A growing body of data suggests that cholesterol and other lipids may be useful targets in the treatment of prostate cancers. Statins have already shown utility in protecting against aggressive prostate cancer, at least in part as a result of their cholesterol lowering effects.
“We have known for nearly 100 years that cancer pertubates metabolic pathways,” said Michael R. Freeman, PhD, Director of Cancer Biology and Therapeutics and Biomedical Sciences at Cedars-Sinai Medical Center. “Prostate cancer up-regulates lipogenic pathways, and more so in more aggressive disease.”
Dr. Freeman discussed current research efforts to understand the role of cholesterol and other lipids in a state-of-the-art lecture during Sunday morning’s Plenary I program.
High levels of circulating cholesterol activate oncogenic pathways and inhibit tumor cell apoptosis to promote prostate cancer progression, he noted. The impact is so potent that mice with high circulating levels of cholesterol show an increase in prostate cancer even after castration.
“Cholesterol is a central metabolite in lipid metabolism, inflammatory responses and other elements of cancer promotion and progression,” Dr. Freeman said. “It’s also a precursor to androgens, estrogen and other hormones that are active in prostate cancer. High circulating levels of cholesterol can cause the accumulation of androgen in tumor cells even in the presence of normal levels of circulating androgen.”
Androgens and cholesterol have mutually beneficial effects in prostate cancer. Androgens promote lipid accumulation in prostate cancer cells and the androgen receptor up-regulates transcriptional activators of fatty acid and cholesterol synthesis. The net effect is to increase accumulation of lipids in prostate cancer cells.
At the same time, androgens downgrade cholesterol efflux mechanisms in prostate cancer cells. And while high low-density lipoprotein (LDL) cholesterol levels retard the growth of epithelial cells in the normal prostate, high LDL cholesterol levels also stimulate prostate cancer cell growth.
“The clinical implication is that drugs such as statins that reduce cholesterol may affect the progression of prostate cancer,” Dr. Freeman said. “We have seen that the use of statins after surgery is associated with a 30 percent lower risk of recurrance of prostate cancer. And the effect is dose dependent.”
As a major component of cell membranes, cholesterol imposes a structural order by partitioning the plasma lipid membrane into discrete micro domains. These micro domains increase oncogenic signal transduction, suggesting that any disruption to the accumulation and organization of cholesterol could disrupt these micro domains and inhibit signal transduction.
Targeting cholesterol metabolism may also potentiate immunotherapy in prostate cancer. The data are unclear, in part because prostate cancer tumors are heterogeneous.
Dr. Freeman’s laboratory has developed a novel RNA-based profiling and classification system for prostate cancer tumors. The profiling system has been validated in a variety of preclinical systems, as well as in metastatic human prostate cancer.
“Statins are clearly chemoprotective against aggressive prostate cancer,” Dr. Freeman said. “Prostate cancer subtyping may allow approaches to patient stratification that will improve our current rates of recurrance and slow disease progression.”