UCLA researchers in the Department of Molecular and Medical Pharmacology have developed an analoging and SAR-based chemical approach to generate novel, safe, and effective small-molecule inhibitors for preventing and treating cancer metastasis.
BACKGROUND: The limited understanding of the biological mechanisms underlying metastasis in clear cell renal cell carcinoma (ccRCC) contributes to the poor prognosis of this disease, despite the advent of new targeted therapies. Annually, approximately 25,000 ccRCC patients are at risk of developing metastatic disease, with those experiencing lung metastases facing a median survival of just 7 months. Studies of von Hippel-Lindau (VHL) disease, a rare hereditary cancer syndrome associated with renal, central nervous system (CNS), adrenal, and pancreatic tumors, led to the discovery of the VHL tumor suppressor gene. In the most common sporadic form of kidney cancer, ccRCC, the loss of VHL function is also known to be causative of this malignancy. However, the precise roles play by the functional loss of VHL and the subsequent activation of hypoxia program in the oncogenic process, especially in metastatic progression remain poorly understood. There is an urgent need for novel therapeutic strategies to combat metastasis in ccRCC and other aggressive solid tumors.
INNOVATION: UCLA researchers have discovered a novel metastatic mechanism in ccRCC. They found that ccRCC tumors often are heterogeneous, consist of a mixture of VHL(-) and VHL(+) tumor cells. It is the paracrine cross signaling between the 2 populations of cells that leads to metastasis. Importantly, they identified that the VHL(-) cells are the metastatic drivers. Thus, they set forth a a high-throughput screen of 2530 FDA-approved drugs to identified drugs that could selectively inhibits VHL(-) metastatic driving cells. Through this drug screen strategy, they identified and verified 7 hits that selectively inhibited VHL(-) but not the VHL(+) RCC cells. Amongst the 7 hits, four are in the statin family, with the outmoded statin, fluvastatin, being the most potent, while current statins, such as atorvastatin and rosuvastatin, are inactive. To optimize potency of lead compounds, the researchers developed a structure-activity relationship (SAR)-based approach, synthesizing fluvastatin analogs with targeted modifications. So far, 8 novel compounds have been synthesized and tested, each demonstrating distinct activity profiles against VHL(+) and VHL(-) RCC cells. These compounds exhibited anti-metastatic effects in vitro and in vivo not only in both murine and human ccRCC models, but they also exhibited selective toxicity against aggressive metastatic forms of prostate cancer (neuroendocrine prostate cancer) and breast cancer (triple negative breast cancer) over their less aggressive subtypes. This technology opens a new direction for developing novel and safe small-molecule drugs to treat metastatic cancers, such as ccRCC, prostate and breast cancer.
POTENTIAL APPLICATIONS:
- Development of novel small-molecule drugs for inhibiting metastasis
- Treatment of cancer metastasis, including ccRCC, breast cancer, prostate cancer, and other cancers
ADVANTAGES:
- Statins are already widely taken, and safe, oral drugs
- A new direction for developing novel and safe small-molecule drugs to inhibit metastasis
- Improve the therapeutic potency of small-molecule inhibitors of metastasis
DEVELOPMENT-TO-DATE: Successfully synthesized novel small-molecule drugs and evaluated their therapeutic efficacy in metastatic renal cell carcinoma mouse models.
Related papers: Hu, Junhui, et al. “Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma.” Signal transduction and targeted therapy 8.1 (2023): 155.
Lead Inventor: Lily Wu
OTT/iBridge Category Keywords:
Medical > Disease: Cancer
Medical > New Chemical Entities, Drug Leads
Medical > Therapeutics
TDG Keywords:
Therapeutics > Oncology
Keywords: Small-molecule inhibitors, cancer metastasis, clear cell renal cell carcinoma, tumor suppressor gene, structure-activity relationship, analog, chemical approach, SAR, statins, therapeutic, VHL, HIF1a, HIF2a, ccRCC, NEPC, TNBC