Abstract Book - Pathology and Laboratory Medicine - University of ...

oral presentationGRADUATE STUDENTBASIC SCIENCESABSTRACT #21Inhibition of castration resistant prostate cancer by sintokamide A-a novelantagonist of the amino-terminus of the androgen receptorIran Tavakoli 1 , Nasrin R Mawji 1 , Jun Wang 1 , Luping Yan 2 , David E Williams 2 , Raymond JAndersen 2 , and Marianne D Sadar 11Department of Genome Sciences Centre, BC Cancer Agency; 2 Chemistry and Earth & OceanSciences, University of British ColumbiaBackground /objectivesLethal castration resistant prostate cancer (CRPC) is considered to involve a transcriptionally active androgenreceptor (AR). All current therapies target AR ligand-binding domain (LBD) to inhibit receptor activity.Unfortunately these therapies fail presumably by mechanisms involving breakthrough of androgen synthesis and/or expression of constitutively active AR splice variants that lack LBD. Recent studies have provided proof-ofconceptthat AR N-terminus domain (NTD) is druggable with the development of EPI-001, an antagonist thathas specificity and efficacy on both androgen-sensitive and CRPC xenografts. Here we reveal an unrelated class ofcompounds called SINT1 as a potent therapeutic agent for CRPC that targets AR NTD.MethodsCandidate compounds were identified by high throughput screening methods. The potency of compoundswere demonstrated by effects on AR regulated transcriptional activity and gene expression, steroid receptorspecificity, cell proliferation, and CRPC xenografts. Materials & Method: To examine the effects of SINT1 onAR transcriptional activity, both endogenous gene expression and reporter gene constructs that are regulated byAR were examined. The ability of SINT1 to directly inhibit transactivation of the AR NTD was tested using achimera of AR NTD fused to the DNA-binding domain of Gal4. Reporter assays for glucocorticoid (GR) andprogesterone receptor (PR) were measured to ensure specificity. BrdU incorporation was analyzed to indicatechanges in proliferation of AR positive and negative cell lines. Animals bearing LNCaP subcutaneous xenograftswere castrated when tumours were 100 mm3 and randomized into two groups. One week after castration, theanimals were treated every 3 days with an intratumoral dose of SINT1(30 mg/kg) or vehicle.ResultsSINT1 blocked AR activity as measured by reduction in PSA mRNA and reporter activity induced by androgen.SINT1 reduced transactivation of AR NTD to baseline levels. SINT1 had no effects on transcriptional activitiesof related steroid receptors, GR and PR. SINT1 was effective in blocking androgen-induced proliferation inLNCaP cells but did not decrease proliferation of PC3 cells that lack functional AR. Importantly, some SINT1-treated CRPC xenografts regressed while others did not grow (mean = 103.3± 11.97 mm3, n=7) with no changein animal body weight compared to DMSO-treated tumors (n=11) that grew to 153.7± 11.87 mm3 (p=0.011).ConclusionsTogether these data support that SINT1 is a specific inhibitor of the AR NTD without effects on highly relatedsteroid hormone receptors and no apparent toxicity in animals. SINT1 is an antagonist to AR NTD that causesregression of CRPC xenografts.Oral/Poster Presentations * 2012 33