Clinical development landscape in GIST: from novel agents that target accessory pathways to revisiting non-targeted therapies

ABSTRACT

Introduction: Activating mutations in the genes encoding the tyrosine receptor kinases KIT and platelet-derived growth factor receptor occur in 85%–90% of patients with gastrointestinal stromal tumors (GIST). Although imatinib and other tyrosine kinase inhibitors have revolutionized the treatment of GIST, most patients progress within a few years.

Areas covered: Monoclonal antibodies and small-molecule inhibitors targeting specific signaling pathways or proteins associated with resistance to existing treatments are being explored as alternative treatment approaches for GIST. Other alternative approaches include inhibiting more general regulators of protein folding, chromatin packaging, and cell-cycle regulation; nontargeted approaches are also being evaluated in select patient populations. This review summarizes preclinical and clinical data from agents using these accessory pathways.

Expert opinion: As we learn more about GIST biology, it is becoming clear that treatment strategies will become more personalized, as reflected by the fact that several trials are enrolling specific subpopulations of patients with GIST. Going forward, researchers should evaluate these new drugs alone or in combination with other types of drugs to better meet patient needs.

KEYWORDS:

• GIST
• tyrosine kinase inhibitors
• accessory pathway
• PI3K
• MAPK
• HDAC
• HSP90

Article highlights

• Imatinib therapy revolutionized the treatment of GIST and will continue to be a major therapy for the majority of patients with GIST.

• There is an unmet need in patients who progress on or do not respond to currently available TKI therapies, particularly patients with WT GIST (10% to 15% of diagnosed patients).

• Several agents targeting different accessory pathways are currently in development, including novel therapeutics such as immune response blockers.

• Several combination therapy approaches targeting a single signaling cascade or multiple signaling pathways are being investigated to reduce the occurrence of secondary resistance mutations.

• A comprehensive approach that includes therapies currently approved for patients with GIST, as well those outside the TKI box, should be considered for specific patient groups, particularly when genotyping is available.

This box summarizes key points contained in the article.

Acknowledgments

We thank Pamela Tuttle, PhD, CMPP, and Katherine Mills-Lujan, PhD, of ArticulateScience, LLC for medical editorial assistance with this manuscript.

Declaration of interest

The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.