A late-stage prostate cancer therapy, being developed by a company founded by researchers at Purdue University, may help to improve outcomes for patients by working to overcome the resistance they often develop to hormone therapy.
Prostate cancer depends on the male sex hormone, testosterone, to grow. Hormone therapy, which blocks the production of these hormones (androgens), or their ability to bind to specific androgen receptors, is often used to lower the risk of an early prostate cancer coming back after treatment, and to shrink advanced prostate tumors.
“Hormone therapies have a goal to reduce male hormones, called androgens, in the body, or to stop them from affecting prostate cancer cells,” Ji-Xin Cheng, a professor in biomedical engineering at Purdue University with experience in cancer biology and pharmaceutical development, said in a news release.
But one of the main challenges that patients face is resistance to hormone treatments. The researchers’ treatment approach consists in targeting cholesterol metabolism instead of the androgen pathway.
“Almost 100 percent of cancer patients will eventually develop a resistance to hormone therapies,” Cheng said. “Every year in the United States around 32,000 new [prostate] cancer cases become resistant, lessening the likelihood of survival.”
Cheng founded the startup, Resarci Therapeutics, along with Junjie Li, a postdoctoral researcher in the Weldon School of Biomedical Engineering, and Timothy L. Ratliff, director of Purdue’s Center for Cancer Research.
“By targeting the cholesterol metabolism, which is specific to cancer cells and independent of the hormone signaling pathway, we are able to eliminate the hormone resistance,” Li said.
The researchers found that the inhibitor avasimibe was able to overcome resistance to hormone therapy in mouse models. Avasimibe (CI-1011) is an orally bioavailable Acyl-CoA:Cholesterol O-Acyltransferase (ACAT) inhibitor that significantly reduces plasma total triglyceride and VLDL cholesterol (a type of what is known as “bad cholesterol”).
“We target the aberrant cholesterol metabolism using an inhibitor of cholesterol esterification enzyme ACAT-1, named avasimibe. Avasimibe selectively kills cancer cells by preventing the cholesteryl ester accumulation and inducing free cholesterol-related toxicity in cancer cells,” Li said.
Researchers are now applying for funding to move their discovery into clinical trials.
“We want to improve the formulation of our product, test it in preclinical settings and launch an early-stage clinical trial,” Ratliff said. “We are applying for funding from NIH and other agencies, but are also looking for investors or potential partnerships with pharmaceutical companies.”