Abstract
Gastrointestinal Stromal Tumors (GISTs) are the most common mesenchimal tumors of the gastrointestinal tract. Such tumors usually have activating mutations in either KIT (75 – 80%) or Platelet Derived Growth Factor Receptor alpha (PDGFRa) (5 – 10%) which lead to ligand-independent signal transduction. Targeting these activated proteins with Imatinib mesylate, a small-molecule kinase inhibitor, has proven useful in the treatment of recurrent or metastatic GISTs. However, more than half of patients develop resistance to Imatinib after about 2 years. Therefore, other targets have been studying in order to implement the therapeutical armamentarium for this disease. Sunitinib malate is an oral multikinase inhibitor that targets several receptor tyrosine kinases and has proved to prolong survival in Imatinib-resistant patients. Other molecules, such as Nilotinib, Sorafenib and Dasatinib were shown to be useful in Imatinib resistant mutant cell lines and the results of their activity in humans are being awaited. Recent evidence suggests that GIST cells acquire the capability to escape from the control of KIT and PDGFRa through the activation of alternative pathways. Therefore, further effort should be invested in the discovery of new signaling pathways, such as AXL, MET, IGF-R, which might be involved in the evolution of the disease. After a description of KIT and PDGFRa as known targets of anti-GIST treatments, we review other mechanisms and mediators that might be potential targets of new therapies, providing a comprehensive revision of the new molecular strategies under investigation.
Keywords: GIST, targeted therapies, Imatinib, Sunitinib, growth factor receptors, intracellular signaling
Current Cancer Drug Targets
Title: Molecular Targets in Gastrointestinal Stromal Tumors (GIST) Therapy
Volume: 8 Issue: 5
Author(s): C. Braconi, R. Bracci and R. Cellerino
Affiliation:
Keywords: GIST, targeted therapies, Imatinib, Sunitinib, growth factor receptors, intracellular signaling
Abstract: Gastrointestinal Stromal Tumors (GISTs) are the most common mesenchimal tumors of the gastrointestinal tract. Such tumors usually have activating mutations in either KIT (75 – 80%) or Platelet Derived Growth Factor Receptor alpha (PDGFRa) (5 – 10%) which lead to ligand-independent signal transduction. Targeting these activated proteins with Imatinib mesylate, a small-molecule kinase inhibitor, has proven useful in the treatment of recurrent or metastatic GISTs. However, more than half of patients develop resistance to Imatinib after about 2 years. Therefore, other targets have been studying in order to implement the therapeutical armamentarium for this disease. Sunitinib malate is an oral multikinase inhibitor that targets several receptor tyrosine kinases and has proved to prolong survival in Imatinib-resistant patients. Other molecules, such as Nilotinib, Sorafenib and Dasatinib were shown to be useful in Imatinib resistant mutant cell lines and the results of their activity in humans are being awaited. Recent evidence suggests that GIST cells acquire the capability to escape from the control of KIT and PDGFRa through the activation of alternative pathways. Therefore, further effort should be invested in the discovery of new signaling pathways, such as AXL, MET, IGF-R, which might be involved in the evolution of the disease. After a description of KIT and PDGFRa as known targets of anti-GIST treatments, we review other mechanisms and mediators that might be potential targets of new therapies, providing a comprehensive revision of the new molecular strategies under investigation.
Export Options
About this article
Cite this article as:
Braconi C., Bracci R. and Cellerino R., Molecular Targets in Gastrointestinal Stromal Tumors (GIST) Therapy, Current Cancer Drug Targets 2008; 8 (5) . https://dx.doi.org/10.2174/156800908785133169
DOI https://dx.doi.org/10.2174/156800908785133169 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...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
Related Articles
-
Oligonucleotide-Based Molecular Therapy for Restenosis after Angioplasty
Current Drug Targets Seeing Genes at Work in the Living Brain with Non-Invasive Molecular Imaging
Current Gene Therapy Pathological and Therapeutic Aspects of Long Noncoding RNAs in Osteosarcoma
Anti-Cancer Agents in Medicinal Chemistry Real-Time PCR: Revolutionizing Detection and Expression Analysis of Genes
Current Genomics Role of Nuclear Steroid Receptors in Apoptosis
Current Medicinal Chemistry Gene Delivery Strategies Targeting Stable Atheromatous Plaque
Current Pharmaceutical Design MicroRNA and Bone Tumor: To Up Date
Current Signal Transduction Therapy Pulmonary Neuroendocrine Cell System in Health and Disease
Current Respiratory Medicine Reviews Antitumor Activity of Novel Benzensulfonamide Derivatives in View of their Physiochemical Properties Searched by Principal Component Analysis
Medicinal Chemistry Gene Therapy for Pituitary Tumors
Current Gene Therapy Inhibiting Cyclin-Dependent Kinase / Cyclin Activity for the Treatment of Cancer and Cardiovascular Disease
Current Pharmaceutical Biotechnology Synergistic Interaction of Telomerase-Specific Oncolytic Virotherapy and Chemotherapeutic Agents for Human Cancer
Current Pharmaceutical Biotechnology Epigenetic Targets and their Inhibitors in Cancer Therapy
Current Topics in Medicinal Chemistry New Strategies and Patent Therapeutics in EBV-Associated Diseases
Mini-Reviews in Medicinal Chemistry IP6 (Inositol Hexaphosphate) as a Signaling Molecule
Current Signal Transduction Therapy Ultrasound Therapeutics– A Review
Current Medical Imaging Histone Deacetylase Inhibition: A Differentiation Therapy for Cultured Primary Hepatocytes?
Current Enzyme Inhibition Signal Transduction and Photodynamic Therapy
Current Signal Transduction Therapy Intracellular Delivery of Potential Therapeutic Genes: Prospects in Cancer Gene Therapy
Current Gene Therapy Carotenoids as Modulators of Intracellular Signaling Pathways
Current Signal Transduction Therapy