Abstract PO-024: Targeting cellular metabolism with CPI-613 sensitizes pancreatic cancer cells to radiotherapy

Novel treatment strategies for pancreatic ductal adenocarcinoma (PDAC) are desperately needed. Local tumor progression is a cause of significant morbidity and mortality in patients with surgically unresectable disease. Often, regional anatomic structures limit the total doses of radiation therapy (RT) that can be safely delivered. Conventional doses of concurrent chemotherapy and RT (chemo-RT) have shown suboptimal results in local control of disease, progression free survival, and overall survival. Therefore, novel and effective approaches to enhance the efficacy of RT are urgently needed to improve overall survival in unresectable PDAC. Metabolic reprogramming enables cancer cells to adjust their metabolism to support increased energy requirements associated with continuous growth and proliferation. Indeed, metabolic reprogramming is a hallmark of PDAC and is associated with increased tumor cell plasticity and chemo-RT resistance. Cancer-cell mitochondria are key regulators of deranged tumor metabolism and have been shown to guide molecular pathways involved in radio-resistance. There is also expanding data that the presence of metabolites modulates the response of cancer cells to RT primarily by impacting the ability to repair DNA. This makes them an optimal candidate for novel radiosensitization strategies, as these characteristics are unique to PDAC cells, and are limited in normal cells. CPI-613, is an analog of lipoic acid which inhibits pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (α-KGDH), thereby disrupting mitochondrial metabolism leading to selective tumor cell killing. The drug has demonstrated significant clinical activity in patients with metastatic PDAC in combination with standard of care chemotherapies. It remains unknown as to the efficacy in patients treated with concurrent chemo-RT. Here we show that combined treatment of RT (2 and 10 Gy) with CPI-613 (used at 200 and 300 μM) causes superior inhibition of pancreatic cancer cell growth (MTT assay and colony formation assay). In addition, we demonstrate enhanced apoptosis (Annexin V FITC and 7AAD assay) of PDAC cells when treated with a combination of RT and CPI-613. Molecular analysis revealed superior inhibition of PDH and α-KGDH at the protein level. Targeted metabolomic analysis on PDAC cells post CPI-613-RT treatment revealed alterations in key mitochondrial metabolites, leading to these findings. These results indicate broader target engagement by this combination treatment, indicating the sensitization of CPI-613 treated PDAC cells to radiotherapy at doses as low as 2 Gy. Furthermore, in our preclinical cellular models, a combination treatment of CPI-613 with either Gemcitabine or 5-FU has shown synergistic effects on the proliferation of PDAC cells. Pre-clinical anti-tumor efficacy of the CPI-613-RT and CPI-613-RT-chemo using subcutaneous and orthotopic PDAC models is planned. Our results bring forward a novel combination of CPI-613-RT that warrants further pre-clinical and early phase clinical investigations. Citation Format: William A. Hall, Husain Y. Khan, Mandana Kamgar, Susan Tsai, Kathleen Christians, Douglas B. Evans, Philip Philip, Callisia Clarke, Ben George, Beth Erickson, Asfar S. Azmi. Targeting cellular metabolism with CPI-613 sensitizes pancreatic cancer cells to radiotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-024.