Researchers at Washington University School of Medicine in St. Louis recently conducted a study on mice to investigate how prostate cancer adapts to common anti-hormone therapy. The study discovered that when prostate cancer cells sense a decrease in testosterone levels due to therapy, they begin producing cholesterol, a vital precursor to testosterone, to generate their own testosterone to fuel tumor growth. However, the research also identified a potential drug combination that may prevent cancer from producing its own hormonal fuel.
The research provides crucial insights into how prostate cancer cells adapt to testosterone-deprivation therapy, which is a common treatment option. Unlike healthy prostate cells, cancer cells can generate their own hormonal fuel when deprived of testosterone. The study also revealed that treating aggressive prostate tumors with inhibitors that block parts of the hormonal fuel supply chain can slow tumor growth in mice. This research offers a promising new treatment strategy for prostate cancer that has become resistant to standard anti-testosterone therapy, such as abiraterone.
The study was published on June 9 in the journal Nature Communications and may also provide an explanation for why Black men have a higher risk of developing prostate cancer and are more likely to develop aggressive forms of the disease than White men of European descent.
“We’ve known for a long time that androgens, or male hormones such as testosterone, fuel prostate tumors — and we have drugs to treat prostate cancer that block the body’s ability to make testosterone,” said senior author Nupam Mahajan, Ph.D., a professor of surgery in the Division of Urologic Surgery. “But after about a year, these drugs stop working, and the androgen levels rise again. Where is this androgen coming from? Turns out, prostate cancer cells have learned a new trick; they start producing more cholesterol, which they divert to generate their own androgen. Our study shows how to block this, revealing a possible drug combination that could stop prostate cancer from fueling its own growth.”
Mahajan, a member of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, conducted a study on how prostate cancer cells detect a drop in androgen levels. The study discovered that a key protein called SREBF1 acts as an androgen sensor when bound to the androgen receptor. This protein enters the nucleus of the cancer cell when androgen levels are low and recruits an enzyme called GCN5 to modify histone proteins through acetylation. This epigenetic modification activates various genes that are important for producing cholesterol and lipids. As a result, the cells can produce large amounts of cholesterol, which is necessary for testosterone production.
“The cancer cells essentially load up the tumor with cholesterol and use that cholesterol to churn out more testosterone,” Mahajan said. “That’s the trick. They overload the prostate with cholesterol, and the normal systems for making androgen from cholesterol just work as they typically would, making drugs like abiraterone ineffective.”
Mahajan and his team conducted an experiment using two inhibitors to block the molecular events responsible for high cholesterol production. They treated mice with prostate tumors taken from human patients with these inhibitors.
The first drug, afatinib, is an FDA-approved EGFR inhibitor used to treat certain lung cancers. The second drug is a GCN5 inhibitor that has yet to enter clinical trials. However, it is being developed due to its potential effect on gene regulation, cell growth, and inflammation. Mice treated with a combination of both inhibitors showed significant reductions in tumor size compared to mice treated with a placebo or anti-testosterone drug, abiraterone, alone.
The study also revealed that the abundance of cholesterol in aggressive prostate cancer may explain the racial disparities observed in this type of tumor. The research showed that the lipid profile of prostate cancer in African American men is similar to the lipid profile of treatment-resistant prostate cancer discovered in the study. This suggests that African American men with prostate cancer may be more prone to having high levels of cholesterol in their tumors than white men with the same tumor type, although the cause of this disparity remains unclear.
“This is preliminary data, so we need to verify it in larger studies,” Mahajan said. “But our study suggests that this cholesterol profile may play an important role in African American patients with prostate cancer. African American men are at higher risk of prostate cancer, are diagnosed at earlier ages, and now we see that the kinds of cholesterol molecules that are generated in their cancers are similar to what we see in this overactive cholesterol manufacturing pathway. Their cancers are more likely to already be making these lipids, even before beginning anti-testosterone treatment.”
“We are hopeful this study will provide a solid rationale for undertaking a clinical trial of these two inhibitors combined — to block this cholesterol pathway — in patients with treatment-resistant prostate cancer,” Mahajan added.
