San Diego, CA USA (UroToday.com) In today’s Society of Basic Urologic Research session, Dr. Timothy Thompson introduced the topic of identification and targeting resistance in CRPC by reviewing resistance mechanisms. He began by emphasizing the need or more investment in basic science to find meaningful clinical answers in CRPC. There are currently no curative treatments, although there are 11 FDA-approved agents.
Targeted therapies require genomics and/or gene expression analysis.
Whole exome sequencing of advanced CaP can demonstrate potential therapy targets. For example, germline and sporadic DNA damage response and repair alterations such as BRCA1 and 2 are present in 1/4th of mCRPC patients. Androgen signaling upregulates DNA damage response (DDR) gene expression, which is associated with the development of metastatic disease and poor prognosis in high risk patients.
Most growth and morphogenesis is directed by growth factor. AR is expressed late in morphogenesis where it exhibits cytodifferentiation. Meanwhile, DDR and repair is paramount. Later in the pathway “100s of genes are regulated by androgens.” The challenge is identifying how to fit the molecular biology of androgen action into the clinical development of CRPC.
An adaptive response to AR signaling inhibition leads to maintenance and/or upregulation of DNA damage response signaling through gene depression. Adaptive responses to AR signaling involve upregulation of “oncogenic” DDR gene expression. The combination of AR signaling inhibition and PAARP inhibition may have a synergistic effect through downregulation of specific DDR gene functions.
One closely examined oncoprotein that may play an important role is c-Myb. This is upregulated in patients with bone mets (CRPC, heavily pre-treated men). In settings where AR is highly expressed, there is minimal myb expression. However, where AR expression is low, upregulation of cMyb is identified. Enza treatment was found to induce c-Myb substantially, and administration with androgen R1881 is associated with repressed c-Myb. Interestingly, C-Myb silencing can inhibit prostate cancer growth in vivo and vitro via apoptosis. Other functions of malignant transformation are also suppressed such as motility and colony formation. Overlapping genes between AR and C-myb have been identified for both upregulation and downregulation pathways; utilization of these pathways may impact drug resistance and may provide targets for therapy.
AR is highly expressed in PDX 133 adenocarcinoma. When there is a shift to AR-, myb becomes elevated. This may be associated with PTTG1, a gene that is upregulated in mCRPC. While PTTG1 is upregulated by androgen, regulation shifts to c-Myb in the setting androgen resistance.
Dr. Thompson concluded that adaptive response to AR signaling inhibition via c-Myb leads to maintenance and upregulation of DDR gene expression and signaling. This may result in transforming activities such as PTTG1 which are involved in castration-resistance. The combination of treatment with AR signaling inhibitors and DDR agents such as PARP inhibitors may be useful in sppressing specific genetic programs that support castration resistance.
Presented By: Timothy C Thompson, PhD
Written By: Nikhil Waingankar, MD; Fox Chase Cancer Center, Philadelphia, PA., at the 2016 AUA Annual Meeting - May 6 - 10, 2016 – San Diego, California, USA
Follow on Twitter: @nwaingankar