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2021 National Cancer Institute – PCF Young Investigator Award

Identification and Mechanistic Analysis of RB1/TP53 Loss Dependent Transcription and Epigenetic Factors Encoding Lineage Plasticity and Growth

Sonam Raj, PhD
National Cancer Institute (NCI)

Mentors: Kathleen Kelly, PhD, David Takeda, MD, PhD

Description:

  • Castration resistant prostate cancer (CRPC) is an advanced form of prostate cancer which has become resistant to androgen receptor (AR)-targeted therapy. Neuroendocrine prostate cancer (NEPC) is an aggressive form of CRPC that has lost prostate cell phenotype and gained neuroendocrine cell phenotype.
  • Progression of CRPC to NEPC is often associated with mutations in the tumor suppressor genes RB1 and TP53. However the mechanisms by which these mutations and other factors drive NEPC development are unclear.
  • Dr. Sonam Raj is investigating the molecular features that are required for growth of CRPC and NEPC.
  • In this project, Dr. Raj will identify essential genes that cooperate with RB1 loss to drive CRPC and NEPC. The separate contributions of RB1 and TP53 loss in the development of NEPC will also be determined.
  • If successful, this project will identify novel essential transcription and epigenetic factors in CRPC that drive NEPC or adenocarcinoma, and are TP53 and/or RB1 dependent, thus increasing knowledge of NEPC and identifying possible therapeutic targets. The results of these unique screens will also serve as a resource for the community.

What this means to patients: NEPC is an aggressive form of CRPC that arises from “transdifferentiation” – the conversion from one cell phenotype to another. Dr. Raj will identify critical drivers of the NEPC phenotype and create new experimental models for studying NEPC. This will improve understanding of NEPC and may lead to new treatments for this lethal form of prostate cancer.