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2021 Patrice and Precious Motsepe-PCF Young Investigator Award

PARP Inhibitors and Clonal Hematopoiesis in Men with Advanced Prostate Cancer

Catherine Marshall, MD
Johns Hopkins University

Mentors: Emmanuel Antonarakis, MD, Jun Luo, PhD Lukasz Gondex, MD, PhD

Description:

  • Clonal hematopoiesis (CH) is an age-related process by which hematopoietic cells acquire somatic mutations associated with myeloid malignancies. CH is associated with an increased risk of cardiovascular disease, hematologic malignancies, and bone marrow failure. This is important because cardiovascular disease and bone marrow failure are two of the leading causes of death in men with prostate cancer.
  • CH is prevalent in an age-dependent manner in men with advanced prostate cancer and may be associated with shorter metastasis free survival and overall survival in men with prostate cancer. Additionally, therapies used for prostate cancer may contribute to the development of CH which may in turn impact outcomes for men on these therapies.
  • Dr. Catherine Marshall is studying whether PARP inhibitors, a new precision medicine for some patients with prostate cancer, may accelerate the progression of CH, and the mechanisms by which this may occur.
  • In this project, Dr. Marshall will determine if PARP inhibitor treatment in patients with mCRPC is associated with an increase in prevalence of CH over time, compared to patients with mCRPC not on PARP inhibitor therapy.
  • Whether CH contributes to poor clinical outcomes in patients with advanced prostate cancer will be prospectively evaluated.
  • Whether patients with advanced prostate cancer and clonal hematopoiesis (CH) have different inflammatory signatures than patients without CH will be determined. This will help to inform whether poorer outcomes in men with prostate cancer and CH might be because of an increase in inflammatory cytokines.
  • If successful, this project will determine whether PARP-inhibitors increase risk for CH in prostate cancer patients, and whether this contributes to poorer outcomes, allowing identifying subsets of patients with advanced prostate cancer that may need additional or alternative therapies, either for their cancer, or supportive care while on those therapies. Furthermore, it could also identify a subset of patients who may benefit from alternative therapies, especially in early disease.

What this means to patients: Clonal hematopoiesis (CH) is a pre-malignant hematologic condition that is associated with adverse outcomes in the general population, and may contribute to worse outcomes in prostate cancer patients. Dr. Marshall will determine whether PARP-inhibitors accelerate the development of CH compared to other prostate cancer treatments, and enable identification of patients who may benefit from mitigating therapies or alternative treatment approaches, to avoid the ill effects of CH.