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.