Establishment of Patient-Derived Succinate Dehydrogenase–Deficient Gastrointestinal Stromal Tumor Models for Predicting Therapeutic Response

Abstract

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 (TKI). 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 (mSDH) GIST models and interrogated the efficacy of temozolomide on these tumor models in vitro and in clinical trials of patients with mSDH GIST. Results: Molecular and metabolic characterization of our patient-derived mSDH 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 mSDH GIST models. Translating our in vitro discovery to the clinic, a cohort of patients with SDH-mutant GIST 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. Conclusions: We report the first methods to establish patient-derived mSDH tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in patients with mSDH GIST who are refractory to existing chemotherapeutic drugs (namely, TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic. See related commentary by Blakely et al., p. 3

NCCN Guidelines® Insights: Gastrointestinal Stromal Tumors, Version 2.2022

“…33,34 Based on these limited data, the NCCN Guidelines recommend consideration of sunitinib, regorafenib, and pazopanib as options for unresectable SDH-deficient GIST (see GIST-D 1 of 2 and GIST-D 2 of 2, page 1208 and above, respectively). There are other potential treatments on the horizon for patients with SDH-deficient GIST; for example, temozolomide has shown promise in this setting based on preclinical data, 35 and is currently undergoing clinical testing (NCT03556384).…”

Anti-KIT DNA aptamer-conjugated porous silicon nanoparticles for the targeted detection of gastrointestinal stromal tumors

“…Following previously developed intrasplenic GIST-T1 models, we examined pSiNP-NH 2 -Cy5.5-PEG-KIT binding to the tumors. 5,10,27–29 GIST-T1-GFP cells, co-injected with cancer associated fibroblasts (CAFs) were used in this model to visualize the tumor burden. We previously demonstrated that in the spleen-to-liver-GIST metastasis model used here, the CAFs can accelerate GIST growth and metastasis.…”

Current Molecular Profile of Gastrointestinal Stromal Tumors and Systemic Therapeutic Implications

“…Molecular characterization demonstrated that temozolomide (TMZ) elicits DNA damage and apoptosis in SDH-deficient GISTs with a 40% rate of objective responses among five patients treated with this alkylating agent [ 105 ]. Based on this early efficacy data, a phase II study of single-agent TMZ (NCT03556384) in patients with SDH-mutant GISTs is ongoing.…”