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2025 Tom Knight – PCF Young Investigator Award

Defining Evolution of Prostate Cancer Metastasis Under Therapeutic Pressure Using Recordable Barcode

Lise Brault, PhD
Weill Cornell Medicine

Mentors: David Nowak; Christopher Barbieri 

Description:

  • The cornerstone of prostate cancer treatment is androgen deprivation therapy (ADT), which initially slows tumor progression but invariably leads to resistance, resulting in castration-resistant prostate cancer (CRPC) and poor clinical outcomes. CRPC is highly variable, driven by the evolution of aggressive subclones from minor populations in the primary tumor. Under therapeutic pressure, these subclones can emerge as resistant, metastatic populations, culminating in incurable disease. 
  • In this project, Dr. Brault will elucidate the effects of androgen-deprivation therapy (ADT) on prostate cancer evolution and the emergence of therapeutic resistance and clonal diversity, to establish new therapeutic strategies specifically targeting clonal populations prone to recurrence.
  • The team will use a new, lab-developed mouse model that mimics human metastatic prostate cancer’s genetics and behavior and enables single-cell level tracking of how the cancer clones evolve and spread. 
  • This model will be used to identify and compare gene expression and clonal evolution of tumor cells at primary and metastatic sites under therapeutic pressure with ADT, and to uncover novel therapeutic vulnerabilities in metastatic prostate cancer cells post-ADT.
  • If successful, this project will elucidate the impact of ADT on prostate cancer evolution and the emergence of therapeutic resistance and clonal diversity, and provide a new prostate cancer animal model that can be studies to make new insights into the complexity of metastatic and therapy-resistant subclones and the influence of ADT on cancer cell migration and evolution.

What this means to patients: Once prostate cancer develops resistance to ADT, it is rarely curable. Dr. Brault’s project will integrate evolutionary biology principles with cutting-edge modeling, to provide a deep understanding of the evolution and development of resistance to ADT and identify strategies to overcoming therapeutic resistance. By, this work has the potential to transform treatment strategies for advanced prostate cancer and improve patient outcomes.