Targeting the Androgen Receptor to Sensitize Bladder Cancer to Immune Check Point Blockade.

PROJECT SUMMARY: “Targeting the Androgen Receptor in Bladder Cancer to Enhance Sensitivity to Immune Checkpoint Blockade”. Up to 70-80% of patients with bladder cancer demonstrate de novo resistance to PD-1/PDL-1 immune checkpoint blockade (ICB). Of those patients that initially respond to ICB, most ultimately develop resistance [1-

5]. These data support the investigation of additional cooperative targets which may sensitize bladder cancers to immunomodulatory therapies. Androgen deprivation therapy (ADT) is the standard of care treatment for prostate cancer patients. However, ADT has also proven to delay progression of AR positive bladder cancers

and, thus, offers a potentially viable co-target for enhancing the activity of clinically approved PD-1/PDL-1 targeting agents. Emerging evidence in prostate cancer supports an AR-dependent mechanism regulating ICB response whereby T cell intrinsic expression of AR blocks T cell activity and differentiation.

We hypothesize that clinically approved ADTs, including gonadal castration and AR targeted inhibitors, will promote the function of tumor infiltrating T cells while concomitantly inhibiting androgen sensitive epithelia in bladder tumors. We have developed preclinical mouse models and techniques that will test the impact of ADT

on early and late-stage bladder cancer progression. We will leverage established methods in single cell transcriptomics to understand the mechanism(s) of how ADT could alter the immune microenvironment to sensitize tumors to ICB. To further understand the cell intrinsic role of AR, we will leverage an established

preclinical model in the Mulholland laboratory to genetically disrupt AR expression in specifically in T cells. Our team. We will use an effective collaboration between experts in the field of cancer modeling, oncology, urology, bioinformatics and statistics. The translational research team consists of: David Mulholland, PhD

(preclinical mouse modeling), Matthew Galsky, M.D. (GU oncology), John Sfakianos M.D. (surgical urology), Ernesto Guccione, PhD (bioinformatics), and Madhu Mazumdar, PhD (biostatistics). Impact. If successful, our exploratory studies will generate data that is highly impactful for bladder cancer patients who are poorly responsive to standard of care immunomodulatory therapies.