Discovery
November 4, 2018

Prostate cancer steals the kindling from the neighbor’s woodpile – and this may help explain why androgen deprivation therapy stops working: the cancer bypasses it, and makes its own supply of male hormones.

Scientist Marikki Laiho, M.D., Ph.D., is hoping to kill two birds with one stone, shutting down two critical pathways – one for growth, and one for fuel – in aggressive prostate cancer by blocking a single target.

That target, RNA polymerase I, “governs the production of cellular RNA, and is highly activated in cancer,” says Laiho, the Willard and Lillian Hackerman Professor in Radiation Oncology. In work that began with funding from The Patrick C. Walsh Prostate Cancer Research Fund, Laiho found that switching off RNA polymerase I “curbs cancer cell growth and shows therapeutic benefit in preclinical cancer models.” But this work also brought another gene into the spotlight: PTRF, associated with polymerase function, which also plays a critical role in lipid metabolism. “This gene may have high relevance in prostate cancer, because it seems to be shut down in the stromal (connective tissue) cells of the prostate tumors.”

With postdoctoral fellow Jin-Yih (Nick) Low, who is an expert on PTRF, Laiho is exploring the links between RNA synthesis and lipid metabolism. “The early observations are striking,” Laiho says. “They suggest that the loss of PTRF in the stromal cells is a driver event that promotes aggressive characteristics in prostate cancer cells.” Interestingly, this loss of PTRF changes the way fat is metabolized by the cancer. Laiho and Low have discovered “the loss of lipid uptake in the stromal cells and an increase in the lipid content of the prostate cancer cells. For the cancer cells, this is a substantial benefit – they gain more fuel for growth and building blocks for production of androgens.” Basically, prostate cancer steals the kindling from the neighbor’s woodpile – and this may help explain why androgen deprivation therapy stops working: the cancer bypasses it, and makes its own supply of male hormones.

In mice, Laiho and Low are deleting PTRF in the prostate to see how this affects the ability of advanced cancer to invade and spread to distant sites. Further, their new insight on the role of PTRF in lipid metabolism is leading to exciting new studies on how diet affects prostate cancer development and progression. If fat inflames the cancer, could a low-fat diet help slow it down?

Also collaborating on this work are Hopkins colleagues Nathan Brennen, Brian Simons, and Samuel Denmeade, and Elina Ikonen, at the University of Helsinki, Finland.