Older statins reduce metastatic potential in ccRCC: Mechanistic validation of SIM (selective inhibitor of metastasis) development

Purpose: Metastasis is the primary cause of mortality in clear cell renal cell carcinoma (ccRCC), and no current therapy prevents metastatic progression. We sought to define mechanism driving metastasis and develop small molecules capable of blocking dissemination. Methods: Co-culture assays and xenograft models demonstrated that metastasis are promoted by interactions between VHL-deficient HIF1alpha-high (VHL - HIF1alpha+) and VHL-proficient (VHL+) ccRCC cells, with the VHL - HIF1alpha+ cells driving the metastasis by inducing proliferative and migratory programs in neighboring VHL+ cells. A high-throughput screen of over 18,000 small molecule compounds was undertaken to identify drugs selectively toxic to VHL - HIF1alpha+ cells. Amongst the 2500 FDA approved drugs, 7 hits were identified, with 4 of them being older statins. Fluvastatin, being the most potent, was further tested for metastasis prevention in vivo. Transcriptomic and proteomic analyses compared older versus newer statins to assess HIF1alpha-dependent mechanisms. A population-based study of 17,792 RCC patients from the Finnish Cancer Registry linked cancer records with prescription data (1998-2018). Statins were classified as older (fluvastatin, simvastatin, lovastatin) or newer (atorvastatin, pravastatin, rosuvastatin). Logistic regression evaluated odds of metastatic presentation, and time-dependent Cox models assessed RCC-specific mortality, adjusting for demographics, comorbidities, tumor extent, and treatments. Results: Screening identified fluvastatin (SIM-1) as a selective inhibitor, and medicinal chemistry yielded SIM-2 with >4-fold higher potency. Pre-treatment with fluvastatin reduced metastatic burden in vivo. Older statins showed more potent selective cytotoxicity against VHL - HIF1alpha+ ccRCC cells than newer statins despite lower HMGCR affinity. HIF1alpha knockout abrogated fluvastatin sensitivity, suggesting its HIF1alpha dependence. Population analysis showed that pre-diagnostic use of older statins was associated with reduced odds of metastatic RCC at diagnosis, while newer statins did not reduce the risk of metastasis. Conclusions : Mechanistic, pharmacologic, and epidemiologic data converge to identify older statins as inhibitors of metastasis acting through the HIF1alpha pathway. These findings support further development of SIMs towards achieving metastasis-preventive therapy for ccRCC.