Authors:
 CK Miranti, EM Reyes-Reyes, SS Ganguly, and LH Hurley
 
 
 Affiliations:
 University of Arizona
 
 
 Abstract Body:
 Resistance to standard-of-care anti-androgen therapy (ADT) is the primary reason patients with metastatic prostate cancer die. The primary mechanism of ADT-resistance, also known as CRPC, is reactivation of the androgen receptor (AR) such that its dependence on androgen is lost or severely reduced. Under these conditions, AR becomes constitutively activated and remains the major oncogenic driver. To overcome CRPC, it will be absolutely crucial to devise different ways to target AR other than through suppression of its ligand. An ideal approach is to find ways to inhibit AR expression rather than just its activity. Promoter analysis of the AR gene reveals the presence of a G-quadruplex structure ~120 bp upstream of the transcriptional start site. A drug screen using a newly developed G-quadruplex binding library (GSA) identified 3 top candidates with the selective ability to inhibit AR mRNA and protein expression in 4 different AR+ prostate cancer cell lines, including the ARv7 splice variant in CRPC. The ability of the GSA compounds to suppress AR was found to be dependent on their ability to recruit the nuclear scaffold protein, Nucleolin, to the AR G-quadruplex and to stabilize the structure. The most stable structure produces an 11-13 bp loop, which is the likely target of the GSA/Nucleolin complex. A similar extended loop structure is also formed in the G-quadruplex in front of the MYC gene, and its ability to be stabilized also requires Nucleolin. Not surprisingly, the top 3 candidates that suppress AR, were also very efficient at suppressing Myc expression. Preliminary PKA and MTD studies indicate the drugs are well tolerated by mice and have a good PKA profile. Studies are ongoing to determine their effectiveness at suppressing the growth of CRPC in vivo. Given that Myc is also a major driver of prostate cancer, these new compounds offer the potential for dual targeting of Myc and AR in CRPC.
 
 
 Funding Acknowledgments:
 NIH R41 CA224497; ACS 134181-MBG; DOD W81XWH-17-1-0570
 
 
 Corresponding Author Email:
 cmiranti@email.arizona.edu
 
 
 Conflict of Interest:
Dr. Hurley is Chief Scientific Officer at Reglagene. However, the drugs presented are not yet licensed by Reglagene.

Targeting the G-quadruplex in AR to Overcome Metastatic Castration Resistant Prostate Cancer