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Principal Investigator: Samuel R Denmeade
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $181,813
Funding agency: National Cancer Institute
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.
Terms: <5-FU><5-Fluracil><5FU><Affect><After Care><After-Treatment><Aftercare><Androgen Receptor><Androgen Therapy><Androgenic Agents><Androgenic Compounds><Androgens><Animal Model><Animal Models and Related Studies><Assay><Bioassay><Biochemical><Biological Assay><Biopsy><Blood Serum><Blood monocyte><Bone-Derived Transforming Growth Factor><CSIF><CSIF-10><Cancer Patient><Castration><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular biology><Cessation of life><Clinical><Clinical Trials><Computational Biology><Conceptions><Coupling><Cytokine Synthesis Inhibitory Factor><Data><Data Set><Death><Differences between sexes><Differs between sexes><Discipline><Disease><Disease Resistance><Disorder><Effectiveness><Endotoxic Shock><Engraftment><Exposure to><Expression Profiling><Expression Signature><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fluoro Uracil><Fluorouracil><Fluoruracil><Fluouracil><Future><Gene Expression><Gene Expression Profile><Hepatic Proliferation Inhibitor><Human><IL-10><IL10><IL10A><Immune><Immune Markers><Immune Tolerance><Immune system><Immunes><Immunity><Immunologic Markers><Immunologic Tolerance><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Infiltration><Inflammation><Inflammatory><Inflammatory Response><Innovative Therapy><Interleukin 10 Precursor><Interleukin-10><L arginine amidinohydrolase><Left><Literature><Liver Immunoregulatory Protein><Liver-Derived Inhibitory Protein><Lung><Lung Respiratory System><Macrophage><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Marrow monocyte><Mediating><Milk Growth Factor><Modeling><Modern Man><Myeloid Cells><Myeloid-derived suppressor cells><Mφ><NGS Method><NGS system><Nivolumab><Non-Malignant><Oncology><Oncology Cancer><Opdivo><Outcome><PBMC><PD 1><PD-1><PD1><Patients><Peripheral Blood Mononuclear Cell><Phenotype><Platelet Transforming Growth Factor><Population><Predisposition><Prostate CA><Prostate CA therapy><Prostate Cancer><Prostate Cancer therapy><Prostate Neoplasms><Prostate Tumor><Prostate malignancy><Prostatic Cancer><Prostatic Neoplasia><Prostatic Neoplasms><Publishing><QOL><Quality of life><RNA Seq><RNA sequencing><RNAseq><Radiography><Resistance><Resistance development><Resistant development><Resolution><Roentgenography><Role><Serum><Sex Differences><Sexual differences><Subcellular Process><Surgical Castration><Susceptibility><T-Cells><T-Lymphocyte><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Technology><Testing><Testosterone><Therapeutic><Therapeutic Androgen><Therapeutic Testosterone><Toxic effect><Toxicities><Trans-Testosterone><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Treatment Efficacy><Tumor Cell><Tumor Immunity><Tumor-Infiltrating Lymphocytes><Up-Regulation><Upregulation><Xtandi><advanced disease><advanced illness><advanced prostate cancer><androgen ablation therapy><androgen blockade therapy><androgen deprivation therapy><androgen deprivation treatment><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><anti-tumor immune response><anti-tumor immunity><antitumor immunity><arginase><arginine amidinase><canavanase><cancer immunity><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><cell biology><cohort><computer biology><cytokine><data integration><design><designing><developing resistance><enzalutamide><flow cytophotometry><gene expression pattern><gene expression signature><high dimensionality><hormone refractory prostate cancer><immune microenvironment><immune suppression><immune suppressive activity><immune suppressive function><immune system tolerance><immune unresponsiveness><immune-based biomarkers><immunological biomarkers><immunological markers><immunological paralysis><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive myeloid cells><immunosuppressive response><immunosuppressive tumor microenvironment><improved><inhibitor><intervention efficacy><model of animal><monocyte><mouse model><murine model><myeloid suppressor cells><myeloid-derived suppressive cells><neoplastic cell><new approaches><next gen sequencing><next generation sequencing><nextgen sequencing><nonmalignant><novel approaches><novel strategies><novel strategy><palliative><participant enrollment><patient enrollment><post treatment><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><prostate cancer cell><prostate cancer model><prostate cancer resistant to androgen><prostate cancer treatment><prostate tumor cell><prostate tumor model><protein expression><pulmonary><radiologic imaging><radiological imaging><receptor expression><resistance mechanism><resistance to disease><resistant><resistant disease><resistant mechanism><resistant to disease><resolutions><response><response to therapy><response to treatment><scRNA-seq><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sle2><social role><standard of care><success><suppressive myeloid cells><systemic lupus erythematosus susceptibility 2><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutic response><therapy efficacy><therapy response><thymus derived lymphocyte><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><treatment response><treatment responsiveness><tumor><tumor growth><tumor immune microenvironment><tumor-immune system interactions>