New link in cancer care chain

In early March, Purdue researchers announced the publication of a research paper in the journal Cell Metabolism that was authored by researchers associated with the Purdue University Center for Cancer Research and the Indiana University Melvin and Bren Simon Cancer Center at Indiana University School of Medicine. What they discovered and reported was a link between prostate cancer aggressiveness and the accumulation of a compound produced when cholesterol is metabolized in cells. It is anticipated that these findings could lead to entirely new diagnostic and treatment methods.

Moreover, the findings suggest that a class of drugs previously developed to treat atherosclerosis might be repurposed for treatment of advanced prostate cancer.

Specifically, the research showed that depletion of the compound cholesteryl ester significantly reduced prostate cancer cell proliferation, impaired its ability to invade a laboratory tissue culture and suppressed tumor growth in mice, said Ji-Xin Cheng, a professor in Purdue University’s Weldon School of Biomedical Engineering and Department of Chemistry, who adds, “Our study provides an avenue towards diagnosis of aggressive prostate cancer.”

“Prostate cancer is the second-leading cause of cancer-related mortality in American men. Our finding offers a biological foundation that supports the beneficial effect of cholesterol-lowering drugs. Second, our study heralds the potential of using cholesteryl ester as a therapeutic target for advanced prostate cancer,” said study co-author Timothy Ratliff, the Robert Wallace Miller Director of Purdue's Center for Cancer Research. “These results together suggest that cholesteryl ester accumulation might be used for more accurate prediction of prostate cancer aggressiveness, if validated through further examination of a large number of tissue biopsies and correlation assessment of cholesteryl ester levels and clinical outcomes of patients.”

A key area of focus in the reserchers’ work involved the analysis of individual lipid droplets inside single cells, and Purdue researchers have developed an analytical tool called Raman spectromicroscopy that allows compositional analysis of single lipid droplets in living cells and mice.

“It is conceivable that cancer cells require reservoirs for lipids, namely lipid droplets. However, our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases,” Cheng explained.

The researchers learned that cholesteryl ester accumulation, which occurs only in advanced prostate cancer and its metastasis, results from the loss of a tumor-suppressing gene called PTEN and the activation of an intracellular metabolic pathway promoting tumor growth.

“These findings improve current understanding of the role of cholesterol in cancer and also suggest new opportunities for the diagnosis and treatment of aggressive prostate cancer. We have been pleased to be able to collaborate with Dr. Cheng on his important research,” said Michael Koch, John P. Donohue Professor of Urology and chair of the Department of Urology at the Indiana University School of Medicine.

The paper also notes that the drugs avasimibe and Sandoz 58-035 reduced the accumulation of cholesteryl ester and significantly hindered advanced prostate cancer growth in laboratory cell cultures and xenograft mouse models, while showing no toxicity within those animals.

“We note that avasimibe, Sandoz 58-035 and a class of similar drugs were developed to treat atherosclerosis, but the clinical trials were halted due to the lack of effectiveness in reducing plaque size,” Cheng said. “The present study highlights a novel use of these drugs to treat advanced prostate cancer.”