Cotargeting Androgen Receptor Splice Variants and mTOR Signaling Pathway for the Treatment of Castration-Resistant Prostate Cancer
Abstract
Purpose: The PI3K/Akt/mTOR pathway is activated in most castration-resistant prostate cancers (CRPC). Transcriptionally active androgen receptor (AR) plays a role in the majority of CRPCs. Therefore, cotargeting full-length (FL) AR and PI3K/Akt/mTOR signaling has been proposed as a possible, more effective therapeutic approach for CRPC. However, truncated AR-splice variants (AR-V) that are constitutively active and dominant over FL-AR are associated with tumor progression and resistance mechanisms in CRPC. It is currently unknown how blocking the PI3K/Akt/mTOR pathway impacts prostate cancer driven by AR-Vs. Here, we evaluated the efficacy and mechanism of combination therapy to block mTOR activity together with EPI-002, an AR N-terminal domain (NTD) antagonist that blocks the transcriptional activities of FL-AR and AR-Vs in models of CRPC.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 31, 2016
- Source ID
- 10.1158/1078-0432.ccr-15-2119
Entities
People
- Carmen A. Banuelos
- Daniel P. Caley
- Jacky K. Leung
- Jun Wang
- Marianne D. Sadar
- Minoru Kato
- Nasrin R. Mawji
- Yusuke Imamura
Organizations
- BC Cancer Agency
- National Cancer Institute
- United States Department of Defense