Prognostic and Therapeutic Roles of Voltage Gated Potassium Channels in Managing KIT Mutant Gastrointestinal Stromal Tumors (GIST)

PROJECT SUMMARY/ABSTRACT Gastrointestinal stromal tumors (GIST) are most often driven by oncogenic KIT mutations and are treated with FDA-approved tyrosine kinase inhibitors [TKIs, including imatinib (IM)] that target constitutively active KIT. However, these drugs are only modestly effective. Even in the treatment naïve setting, ≤10% of patients have complete responses to treatment. Thus, TKIs do not kill every tumor cell despite the absence of secondary resistance mutations in KIT. Data from our lab demonstrates that treatment naïve KIT mutant GIST contain subpopulations of IM-resistant “persister” tumor cells that lack KIT, but do express Kvβ1.1, the protein product of the KCNAB1 gene. Kvβ1.1 regulates the channel activity of pore-forming α-subunits in voltage-gated potassium channels (VGKCs) that allow cells to modulate plasma membrane potential and cell volume homeostasis that, in turn, critically affects processes central to cancer biology (cell cycle regulation, cell migration and invasion). FDA-approved in 2010 for treatment of multiple sclerosis, 4-AP (fampridine) blocks VGKCs to improve motor skills. We now find that 4-AP synergizes with IM in vitro and in a murine model to better treat KIT mutant GIST vs. IM alone. Our preliminary evidence strongly supports two Central Hypotheses: 1) high Kvβ1.1 protein (or high KCNAB1 mRNA) expression unequivocally identifies TKI-resistant persister cells in KIT mutant GIST; and 2) combined with KIT targeting by IM, the VGKC complex is a novel therapeutic target for eradicating both TKI-sensitive and TKI-resistant tumor cells in KIT mutant GIST. Our Overall Objectives are to: 1) determine the safety and tolerability and to assess the radiologic and pathologic efficacy of IM with 4-AP in a Phase 1 (3+3 design) neoadjuvant trial of 9-18 patients with treatment naïve KIT exon 11 mutant GIST (Aim 1); 2) validate pretreatment Kvβ1.1 protein or KCNAB1 mRNA expression as biomarkers predicting treatment response (Aim 1); 3) determine how genetic and pharmacologic modulation of VGKCs impacts cancer-relevant cell biology to define mechanisms mediating VGKC regulation of GIST aggressiveness (Aim 2); and 4) study KIT mutant GIST tumor prognosis (Aim 3). At our high-volume “GIST Center of Excellence” at the NCI- designated Moores Comprehensive Cancer Center at UC San Diego, we have united eight distinct investigators and their teams towards achieving a common goal: to drastically improve outcomes in KIT mutant GIST. This multi-disciplinary team includes expertise in: i) GIST surgical & medical oncology (Sicklick & Fanta); ii) conduct of clinical trials (Sicklick, Fanta, Messer); iii) radiology & mRECIST measurements (Hahn); iv) GIST pathology (Hosseini); v) GIST cellular & molecular biology (Sicklick); vi) computational biology & single cell omics (Mesirov & Tamayo); vii) VGKC biology (Joiner); and viii) biostatistics (Messer). Our project will: 1) test a new combination strategy for treating KIT mutant GIST; 2) have immediate applications for a follow-on Phase 2 clinical trial to test efficacy in for treating GIST; and 3) validate novel ways to eliminate persister cells that could be paradigm shifting, and ultimately lead to a cure for GIST.