s)
- Saranya Chumsri
- Department of Medicine, University of Maryland, School of Medicine and the Greenebaum Cancer Center, Baltimore, MD, USA
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45
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Aranda F, Vacchelli E, Eggermont A, Galon J, Fridman WH, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Immunostimulatory monoclonal antibodies in cancer therapy. Oncoimmunology 2014; 3:e27297. [PMID: 24701370 PMCID: PMC3961485 DOI: 10.4161/onci.27297] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Accepted: 11/21/2013] [Indexed: 12/16/2022] Open
Abstract
Immunostimulatory monoclonal antibodies (mAbs) exert antineoplastic effects by eliciting a novel or reinstating a pre-existing antitumor immune response. Most often, immunostimulatory mAbs activate T lymphocytes or natural killer (NK) cells by inhibiting immunosuppressive receptors, such as cytotoxic T lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PDCD1, best known as PD-1), or by engaging co-stimulatory receptors, like CD40, tumor necrosis factor receptor superfamily, member 4 (TNFRSF4, best known as OX40) or TNFRSF18 (best known as GITR). The CTLA4-targeting mAb ipilimumab has been approved by the US Food and Drug Administration for use in patients with unresectable or metastatic melanoma in 2011. The therapeutic profile of ipilimumab other CTLA4-blocking mAbs, such as tremelimumab, is currently being assessed in subjects affected by a large panel of solid neoplasms. In the last few years, promising clinical results have also been obtained with nivolumab, a PD-1-targeting mAb formerly known as BMS-936558. Accordingly, the safety and efficacy of nivolumab and other PD-1-blocking molecules are being actively investigated. Finally, various clinical trials are underway to test the therapeutic potential of OX40- and GITR-activating mAbs. Here, we summarize recent findings on the therapeutic profile of immunostimulatory mAbs and discuss clinical trials that have been launched in the last 14 months to assess the therapeutic profile of these immunotherapeutic agents.
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Affiliation(s)
- Fernando Aranda
- Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France
| | - Erika Vacchelli
- Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France ; Université Paris-Sud/Paris XI; Paris, France
| | | | - Jerome Galon
- Université Paris Descartes/Paris V ; Sorbonne Paris Cité; Paris, France ; Université Pierre et Marie Curie/Paris VI; Paris, France ; INSERM, U872; Paris, France ; Equipe 15, Centre de Recherche des Cordeliers; Paris, France
| | - Wolf Hervé Fridman
- Université Pierre et Marie Curie/Paris VI; Paris, France ; INSERM, U872; Paris, France ; Equipe 13, Centre de Recherche des Cordeliers; Paris, France
| | - Laurence Zitvogel
- Gustave Roussy; Villejuif, France ; INSERM, U1015; CICBT507; Villejuif, France
| | - Guido Kroemer
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP; Paris, France ; Metabolomics and Cell Biology Platforms; Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France ; Université Paris Descartes/Paris V ; Sorbonne Paris Cité; Paris, France
| | - Lorenzo Galluzzi
- Gustave Roussy; Villejuif, France ; Université Paris Descartes/Paris V ; Sorbonne Paris Cité; Paris, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France
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46
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Conklin CMJ, Gilks CB. Differential diagnosis and clinical relevance of ovarian carcinoma subtypes. ACTA ACUST UNITED AC 2014. [DOI: 10.1586/eog.12.72] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Liu YC, Chiang IT, Hsu FT, Hwang JJ. Using NF-κB as a molecular target for theranostics in radiation oncology research. Expert Rev Mol Diagn 2014; 12:139-46. [DOI: 10.1586/erm.12.2] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Gilboa E, McNamara J, Pastor F. Use of oligonucleotide aptamer ligands to modulate the function of immune receptors. Clin Cancer Res 2013; 19:1054-62. [PMID: 23460536 DOI: 10.1158/1078-0432.ccr-12-2067] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The paucity of costimulation at the tumor site compromises the ability of tumor-specific T cells to eliminate the tumor. The recent U.S. Food and Drug Administration approval of ipilumimab, an antibody that blocks the inhibitory action of CTLA-4, and clinical trials targeting 4-1BB and PD-1 or PD-L1, have underscored the therapeutic potential of using immunomodulatory antibodies to stimulate protective immunity in human patients. Nonetheless, systemic administration of immunomodulatory antibodies has been associated with dose-limiting autoimmune pathologies, conceivably reflecting also the activation of resident autoreactive T cells. Arguably, targeting immunomodulatory ligands to the disseminated tumor lesions of the patient would reduce such drug-associated toxicities. We have recently developed a new class of inhibitory (CTLA-4) and agonistic (4-1BB and OX-40) ligands composed of short oligonucleotide (ODN) aptamers that exhibited bioactivities comparable or superior to that of antibodies. To reduce toxicity, the immunomodulatory aptamers were targeted to the tumor by conjugation to a second aptamer that bound to a product expressed on the surface of the tumor cell, the targeting aptamer, generating a bispecific aptamer conjugate analogous to bispecific antibodies. In a proof-of-concept study in mice, we have shown that an agonistic 4-1BB-binding aptamer conjugated to a prostate-specific membrane antigen (PSMA)-binding aptamer led to the inhibition of PSMA-expressing tumors, was more effective than, and synergized with, vaccination, and exhibited a superior therapeutic index compared with nontargeted costimulation with 4-1BB antibodies or 4-1BB aptamers. The cell-free chemically synthesized ODN aptamers offer significant advantages over antibodies in terms of synthesis, cost, as well as conjugation chemistry needed to generate bispecific ligand fusions.
