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 (<10% of cases), which all exhibit homologous recombination (HR) deficiency. PARP blockade shifts metabolism towards oxidative phosphorylation. A ketogenic diet also reprograms metabolism in this direction by reducing glucose availability. In Aim 1, we pair wild-type IDH1 (ivosidenib) and PARP1inhibitors (olaparib) in both HR deficient and proficient PDAC using GEMM and PDX models. We will show for the first time that wtIDH1 blockade directly inhibits PARP (through increased NADP+) and induces a BRCA-like phenotype (through decreased αKG and histone hypermethylation), resulting in strong synergy between drugs, even in HR proficient PDAC. The intent of this combination is to expand the indications for olaparib to the majority of PDAC. In Aim 2, we will demonstrate that anti-wtIDH1 therapy is potentiated when combined with a ketogenic diet. The two treatments synergize mechanistically, as a ketogenic diet drives the production of free radicals and shifts metabolism towards oxidative phosphorylation, which magnifies PDAC’s need for wtIDH1. We also show that both therapies reduce histone acetylation: low glucose from a ketogenic diet depletes a carbon source, while reduced TCA cycle activity after wtIDH1 inhibition also affects acetyl CoA pools. In Aim 3, we will analyze PDAC patient samples from an ongoing clinical trial (NCT05209074) for ivosidenib activity against wtIDH1, compared to control samples. Metabolic and DNA repair changes will be assessed. We will also compare tumoral Mg2+ levels to serum. These aims will inform future studies and trials seeking to optimize anti-IDH1-based therapies in patients.
