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).