Investigation of DNA Damaging Agents in GIST with Metabolic Dysfunction

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Gastrointestinal stromal tumor (GIST) is an orphan disease with ~3,000 new malignant cases in the U.S. annually. Mutant SDH (succinate dehydrogenase) A/B/C/D subunit GISTs comprise <7.5% of all cases and occur in the setting of inherited Carney-Stratakis Syndrome (aka Familial Paraganglioma-GIST Syndrome), which affects children, adolescents, and young adults. These GISTs are inherently resistant to imatinib, while sunitinib and regorafenib have limited efficacy (<20% response rates). To date, no drug has shown benefit in this GIST population. It is known that the SDH complex regulates critical enzymatic reactions in cellular metabolism and loss of SDH expression is a critical event in tumorigenesis. At present, the major impediment to all SDH research has been the lack of human cell lines or animal models. It is also unknown how metabolism is specifically reprogrammed in mSDH GIST cells and how this leads to drug susceptibility, as well as may also result in the emergence of synthetic lethalities. But, in a small clinical study of paraganglioma patients, only mSDHB, but not wild-type SDHB, tumors responded to the DNA damaging agent, temozolomide (TMZ). Our group has now developed the first patient-derived mSDH (A/B/C) GIST cell lines. At UC San Diego, we also have preliminary evidence that our patient-derived mSDH GIST cells are TMZ-sensitive in vitro and that a cohort of our mSDH GIST patients have responded to TMZ treatment. We hypothesize that mSDH GIST possess distinct metabolic derangements and are vulnerable to novel agents alone or in combination with DNA damaging agents. We will investigate this in the following: Aim 1, we will evaluate the efficacy of TMZ in a Phase II, single arm study in advanced mSDH GIST patients with the objective of determining overall response rate at 6 months (primary objective), as well as progression-free survival, overall survival, and TMZ safety/tolerability, and serum metabolites biomarkers of TMZ response. In Aim 2, we will characterize reprogramming of central carbon metabolism by mSDH GIST using 13C metabolic flux analysis (MFA). We will apply isotope tracers, mass spectrometry, and computational algorithms to perform MFA in order to identify important roles of Krebs Cycle enzymes in promoting cell growth in cancer cells. In Aim 3, we will determine the cellular and metabolic vulnerabilities of mSDH GIST in response to TMZ alone, or in combination with validated synthetic lethalities, to identify synergistic combination therapies for mSDH GIST. Overall, this represents a novel approach for repurposing an FDA-approved drug, TMZ, to treat an orphan disease without current effective therapy. We anticipate these studies will: 1) identify the first efficacious therapy for mSDH GIST; 2) yield new insights into metabolic reprogramming of mSDH GIST; and 3) define the mechanism of TMZ cytotoxicity in mSDH GIST. These studies have the potential for immediate clinical impact for treating mSDH GIST, as well as other mSDH cancers (renal cell, thyroid, and paraganglioma).