> Our Work > The Work We Fund

2023 Kovler Family Foundation – PCF Young Investigator Award

Defining Lineage-Specific PRC2 Action and Rational Co-Targeting of EZH1/2 in Prostate Cancer

Varadha Balaji Venkadakrishnan, PhD
Harvard: Dana-Farber Cancer Institute (DFCI)

Mentors: Himisha Beltran, Myles Brown

Description:

  • Neuroendocrine prostate cancer (NEPC) is an aggressive form of advanced prostate cancer for which there are limited therapeutic options.
  • The development of NEPC is driven by lineage plasticity, a phenomenon in which cells change identity by losing features of one cell type (prostate luminal cells) and gaining those of another (neuroendocrine cells). Lineage plasticity is enabled by alterations in epigenetics – chemical modifications on DNA determining what genes a cell can and cannot express.
  • EZH1 and EZH2 are major epigenetic regulators playing an important role in cell identity. EZH2 is dysregulated in prostate cancer, however, the role for EZH1 in prostate cancer is not known. While treatments that target EZH2 alone are being tested in trials, studies suggest that EZH1+2 inhibitors may be more effective.
  • Dr. Varadha Balaji Venkadakrishnan is studying the role of EZH1 vs. EZH2 in NEPC and the impact of therapeutically targeting EZH1+2.
  • In this project, Dr. Venkadakrishnan and team will elucidate the specific roles of EZH1 and EZH2 in gene regulation and cell fate determination during lineage plasticity in prostate cancer preclinical models.
  • Mechanisms that increase sensitivity or drive resistance to EZH1+2-inhibitors will be identified, in order to nominate new combinatorial strategies to co-target with EZH1/2 in NEPC.
  • If successful, this project will define the roles of EZH1 and EZH2 in the development of NEPC and identify optimal combinatorial strategies to target with EZH1/2.

What this means to patients: NEPC is a highly aggressive form of advanced prostate cancer, for which new treatments are urgently needed. Dr. Venkadakrishnan and team will determine the role of EZH1 and EZH2 in NEPC and define optimal ways to target this pathway to reverse or prevent the development of NEPC. This will lead to new understandings of NEPC and new treatments for this lethal form of prostate cancer.