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2021 Neal Rodin in Honor of Plum and Jonathan W. Simons, MD-PCF Young Investigator Award

Dissecting the Role of Homologous Recombination Deficiency and Immune Response in Early-Stage Prostate Cancer

Keyan Salari, MD, PhD
Harvard: Massachusetts General Hospital

Mentors: Eliezer Van Allen, MD, Adam Feldman, MD, MPH

Description:

  • Inherited and acquired mutations in BRCA2 and other DNA repair genes increase risk for the development of aggressive prostate cancer. However, the mechanisms by which DNA repair gene alterations drive prostate cancer development is unclear.
  • Dr. Keyan Salari is studying whether DNA repair alterations drives progression to aggressive disease by inducing an altered immune response in early disease stages.
  • The timing of DNA repair alterations in the development of early-stage prostate cancer will be defined using whole genome sequencing data from >500 prostate cancers with clinical and outcome data.
  • Whether prostate tumors with DNA repair alterations are infiltrated with distinct immune cell types and functionalities, that can distinguish clinically aggressive from indolent localized prostate cancers, will be determined.
  • The spatial relationships between tumor cells and immune cells with immunosuppressive and tumor-promoting activities will be determined in prostate tumors with DNA repair alterations.
  • If successful, this project will determine whether DNA repair alterations drive prostate cancer progression by inducing an immunosuppressive tumor microenvironment in early disease stages. This will enable discovery of new treatment targets and biomarkers that can identify tumors destined to remain indolent vs. aggressive.

What this means to patients: More reliable and reproducible prognostic tools to identify localized prostate tumors destined to remain indolent vs. aggressive is needed. Dr. Salari will investigate whether DNA repair gene alterations drive prostate cancer progression by altering immune responses. This data will enhance the ability to reliably identify tumors with lethal potential at an early stage from indolent tumors suitable for active surveillance. This work also has the potential to identify new therapeutic strategies to harness the immune system to prevent progression of disease for patients on active surveillance.