Prostate Cancer Research
Progress Report: Ganesh V. Raj, MD, MPH
Investigator: Ganesh V. Raj, MD, PhD – Assistant Professor, University of Texas, Southwestern Medical Center
Molecular Targeting of the Androgen Receptor Signaling Via its Co-Factors in Prostate Cancer
The androgen receptor signaling pathway drives prostate cancer initiation and progression at all stages of the disease. This pathway is composed of a network of proteins whose coordinated actions induce prostate cancer proliferation and survival. The pathway is fueled by androgens, male hormones such as testosterone, and the androgen receptor, AR: a protein that binds androgens. The interaction of androgens with AR triggers a cascade of cellular events necessary for prostate cancer initiation and progression. AR signaling progresses through 2 distinct pathways: genomic and non-genomic. The genomic pathway involves AR movement into the nucleus where it binds to DNA and turns on cancer-causing genes. The non-genomic action defines a situation when AR interacts with other steroid receptors (proteins that bind steroids, such as estrogen) to elicit a cell growth response. Dr. Raj’s research is focused on identifying other proteins in this pathway, termed co-factors that work as AR teammates in facilitating its deleterious effects.
In the past 2 years as a PCF Young Investigator he has shown that a protein called PELP1 physically binds to AR and is necessary for both the genomic and non-genomic actions of AR in prostate cancer. From the structural analysis of PELP1, Dr. Raj and colleagues have identified the surface region of the PELP1 protein that binds to AR (similar to a key and a lock). This information was used to design a chemical compound, called a peptidomimetic. This compound mimics the chemical structure of the PELP1:AR interface (space between a key and a lock). Treatment of prostate cancer cells with this peptidomimetic showed that the compound interfered with the activity of AR and PELP1 and blocked AR induction of prostate cancer cell proliferation and survival. Dr. Raj and his group were also able to show that using this compound AR was unable to travel to the nucleus, evidence that the genomic action of AR was inhibited. Furthermore, preliminary data from prostate cancer mouse models reveals that this peptidomimetic caused prostate tumor regression. Dr. Raj and colleagues are working on developing this compound for future testing in humans. The hope is that this agent could further blunt the activity of the AR signaling pathway in prostate cancer and provide advanced prostate cancer patients with a new, effective treatment strategy.