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2021 Michael and Lori Milken-PCF Young Investigator Award

Molecular Signatures of SupraT Induced Ferroptosis and its Role in Prostate Cancer Growth Inhibition

Rajendra Kumar, PhD
Johns Hopkins University

Mentors: Sushant Kachhap, PhD, Sam Denmeade, MD

Description:

  • Bipolar androgen therapy (BAT) is a promising experimental treatment strategy for prostate cancer, in which patients are cycled monthly between extremely high (supraphysiological) and extremely low (near-castrate) levels of testosterone. This is achieved by giving patients androgen deprivation therapy (ADT) along with monthly shots of supraphysiological levels of testosterone.
  • Promising response rates to BAT have been seen, with ~25% of patients achieving a >50% decline in PSA levels, and objective responses observed in ~40% of patients.
  • However, the mechanisms by which BAT kills prostate cancer cells remains unclear, as do biomarkers for predicting which patients are most likely to benefit.
  • Dr. Rajendra Kumar and colleagues have found that exposure of prostate cancer cells to supraphysiological testosterone levels induces ferroptosis, an iron-dependent form of cell death. This form of cell death can activate the immune system, suggesting that BAT may induce anti-tumor immune responses and may have synergy with immunotherapy.
  • In this project, Dr. Kumar will investigate the mechanisms by which supraphysiological testosterone induces ferroptosis and whether this contributes to the efficacy of BAT therapy.
  • The mechanisms by which supraphysiological testosterone induces ferroptosis and inhibits the growth of prostate cancer will be determined.
  • The cellular and molecular mechanisms of ferroptosis induced immune responses will be investigated in humanized mouse models of prostate cancer and in tumor samples from patients receiving BAT
  • If successful, this project will provide insights about the role of ferroptosis in BAT responses, and will enable development of ferroptotic signatures as biomarkers for the efficacy of BAT therapy in prostate cancer patients.

What this means to patients: BAT therapy is an experimental prostate cancer treatment with promising response rates seen in clinical trials. Dr. Kumar will demonstrate whether ferroptosis contributes to the efficacy of BAT therapy, and generate biomarkers for selecting patients to receive BAT and rationale for combing BAT with immunotherapy.