> Our Work > The Work We Fund

2020 Tad Smith & Caroline Fitzgibbons-PCF Young Investigator Award

Jimmy Zhao, MD, PhD

Memorial Sloan Kettering Cancer Center

Mentor: Charles Sawyers, MD

Investigating Cell of Origin and Molecular Mechanisms of Lineage Plasticity in Neuroendocrine Prostate Cancer

Description:

  • Next-generation androgen receptor (AR) targeted therapies such as abiraterone and enzalutamide have improved the quality of life and extended survival of patients with metastatic castration resistant prostate cancer (mCRPC). Unfortunately, acquired resistance to AR-targeted therapies inevitably develops.
  • One mechanism of resistance that occurs in ~20-25% of mCRPC is “lineage plasticity,” in which tumors undergo a transformation from a prostate cell identity into a neuroendocrine-like or other cell type in order to lose dependence on the AR pathway for growth and survival. Understanding the mechanisms that drive neuroendocrine transformation and identifying novel therapeutic strategies to treat neuroendocrine prostate cancer (NEPC) remains a significant unmet challenge.
  • Dr. Jimmy Zhao is investigating the cell of origin and the molecular drivers of neuroendocrine transformation in patients with NEPC.
  • In this project, Dr. Zhao will perform single-cell analyses on different prostate cell populations in genetically engineered prostate cancer mouse models, to identify the cells of origin in NEPC.
  • Genes that promote lineage plasticity will be identified by deleting or overexpressing different genes in prostate cancer models.
  • Whether neutrophils, a type of inflammatory immune cell, may contribute to drug resistance and lineage plasticity in will be investigated in prostate cancer models. Whether tumor-associated neutrophils may be promising therapeutic targets will be determined.
  • If successful, this project will identify the critical molecular and cellular drivers of drug resistance and lineage plasticity in patients who develop NEPC. This may reveal promising new targets and therapeutic strategies for patients with one of the most aggressive forms of prostate cancer.

What this means to patients: Dr. Zhao is investigating the molecular drivers and role of neutrophils in lineage plasticity, a major form of treatment resistance in patients with mCRPC. This will lead to new understandings and identify promising new therapeutic strategies for patients with this highly aggressive form of prostate cancer.