Friday, June 13, 2025
6/13/2025
National Succinate Dehydrogenase-deficient GIST Translational Research and Clinical Trial Consortium - PROJECT SUMMARY/ABSTRACT Gastrointestinal stromal tumor (GIST) is often effectively treated with FDA-approved first-line therapies such as imatinib and avapritinib. However, this strategy is ineffective in a particular subset of GIST patients—those with a GIST caused by inherited loss-of-function mutations or sporadic epigenetic silencing of genes encoding the succinate dehydrogenase (SDH) complex. These SDH-deficient (SDH-def) GISTs exhibit quite variable biology, ranging from indolent tumors to rapidly progressive disease that quickly leads to death, often among adolescents and young adults. We recently reported that treatment of SDH-def GISTs with temozolomide (TMZ) resulted in favorable responses in a small patient cohort, and these findings led to a multicenter phase II trial to investigate the efficacy of TMZ in SDH-def GIST patients. We also developed the first and only patient-derived SDH-def GIST cell culture biorepository, which we utilized to discover that TMZ induces expression of death receptor 5 (DR5), a TRAIL receptor. Inhibrx Inc. in La Jolla, CA has developed an entirely new therapeutic agonist that binds to DR5 receptors, and collaboratively, we have used these together with TMZ to initiate apoptosis and reduce cell viability in vitro. This initial finding, together with major new preliminary data we now present, suggests that a synergistic strategy, combining DR5 agonism with TMZ, may lead to more effective treatment outcomes for SDH-def GIST patients, and thus address this unmet medical need. The overall objective of this proposed U01 is to unite NIH intramural and extramural SDH-def GIST clinicians and researchers with expertise in adult and pediatric medical oncology, surgical oncology, basic and translational science, patient advocates, and an industry partner to address two long-term goals: (1) to accurately distinguish SDH-def GIST patients who will have indolent biology from those who will have aggressive biology; and (2) to identify and test safe, effective therapeutic strategies for treating SDH-def GIST patients, especially those with more aggressive forms of this cancer who will otherwise die. Supported by our preliminary data, we hypothesize that SDH-def GISTs possess underappreciated tumor heterogeneity and hence correspondingly complex biology that will require combination therapies to achieve disease control. By accomplishing our aims, we will better understand the biology of these tumors and identify an improved treatment strategy for this disease. We propose to leverage our existing National Succinate Dehydrogenase-Deficient GIST Translational Research and Clinical Trial Consortium along with unique NIH Clinical Center resources to: (1) evaluate the safety and efficacy of TMZ with INBRX-109 (a potent DR5 agonist) among patients with progressive SDH-def GIST in a Phase I/II clinical trial; (2) create a centralized biobank of well-annotated SDH-def GISTs; (3) develop a network of research laboratories to develop improved preclinical models to investigate diverse SDH-def GIST biology; and (4) develop clinical tools to predict SDH- def GIST prognosis. Our project has the potential for immediate clinical impact to manage and treat SDH-def GIST patients, and will provide much-needed near-term hope for these patients, their families, and caregivers.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).