Prostate cancer patients acquire resistance to standard-of-care strategies progressing to advanced disease and
resulting in 350,000 yearly deaths. As acquired resistance is mediated by increased androgen receptor (AR)
expression, we are developing a “Bipolar Androgen” therapy (BAT) cycling serum testosterone from
supraphysiological to near-castrate levels, maximizing toxicity to high and low AR-expressing cells respectively.
BAT is a clinically effective, safe and unique approach to treat castration-resistant prostate cancer (CRPC)
patients that improves quality of life, produces biochemical and objective responses, and re-sensitizes tumors to
AR inhibitors. Our data from a recent clinical trial (NCT03554317) shows that prostate tumor cells produce
inflammatory cytokines following BAT, and patients who benefited most from this therapy have an enriched
inflammatory transcriptional signature in tumors. Thus, despite its conception as a “targeted” therapy, our
understanding of BAT has broadened to consider its effects on the immune system, which appears critical for
success. To capitalize on this unappreciated potential and bridge the gap between patients who benefitted or
not from this novel strategy, we characterized patient peripheral blood mononuclear cells (PBMCs) before and
after treatment with BAT to define the changes it induces in immune cells. Our observations indicate that BAT
elicits the expansion of monocytic-myeloid derived suppressor cells (M-MDSCs) in patients with poor therapy
responses. The association between the abundance of M-MDSCs and reduced therapeutic efficacy, the
precedent in the literature that testosterone dampens the pro-inflammatory phenotype of macrophages, plus the
critical role of the inflammatory response in controlling tumor growth following BAT, lead us to the hypothesis
that increased numbers of M-MDSCs induced by BAT restrict antitumor immunity leading to reduced therapeutic
efficacy. To test this hypothesis, we propose three aims: (1) we will characterize PBMCs from metastatic CRPC
patients treated with BAT utilizing next generation sequencing, to identify transcriptional signatures in M-MDSCs
that are associated with therapeutic response and model M-MDSC tumor engraftment as these cells contribute
to the immunosuppressive tumor microenvironment; (2) we will use high dimensional flow cytometry to
demonstrate that immunosuppressive M-MDSCs are induced by BAT and not by standard-of-care therapy in an
independent cohort of patients, and describe the mechanism behind this induction by exposing isolated human
PBMCs in vitro to supraphysiological levels of testosterone; (3) we will utilize mouse models of prostate cancer
to assess the therapeutic benefit of M-MDSC depletion in combination with BAT. This collaborative effort across
the disciplines of computational biology, oncology, and myeloid cell biology, will build a detailed understanding
of how BAT reprograms tumor immunity and determine if M-MDSCs expansion underpins resistance to BAT,
thus providing a target to improve therapeutic efficacy in the design of future clinical trials.
