WASHINGTON, DC USA (UroToday.com) - Dr. Charles Sawyers presented the Coffey Lectureship on new insights into AR and the ERG fusion protein.
He began by asking why men relapsed on androgen deprivation therapy. Once delineated, they identified MDV3100 in a screen and modified it. MDV3100 inhibits AR binding and co-activators and decreases AR translocation to the nucleus. Only about 20% of AR translocates and even that does not effectively bind to DNA. MDV3100 was tested in Phase I-II trial in CRPC patients. Chemo-naïve and chemo failures were included. 62% of chemo-naïve patients had >50% decline in PSA and 51% of chemo-failures had >50% decline in PSA. It is now in Phase III clinical trials.
There is a resistant population in which they are examining tissue in addition are studying mouse models. They asked whether PTEN loss could explain resistance. They used a PTEN-/- prostate model and found that the tumors were not responsive to MDV3100. Tumor growth was driven through PI3K. They tested BEZ235, a PI3K inhibitor. PI3K inhibition conferred stable disease, but not disease regression. This was puzzling. PI3K pathway inhibition ironically activated AR. They applied data in breast cancer by Dr. Neal Rosen that showed that PI3K inhibition activates AR through HER kinases. They then applied the PI3K inhibitor with AR inhibition using MDV3100 and found that tumors were significantly inhibited. There was a dual reciprocal feedback of mTORC1/2 and FKBP5 that was then blocked. He stated that PSA would not be a useful endpoint in clinical trials.
He then focused on ERG translocations. It is an early event in prostate cancer initiation that occurs in approximately 45% of prostate cancer tumors. It defines a molecular subtype. Forced ERG expression was not able to induce tumorigenesis. They studied an ERG inducible mouse to activate the gene in the entire mouse body. They found that ERG rapidly induces acanthosis (hyperpigmentation of the skin). There was a massive expansion of the transitional layer of cells. Gene profiling was significantly altered, a result of ERG mediated downregulation of terminal differentiation genes. The gene EZH2 maintains basal cells in undifferentiated state, and EZH2 is an ERG target gene in prostate cancer. They found that the ERG transcriptomes resemble squamous skin cancer. They then developed a new and better ERG prostate genetically engineered mouse model. ERG induced hyperplasia and low grade PIN. The ERG transcriptome in the mouse prostate was revealed by Pten loss, identifying a group of genes not appreciated in tumors with active Pten.
Presented by Charles L. Sawyers, MD at the Society for Basic Urologic Research (SBUR)/Society of Urologic Oncology (SUO) joint meeting during the American Urological Association (AUA) Annual Meeting - May 14 - 19, 2011 - Walter E. Washington Convention Center, Washington, DC USA
Reported for UroToday by Christopher P. Evans, MD, FACS, Professor and Chairman, Department of Urology, University of California, Davis, School of Medicine.