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

Abstract

Introduction Gastrointestinal stromal tumor (GIST) is the most common non-epithelial malignancy of the GI tract. With the discovery of KIT and later 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.

Current treatment strategies in pediatric gastrointestinal stromal cell tumor

“…However, their results have been consistent with prior studies and have failed to show any significant clinical improvement in this cohort of patients (37,38). There are several newer cytotoxic agents in various stages of clinical trials but none has shown outstanding promise (39). Radiotherapy for GIST suffers from the drawbacks of a widely irradiated field, difficulties in targeting lesions affixed to mobile organs, and a high rate of gastrointestinal sideeffects.…”

Epigenetics: an alternative pathway in GISTs tumorigenesis

“…The first is interaction of SAHA with KIT protein chaperone Hsp90 and maintenance of its hyperacetylation [167,170,171]. Hsp90 helps KIT protein to fold into a functional structure and stabilizes it in that form, and moreover it is important in KIT activation [170,172]. The second method is mediated through reduction of KIT mRNA [167,171].…”