Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

Abstract

Introduction: Gastrointestinal stromal tumor (GIST) is the most common nonepithelial malignancy of the GI tract. With the discovery of KIT and later platelet-derived growth factor α (PDGFRA) gain-of-function mutations as factors in the pathogenesis of the disease, GIST was the quintessential model for targeted therapy. Despite the successful clinical use of imatinib mesylate, a selective receptor tyrosine kinase (RTK) inhibitor that targets KIT, PDGFRA and BCR-ABL, we still do not have treatment for the long-term control of advanced GIST.

Areas covered: This review summarizes the drugs that are under investigation or have been assessed in trials for GIST treatment. The article focuses on their mechanisms of actions, the preclinical evidence of efficacy, and the clinical trials concerning safety and efficacy in humans.

Expert opinion: It is known that KIT and PDGFRA mutations in GIST patients influence the response to treatment. This observation should be taken into consideration when investigating new drugs. RECIST was developed to help uniformly report efficacy trials in oncology. Despite the usefulness of this system, many questions are being addressed about its validity in evaluating the true efficacy of drugs knowing that new targeted therapies do not affect the tumor size as much as they halt progression and prolong survival.

Keywords:

• gastrointestinal stromal tumor
• imatinib mesylate
• investigational drugs
• repurposed drugs
• targeted therapy
• tyrosine kinase inhibitor

Declaration of interest

The following article was supported by the Kansas Bioscience Authority Eminent Scholar Program, the National Cancer Institute (R01 CA106528) and the National Center for Advancing Translational Science (KL2TR000119-04 awarded to ZY Pessetto). Furthermore, HJ Alturkmani is sponsored by the Kansas Bioscience Authority Eminent Scholar Program (KBA 4468718) while AK Godwin is sponsored by National Cancer Institute grants U01 CA113916, 5R01CA140323, P30CA168524, SABOR (UO1CA086402) and 1R21CA186846. AK Godwin also is supported through DOD grant W81XWH-10-1-0386 and is the Chancellors Distinguished Chair in Biomedical Sciences endowment at University of Kansas. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

This box summarizes the major points of this review.