UCLA

Metastasis occurs in one-third of clear cell renal cell carcinoma (ccRCC) patients and accounts for the majority of ccRCC-related deaths. Unfortunately, no therapy is available for this lethal disease because the molecular mechanism of metastasis is not fully understood. Although it has been known for 25 years that the loss of function of the VHL tumor suppressor gene is pathognomonic of RCC, its involvement in malignant progression remains elusive. Using a CRISPR/ Cas9 gene editing system and a mouse orthotopic implantation model, we previously found that the intratumoral heterogeneity of VHL expression is essential in ccRCC metastasis. Specifically, the VHL(-) cell population serves as the metastatic driver. Therefore, in this study, we sought to develop 1) a novel animal model of cooperative ccRCC metastasis and 2) small molecules with selective toxicity against the VHL(-) cells. For the first aim, we have utilized the chicken chorioallantoic membrane (CAM) model to establish a novel, cost- and labor-efficient animal model of cooperative metastasis, which almost perfectly recapitulated the characteristic phenomena observed in the mouse orthotopic implantation model. Using this model, we have also further explored exosome’s involvement in cooperative metastasis.For the second part of the project, we hypothesize that targeting the metastatic driver population, VHL(-), will effectively inhibit metastases. We have utilized high-throughput screening (HTS) for this purpose. A ratiometric black-box approach was employed to identify selective modulators of cell growth and survival of murine VHL(-) ccRCC cell lines with little to no effect on VHL(+) cells. Statins, the commonly used cholesterol-lowering drugs, showed up as hits. Dosage curves confirmed this result, and animal studies suggest its efficacy against ccRCC metastasis. The mechanism of action (MOA) is currently under investigation, but data implies that it may be distinct from statin's primary role as cholesterol-lowering. Strikingly, other metastatic cancer subtypes, such as triple-negative breast cancer (TNBC) and neuroendocrine prostate cancer (NEPC), were found to be more sensitive to statin treatment compared to their less aggressive counterparts. By investigating this further, we can potentially develop a pan-cancer small-molecule inhibitor of metastasis based on the FDA-approved, cheap, and widely available statins.