Optimizing anti-wild-type IDH1 therapy in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the most deadly of the common cancers, with limited treatment options. Chemotherapy is marginally effective, while targeted or immunologic agents have little benefit. We recently showed that wild-type IDH1 (wtIDH1) is required for PDAC cells to survive their harsh and nutrient-

limited microenvironment (TME). The cytosolic enzyme, IDH1, converts isocitrate to α-ketoglutarate (αKG), using NADP+ as a cofactor. In the setting of nutrient scarcity, the reaction products (NADPH and αKG) help neutralize free radicals and boost mitochondrial function, respectively. Under TME-associated conditions, we discovered

that allosteric IDH1 inhibitors, designed and approved to selectively treat mutant-IDH1 tumors, actually target the wtIDH1 enzyme. Tumors have very low Mg2+ levels, which permits drugs like FDA-approved ivosidenib to outcompete the cation in the allosteric pocket, leading to increased efficacy against wtIDH1 PDAC across tumor

models (see Nature Cancer, 2022). While anti-wtIDH1 therapy is promising, especially in combination with chemotherapy, in this proposal we identify practical, safe, and chemo-sparing treatments that optimize anti- wtIDH1 therapy based on our recently acquired insights. Specifically, strategies (pharmacologic or dietary) that

further enhance PDAC reliance on antioxidant defense and mitochondrial metabolism for survival are particularly effective. Relevant to this work, olaparib is the only FDA-approved targeted treatment of PDAC. The drug inhibits PARP1-mediated DNA repair and is indicated for BRCA-mutant PDAC (