Abstract 2236: The role of CPI-613 in cholangiocarcinoma treatment
Authors: Wuchu Fulei , Animasahun Olamide , Choppara Srinadh , Gunchick Valerie , Nenwani Minal , Roy Jyotirmoy , Paserba Miya , Achreja Abhinav , Sahai Vaibhav , Nagrath Deepak 
Published: April 2023

Cholangiocarcinoma is the second most common primary liver cancer with extremely low survival rates. However, a combination of gemcitabine and cisplatin is the only treatment for advanced unresectable cholangiocarcinoma currently, and the cancer can become resistant to the treatment, contributing to the high mortality. CPI-613 is a lipoic acid analog, which can inhibit dehydrogenases and disrupt mitochondrial metabolism. It is regarded as a promising anti-cancer drug and has been tested in multiple clinical trials. Efficacy and working mechanisms of CPI-613 have not been established in cholangiocarcinoma. In this study, we aim to evaluate the performance of CPI-613 in combination with other therapeutic drugs and unravel the metabolic underpinnings. We treated cholangiocarcinoma cell lines with different genetic backgrounds with standard of care chemotherapy (gemcitabine and cisplatin) alone, CPI-613 alone, or the combination of the two. Results from viability assay showed that CPI-613 had synergistic (not simply additive) effects with standard of care chemotherapy. CPI-613 has a relatively short half-life, so longer infusion may be more beneficial even if the total dose remains the same. To mimic longer infusion, we treated the cells with multiple times of drug addition (fractional dosing), and compared the results to single addition. Oxygen consumption rate (an indicator of mitochondrial function) of cells under fractional dosing regimen was significantly lower in both short and long term, as measured by Agilent Seahorse and Resipher respectively. The results provided mechanistic support for longer infusion in clinical practice. We also collected plasma from patients before, during and after CPI-613 treatment in a clinical trial, and global metabolomics was performed. Global metabolomic changes induced by CPI-613 were identified and specific alternations in patients with complete response could be exploited as treatment targets or prediction markers. High frequency of isocitrate dehydrogenase 1 (IDH1) mutation is a characteristic of cholangiocarcinoma. Ivosidenib, an IDH1 inhibitor, has been shown to improve survival in chemotherapy-refractory cholangiocarcinoma patients in a phase 3 clinical trial. However, ivosidenib can increase alpha-ketoglutarate concentration, hence increasing the flux of TCA cycle and boosting mitochondrial fitness of the cancer cells. We hypothesized that the combination of CPI-613 and Ivosidenib could negate this effect and have better anti-cancer activities. Indeed, results from viability assay demonstrated synergy between CPI-613 and Ivosidenib. Metabolic flux analysis and global metabolomics were performed to illustrate the metabolic mechanisms of the combination of CPI-613 and Ivosidenib. Our study provides the mechanistic support for the use of CPI-613 in combination with other therapeutic agents and the results should be translated to clinical studies.

Citation Format: Fulei Wuchu, Olamide Animasahun, Srinadh Choppara, Valerie Gunchick, Minal Nenwani, Jyotirmoy Roy, Miya Paserba, Abhinav Achreja, Vaibhav Sahai, Deepak Nagrath. The role of CPI-613 in cholangiocarcinoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2236.