Abstract 4248: Statin-derived small-molecule inhibitors of metastasis (SIM) for high-risk epithelial cancers

Abstract Background: Metastasis is the deadliest cancer stage, and there is no universal treatment. Different tumors have distinct tissue-specific signatures, but as cancer progresses, they follow a common evolutionary trajectory toward invasiveness and metastasis. Targeting this shared vulnerability in metastatic tumors holds significant translational potential. Recent insights from kidney cancer reveal a novel metastatic mechanism, leading to the discovery of small-molecule drugs, SIMs, that selectively inhibit metastasis across cancers. By understanding SIMs, we aimed to create safer, more effective treatments, potentially saving over 500, 000 lives annually in the U.S. Methods & Results: 1) New concept: Metastasis requires cooperation between VHL+ and VHL- cells, with VHL- cells driving growth and migration in VHL+ cells. 2) SIM candidates: In high-throughput screening of 2, 530 FDA-approved drugs, small-molecule compounds selectively inhibiting VHL cells were identified, with fluvastatin being the most potent ("SIM-1"). Subsequent SAR studies identified SIM-2, four times more potent than fluvastatin (IC50 < 0.1uM). 3) Older statins (fluvastatin, simvastatin) were more cytotoxic than newer statins (e.g., atorvastatin and rosuvastatin) despite a lower affinity for their known target, HMG-CoA reductase (HMGCR). Thus, SIMs target a pathway distinct from cholesterol-lowering or HMGCR.4) Transcriptomics and proteomics analyses suggest that older statins may target a non-HMGCR molecule in their anti-metastatic activities, possibly explaining mixed clinical trial results regarding statin use as antineoplastics.5) SIMs are effective in treating various cancers, including kidney, breast (TNBC), and prostate (NEPC). Conclusions: Critical steps to advancing SIM development toward clinical translation are (i) target identification and (ii) target and therapeutic validation. While our focus is on metastatic renal cell carcinoma (mRCC) to identify SIM's drug target, strategic findings from this project will be directly relevant to other high-risk urological cancers. By investigating this further, we could develop a novel pan-cancer anti-metastatic drug. Citation Format: Moe Ishihara, Junhui Hu, Glen Brodie, Elizabeth Bowen, Shannon Shams, Diana Vaca, Jimin Kim, Stuart Conway, Robert Damoiseaux, Lily Wu. Statin-derived small-molecule inhibitors of metastasis (SIM) for high-risk epithelial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4248.