Anh Nguyen
Pronouns: he/him/his
Research Mentor(s): Yatrik Shah
Research Mentor School/College/Department: Molecular & Integrative Physiology / Medicine
Program: UROP
Session: Session 6 (3:40pm – 4:30pm)
Authors: Anh Nguyen, Yatrik Shah, Rashi Singhal
Abstract
Colorectal cancer (CRC) is one of leading cause of cancer-related deaths globally. Hypoxia plays a critical role in cancer progression via increasing angiogenesis, glycolysis, apoptotic resistance, therapy resistance, and tumor metastasis. Hypoxic responses are transcriptionally controlled by hypoxia-inducible factor (HIF)-1a and HIF-2a. Our previous work shows that HIF-2a is necessary for CRC progression. Interestingly, a HIF-2a specific inhibitor-PT2385 has been employed for targeting CRC, but these inhibitors do not promise long-term benefits due to acquired resistance by tumor cells. Our data also shows CRC growth is not affected by PT2385 in vitro and in vivo. Therefore, our aim was to find cell-specific metabolic vulnerabilities to better target CRC. To do so we performed a metabolic CRISPR screen on HCT116 cells and identified cholesterol biosynthesis pathway as most essential for CRC survival. One key enzyme that is crucial to the cholesterol production pathway is HMGCoA Reductase (HMGCR). We next used statins, an inhibitor for HMGCR which is routinely used by patients to treat hypercholesterolemia. Our data shows an inhibition of growth and potentiation of HCT116 and SW480 cell death when cells were co-treated with statins and PT2385 in comparison to their treatment alone. Consistent with this data, HIF-2a knock-out HCT116 and SW480 were also sensitive to statin mediated growth inhibition. Our next aim is to characterize the form of cell death initiated by statins and PT2385 to inhibit CRC growth and to assess the tumor growth in vivo by utilizing statins and PT2385 in a syngeneic mouse model. Our study so far reveals the role of HIF-2a inhibitors in combination with cholesterol inhibitors in increasing CRC cell death. This vulnerability associated with cholesterol metabolism in hypoxic cancer cells could be exploited for chemotherapeutic development and CRC treatment.
