Abstract B027: Repurposing ion channel drugs: the Na+ channel modifying drug DPI-201-106 significantly enhances the anti-tumor activity of multiple classes of drugs targeting DNA damage repair
Authors: Johns Terrance G. 
Published: March 2024

Abstract
High-grade glioma (HGG) cells intimately interact with neurons in a two-way dance that drives tumorigenicity in one direction, and neuronal dysfunction in the other. Recent studies have highlighted the role of ion channels in mediating neuron/HGG interactions, including the formation of synapses. The FDA has approved hundreds of drugs that target ion channels, many of which are used for the treatment of neurological conditions, and therefore cross the blood brain barrier. We used an unbiased approach to drug discovery and screened patient-derived HGG cell lines against a library of ion channel drugs. Less than 15% of ion channel drugs inhibited the growth of HGG cells in vitro. Many active drugs were Ca2+ channel blockers, a class of drugs previously identified. One novel compound identified was DPI-201-106, a Na+ channel modifier, that blocks some Na+ channels and activates others. DPI-201-106 is an off-patent drug previously evaluated in a Phase 2 trial for the treatment of heart failure. DPI-201-106 had a cytostatic effect on numerous HGG cell lines that mechanistically was mediated through arresting cells in S-phase of the cell cycle. Activation of Chk1 kinase is a critical mediator of both S and G2/M cell cycle arrest. Blockade of Chk1 kinase activity with the small molecule Prexasertib forces cells to continue through the S-phase without pausing. The combination of DPI-201-106 and Prexasertib showed greater than additive anti-tumor activity in vitro against HGG cell lines by significantly increasing apoptosis. Treatment of mice bearing GBM6 or WK1 orthotopic xenografts with the combination of DPI-201-106 and Prexasertib resulted in synergistic anti-tumor activity. Extending this work, the combination of DPI-201-106 with small molecule inhibitors of ATR and Wee1, two kinases directly upstream of Chk1, also resulted in greater than additive inhibition of HGG growth. A major function of the CHK1 pathway is to pause the cell cycle, allowing cells time to repair DNA damage before completing the cycle. As such we examined the efficacy of DPI-201-106 in combination with PARP inhibitors, which target a different aspect of DNA damage repair. The combination of DPI-201-106 and the clinically approved PARP inhibitor niraparib showed significant anti-tumor activity. Overall, DPI-201-106 dramatically enhances the activity of different classes of agents targeting DNA damage repair. We have patented the combination of DPI-201-106 with DNA damaging agents and are working with several biotech companies to bring this discovery to the clinic.
Citation Format: Terrance G. Johns. Repurposing ion channel drugs: the Na+ channel modifying drug DPI-201-106 significantly enhances the anti-tumor activity of multiple classes of drugs targeting DNA damage repair [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B027.