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2024 National Cancer Institute – PCF Young Investigator Award

Uncover the Molecular Impact of Structural Variants that Drive Castration-Resistant Prostate Cancer Using Patient-Derived Models

Chennan Li, PhD
National Cancer Institute

Mentors: Adam Sowalsky, PhD; William Figg, PharmD; Mikhail Kolmogorov, PhD

Description:

  • The high mortality of castration-resistant prostate cancer (CRPC) is due to therapy failures driven in part by various genetic and epigenetic mechanisms. Large-scale genomic rearrangements involving structural variants are associated with therapy outcomes of CRPCs and some structural variantsstructural variants drive disease progression through altering the activity of multiple genes simultaneously. However, only a small fraction of the structural variants identified in CRPC have been functionally characterized. 
  • Dr. Chennan Li hypothesizes that structural variants regulate multiple genetic programs, leading to distinct pathological phenotypes and therapy outcomes observed in different CRPC patients. This project will identify clinically relevant structural variants in CRPC and evaluate their functional impact.
  • Deep molecular profiling will be applied on patient-derived CRPC models to precisely identify structural variants and relevant genetic alterations in CPRC.
  • Novel drivers of CRPC disease progression mediated by structural variants will be identified. 
  • The functional roles that structural variants and relevant driver genes play in disease progression and therapy resistance will be evaluated in models of CRPC.
  • If successful, this project will define the mechanisms by which structural genomic rearrangements drive CRPC progression and drug resistance, and identify novel targets dysregulated by these genomic rearrangements that may have potential as therapeutic targets in CRPC. 

What this means to patients: Prostate cancer is characterized by large-scale structural genomic rearrangements that drive disease progression and treatment resistance. Dr. Li’s project will systematically assess the mechanisms by which complex structural variants function in a diverse cohort of CRPC, to defineunderlying mechanisms of therapy-resistance that can be clinically targeted, and identify evidence-supported therapeutic strategies for patients with advanced prostate cancer.