Abstract
The receptor tyrosine kinase mesenchymal-epithelial transition factor (c-Met) plays a pivotal role in regulation of cell proliferation and migration. Abnormal expression of c-Met has been associated with poor prognosis in several cancer types, including upper gastrointestinal malignancies. Moreover, c-Met interaction with multiple signalling pathways involved in tumor growth and invasive/metastatic phenotype has gained substantial attention in the last few years, suggesting the therapeutic potential of this target. This has led to the development and evaluation of a number of c-Met inhibitors. Here we describe the critical role of the HGF/c-Met pathway in cancer, as well as the preclinical and clinical investigations on c-Met inhibitors in solid tumors, with particular emphasis on recent findings with small-molecule inhibitors in gastrointestinal cancers. Clinical trials with several of these novel inhibitors have been encouraging and one of them, crizotinib (dual c-Met/ALK inhibitor), has recently been approved for lung cancers with ALK-rearrangement. There are accumulating evidences on the therapeutic potential of this and other c-Met inhibitors for the treatment of other malignancies, such as gastric and pancreatic cancers. These inhibitors might be used in combination with chemotherapy as well as with other biological agents, in order to overcome different resistance mechanisms. However, further studies are needed to identify determinants of the activity of c-Met inhibitors, through the analysis of genetic and environmental alterations affecting c-Met and parallel pro-cancer pathways. These studies will be critical to improve the efficacy and selectivity of current and future anticancer strategies targeting c-Met.
Keywords: Antitumor therapy, cancer aggressive behaviour, clinical development, c-Met inhibitors, HGF, MET, personalized medicine, preclinical studies, resistance to targeted agents, upper gastrointestinal cancers.
Current Medicinal Chemistry
Title:MET As a Potential Target for the Treatment of Upper Gastrointestinal Cancers: Characterization of Novel c-Met Inhibitors from Bench to Bedside
Volume: 21 Issue: 8
Author(s): A. Avan, M. Maftouh, N. Funel, M. Ghayour-Mobarhan, U. Boggi, G.J. Peters and E. Giovannetti
Affiliation:
Keywords: Antitumor therapy, cancer aggressive behaviour, clinical development, c-Met inhibitors, HGF, MET, personalized medicine, preclinical studies, resistance to targeted agents, upper gastrointestinal cancers.
Abstract: The receptor tyrosine kinase mesenchymal-epithelial transition factor (c-Met) plays a pivotal role in regulation of cell proliferation and migration. Abnormal expression of c-Met has been associated with poor prognosis in several cancer types, including upper gastrointestinal malignancies. Moreover, c-Met interaction with multiple signalling pathways involved in tumor growth and invasive/metastatic phenotype has gained substantial attention in the last few years, suggesting the therapeutic potential of this target. This has led to the development and evaluation of a number of c-Met inhibitors. Here we describe the critical role of the HGF/c-Met pathway in cancer, as well as the preclinical and clinical investigations on c-Met inhibitors in solid tumors, with particular emphasis on recent findings with small-molecule inhibitors in gastrointestinal cancers. Clinical trials with several of these novel inhibitors have been encouraging and one of them, crizotinib (dual c-Met/ALK inhibitor), has recently been approved for lung cancers with ALK-rearrangement. There are accumulating evidences on the therapeutic potential of this and other c-Met inhibitors for the treatment of other malignancies, such as gastric and pancreatic cancers. These inhibitors might be used in combination with chemotherapy as well as with other biological agents, in order to overcome different resistance mechanisms. However, further studies are needed to identify determinants of the activity of c-Met inhibitors, through the analysis of genetic and environmental alterations affecting c-Met and parallel pro-cancer pathways. These studies will be critical to improve the efficacy and selectivity of current and future anticancer strategies targeting c-Met.
Export Options
About this article
Cite this article as:
Avan A., Maftouh M., Funel N., Ghayour-Mobarhan M., Boggi U., Peters G.J. and Giovannetti E., MET As a Potential Target for the Treatment of Upper Gastrointestinal Cancers: Characterization of Novel c-Met Inhibitors from Bench to Bedside, Current Medicinal Chemistry 2014; 21 (8) . https://dx.doi.org/10.2174/09298673113209990231
DOI https://dx.doi.org/10.2174/09298673113209990231 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
EGFR-Targeted Therapy in Malignant Glioma: Novel Aspects and Mechanisms of Drug Resistance
Current Molecular Pharmacology Neuroimmune Interactions and Psychologycal Stress Induced by Cohabitation with a Sick Partner: A Review
Current Pharmaceutical Design The Potential for Substance P Antagonists as Anti-Cancer Agents in Brain Tumours
Recent Patents on CNS Drug Discovery (Discontinued) The Synergistic Effect of Humanized Monoclonal Antibodies Targeting Insulin-Like Growth Factor 1 Receptor (IGF-1R) and Chemotherapy
Current Drug Targets Editorial [Hot Topic: Novel Physiological and Pharmacological Avenues in the Mechanism of Gastrointestinal Integrity, Protection and Ulcer Healing (Guest Editors: Thomas Brzozowski)]
Current Medicinal Chemistry Italian Association of Clinical Endocrinologists (AME) and Italian AACE Chapter Position Statement for Clinical Practice: Assessment of Response to Treatment and Follow-Up in Gastroenteropancreatic Neuroendocrine Neoplasms
Endocrine, Metabolic & Immune Disorders - Drug Targets COX-2 and Colorectal Cancer
Current Pharmaceutical Design Ligand-Targeted Liposomes for Cancer Treatment
Current Drug Delivery HGF/MET Signaling in Ovarian Cancer
Current Molecular Medicine Cellular Responses to 24R,25-dihydroxyvitamin D3 in Bone and Cartilage
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) The CNS Melanocortin System: A Biological Weapon Against the Threat of Obesity
Current Medicinal Chemistry - Central Nervous System Agents Viral Origins of Human Cancer
Current Medicinal Chemistry Molecular Mechanism of Anti-tumor Effect by Triptolide in Hematological Malignancies
Current Signal Transduction Therapy An Overview of Dietary Supplements on Obesity and Type 2 Diabetes: Efficacy and Mechanisms
Current Drug Metabolism Clinical Uses of Low – Dose Ketamine in Patients Undergoing Surgery
Current Drug Targets The Role of Antiangiogenetic Agents in the Treatment of Breast Cancer
Current Medicinal Chemistry Flavonoid Antioxidants
Current Medicinal Chemistry Anticancer Potential of Ginger: Mechanistic and Pharmaceutical Aspects
Current Pharmaceutical Design Bromodomain-Containing Protein 4: A Druggable Target
Current Drug Targets Cyclodextrin Based Nanosponges: A Multidimensional Drug Delivery System and its Biomedical Applications
Current Drug Delivery