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Affiliation(s)
- Eli Gilboa
- Department of Microbiology & Immunology, Dodson Interdisciplinary Immunotherapy Institute and the Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
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Melero I, Grimaldi AM, Perez-Gracia JL, Ascierto PA. Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res 2013; 19:997-1008. [PMID: 23460531 DOI: 10.1158/1078-0432.ccr-12-2214] [Citation(s) in RCA: 142] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Immune system responses are under the control of extracellular biomolecules, which express functions in receptors present on the surface of cells of the immune system, and thus are amenable to be functionally modulated by monoclonal antibodies. Some of these mechanisms are activating and dictate whether the response ensues, while others play the role of powerful repressors. Antagonist antibodies acting on such repressors result in enhanced immune responses, a goal that is also achieved with agonist antibodies acting on the activating receptors. With these simple logics, a series of therapeutic agents are under clinical development and one of them directed at the CTL-associated antigen 4 (CTLA-4) inhibitory receptor (ipilimumab) has been approved for the treatment of metastatic melanoma. The list of antagonist agents acting on repressors under development includes anti-CTLA-4, anti-PD-1, anti-PD-L1 (B7-H1), anti-KIR, and anti-TGF-β. Agonist antibodies currently being investigated in clinical trials target CD40, CD137 (4-1BB), CD134 (OX40), and glucocorticoid-induced TNF receptor (GITR). A blossoming preclinical pipeline suggests that other active targets will also be tested in patients in the near future. All of these antibodies are being developed as conventional monoclonal immunoglobulins, but other engineered antibody formats or RNA aptamers are under preclinical scrutiny. The "dark side" of these immune interventions is that they elicit autoimmune/inflammatory reactions that can be severe in some patients. A critical and, largely, pending subject is to identify reliable predictive biomarkers both for efficacy and immune toxicity. Preclinical and early clinical studies indicate a tremendous potential to further improve efficacy, using combinations from among these new agents that frequently act in a synergistic fashion. Combinations with other more conventional means of treatment such as radiotherapy, chemotherapy, or cancer vaccines also hold much promise.
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Affiliation(s)
- Ignacio Melero
- Department of Oncology, Centro de Investigación Médica Aplicada, Clinica Universidad de Navarra, Pamplona, Spain.
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Vari S, Pilotto S, Maugeri-Saccà M, Ciuffreda L, Cesta Incani U, Falcone I, Del Curatolo A, Ceribelli A, Gelibter A, De Maria R, Tortora G, Cognetti F, Bria E, Milella M. Advances towards the design and development of personalized non-small-cell lung cancer drug therapy. Expert Opin Drug Discov 2013; 8:1381-97. [PMID: 24088065 DOI: 10.1517/17460441.2013.843523] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
INTRODUCTION Non-small-cell lung cancer (NSCLC) subtypes are driven by specific genetic aberrations. For reasons such as this, there is a call for treatment personalization. The ability to instigate NSCLC fragmentation poses new methodological problems, and new 'driver' molecular aberrations are being discovered at an unprecedented pace. AREAS COVERED This article describes the clinical development of epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKIs) and crizotinib for EGFR-mutant and anaplastic lymphoma kinase (ALK)-rearranged NSCLC. Further, the authors briefly describe the emerging molecular targets in NSCLC, in terms of both rationale for therapeutic targeting and strategies, for clinical development. EXPERT OPINION Target identification and validation in NSCLC still requires considerable effort, as not all of the molecular alterations are clear 'drivers' nor can they be efficiently targeted with available drugs. However, 50% of the NSCLC cases are without clear-defined molecular aberrations. Clinical trial methodology will need to develop novel paradigms for targeted drug development, aiming at the validation of an ideal 'biology-to-trial' approach. Despite significant challenges, a truly 'personalized' approach to NSCLC therapy appears to be within our reach.
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Affiliation(s)
- Sabrina Vari
- Regina Elena National Cancer Institute, Division of Medical Oncology A , Via Elio Chianesi 53, 00144, Rome , Italy +39 06 52666919 ; +39 06 52665637 ; ;
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