Establishment of Patient-derived Succinate Dehydrogenase-deficient Gastrointestinal Stromal Tumor Models For Predicting Therapeutic Response.

PURPOSE: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract with mutant succinate dehydrogenase ( SDH ) subunits (A-D) comprising less than 7.5% (i.e. 150-200/year) of new cases annually in the United States. Contrary to GISTs harboring KIT or PDGFRA mutations, SDH -mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKIs). Lack of human models for any SDH- mutant tumors, including GIST, has limited molecular characterization and drug discovery.

EXPERIMENTAL DESIGN: We describe methods for establishing novel patient-derived SDH -mutant (m SDH ) GIST models and interrogated the efficacy of temozolomide on these tumor models in vitro and in clinical trials of m SDH GIST patients.

RESULTS: Molecular and metabolic characterization of our patient-derived m SDH GIST models revealed that these models recapitulate the transcriptional and metabolic hallmarks of parent tumors and SDH-deficiency. We further demonstrate that temozolomide elicits DNA damage and apoptosis in our m SDH GIST models. Translating our in vitro discovery to the clinic, a cohort of SDH -mutant GIST patients treated with temozolomide (n=5) demonstrated a 40% objective response rate and 100% disease control rate suggesting that temozolomide represents a promising therapy for this subset of GIST.

CONCLUSION: We report the first methods to establish patient-derived m SDH tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in m SDH GIST patients who are refractory to existing chemotherapeutic drugs (namely TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic.