Cholesterol receptor emerges as novel therapeutic target in kidney cancer

Researchers at the Perelman School of Medicine at the University of Pennsylvania showed that inhibiting the HDL cholesterol receptor SCARB1 can kill and stop the proliferation of clear cell renal cell carcinoma (ccRCC) cells, according to findings published in Cancer Discovery.^1,2

The investigators also found evidence that a diet focused on controlling cholesterol could block ccRCC tumor growth.

“Previous studies demonstrated that SCARB1 and cholesterol were both part of the story of ccRCC, but our work here shows a causal role,” lead study author M. Celeste Simon, PhD, Arthur H. Rubenstein, MBBCh, professor in the department of Cell and Developmental Biology, Perelman School of Medicine, and scientific director of the Abramson Family Cancer Research Institute, stated in press release. “My colleagues and I hope these investigations at the bench can translate to new and successful SCARB1 inhibitors and treatments for people facing this aggressive cancer.”

Simon et al cultured ccRCC cells and examined them in environments with different levels of available cholesterol. While healthy kidney cells can produce cholesterol for standard cellular functions, the researchers observed that tumor cells required exogenous cholesterol.

“That difference between cancer cells and regular kidney cells is important because it suggests that kidney cells can create cholesterol they need if cholesterol, available in the body, is restricted,” Simon stated in the press release.

Following their initial discovery, the investigators found that ccRCC tumors have a higher number of SCARB1, which are receptors for the cellular import of cholesterol. Building on this discovery, Simon et al examined the impact of knocking out SCARB1 in both vitro and in vivo mouse models. The researchers also assessed the effect of blocking SCARB1 with the molecule BLT-1.

These analyses revealed that without properly functioning SCARB1, the ccRCC tumor cells were unable to survive.

Although they consider their research to be highly promising, Simon et al maintain that additional studies now need to be conducted to examine the efficacy and safety of using SCARB1 inhibitors, such the investigational agent ITX-5061, in patients with ccRCC.

“This study [also] suggests a causative relationship between obesity, BMI, and circulating HDL cholesterol and likelihood of developing ccRCC that can be further investigated,” according to the press release.

The research was supported by the National Institutes of Health (P01CA104848) (R35CA197602), Diabetes UK (17/0005587), the Wellcome Trust (202802/Z/16/Z), the World Cancer Research Fund and their international grant program (IIG_2019_2009), and the National Institute of Environmental Health Sciences (P30ES013508).

Reference

1. Penn Study Finds New Possible Cell Target to Treat Clear Cell Renal Cell Carcinoma. Published online August 10, 2021. Accessed August 10, 20201. https://bit.ly/3xzBolC.

2. Riscal R, Bull CJ, Mesaros C, et al. Cholesterol auxotrophy as a targetable vulnerability in clear cell renal cell carcinoma [published online ahead of print July 8, 2021]. Cancer Discov. doi: 10.1158/2159-8290.CD-21-0211