Treating prostate cancer is challenging, but help may be on the way.

Joshi Alumkal, Wicha family professor of oncology at the University of Michigan Rogel Cancer Center, explores how.

Alumkal spent most of his childhood and early adulthood in Texas. He graduated summa cum laude from the University of Texas with a bachelor’s in biology. He received his medical degree from Baylor College of Medicine. He completed an internship, residency, and chief residency at UT Southwestern Medical Center. Dr. Alumkal completed a clinical fellowship in medical oncology and a post-doctoral fellowship focused on cancer epigenetics at Johns Hopkins University. Dr. Alumkal joined the Knight Cancer Institute Prostate Cancer Research Program at Oregon Health and Science University in 2007 and became the co-leader of the program in 2013. In 2014, Dr. Alumkal was honored with the Richard T. Jones New Investigator Award for exceptional promise early in a career in biomedical research in Oregon. In 2019, Dr. Alumkal re-located to the University of Michigan to lead the Genitourinary Medical Oncology Section in the Division of Hematology-Oncology and the Rogel Cancer Center, where he is a professor of Internal Medicine. He also serves as co-leader of Rogel’s Translational and Clinical Oncology Program. He was named a Rogel Cancer Center Rogel Scholar in 2019.

The Gene PROX1 is an Early Driver of Prostate Cancer Aggressiveness

Reducing levels of male hormones and blocking the function of the androgen receptor is the main treatment for men with metastatic prostate cancer. My lab previously found that after male hormone lowering treatments, some tumors lose androgen receptor signaling and change their identity through a process called lineage plasticity. These tumors are particularly deadly.

We wanted to understand what factors might be causing this transition. By examining patient tumor biopsies that had undergone lineage plasticity after androgen receptor targeting, we found PROX1 was the top upregulated gene. By evaluating hundreds of prostate cancer patient tumors, we confirmed that increased levels of PROX1 correlated with loss of androgen receptor signaling, suggesting PROX1 may be responsible for androgen receptor loss. In fact, when we overexpressed PROX1 in prostate cancer cells, it caused the androgen receptor levels to drop.

We also eliminated PROX1 with genetic methods in prostate cancer cells that had undergone lineage plasticity. When we did so, they stopped growing and began to die, suggesting that targeting PROX1 could be an effective way to control these tumors.

One challenge is that PROX1 is a type of protein called a transcription factor, which are notoriously difficult to target with drugs. Looking for a workaround, we examined proteins that bind to PROX1. Among the top partners were histone deacetylases, or HDACs.

HDACs are known to play a role in cancer, and several HDAC inhibitors have been approved by the U.S. Food and Drug Administration for cancers other than prostate.

Importantly, we found that PROX1-expressing prostate cancer cells were very sensitive to HDAC inhibitors, and treatment with these drugs depleted PROX1—an effect similar to genetically removing PROX1 from the cells.

Our results suggest PROX1 is an important regulator of lineage plasticity, and HDAC inhibitors are worthy of further study in prostate cancers that have undergone this transition—tumors for which there are limited treatment options.

The post Joshi Alumkal, University of Michigan – The Gene PROX1 is an Early Driver of Prostate Cancer Aggressiveness appeared first on The Academic Minute.