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2025 Clay & Lynn Hamlin – PCF Young Investigator Award

Targeting Sox2 Regulatory Networks that Drive Distal-Proximal Lineage Plasticity in Prostate Cancer Progression 

Jinqiu Lu, PhD          
Columbia University Medical Center  

Mentors: Michael Shen, Max Loda

Description:

  • Lineage plasticity, a phenomenon when cells can change from one cell type to another, is a driver of cancer cell variability and drug resistance. Neuroendocrine prostate cancer (NEPC) is a highly aggressive form of advanced prostate cancer, in which, via lineage plasticity, prostate cancer cells lose prostate features and gain neuroendocrine features. It is critical to understand the drivers and biology of NEPC lineage plasticity to identify new therapeutic strategies for this lethal disease state.
  • Dr. Jinqiu Lu has found that deletion of the SOX2 gene in prostate cancer mouse models prevents progression to NEPC, suggesting potential as a therapeutic target for treatment or prevention of neuroendocrine prostate cancer. 
  • In this project, Dr. Lu will determine a genomic and molecular signature of SOX2-mediated plasticity, and identify other proteins that are critical in the SOX2 pathway for lineage plasticity. The potential for these factors as therapeutic targets will be investigated, and drugs that could prevent or overcome treatment resistance will be identified from existing drug databases.
  • If successful, this project will provide a molecular map of SOX2-driven lineage plasticity regulatory pathways in prostate cancer, and provide a molecular foundation for pharmacological targeting of these networks to prevent or revert prostate cancer lineage plasticity.

What this means to patients: Neuroendocrine prostate cancer (NEPC) is a lethal form of advanced prostate cancer that arises due to lineage plasticity and has no effective treatments. Dr. Lu’s project will determine the signature of SOX-2-driven lineage plasticity and identify molecular mechanisms as well as therapeutic targets in these pathways. This will facilitate the development of biomarkers that can help stratify patients at risk of therapy resistance or NEPC and pave the way for the development of novel therapeutic strategies that disrupt SOX2-driven tumor plasticity, ultimately improving patient survival and reducing recurrence rates.