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2020 Tad Smith & Caroline Fitzgibbons-PCF Young Investigator Award

Uncovering Lineage Plasticity in the Context of Specific Genomic Alterations in High Risk Prostate Cancer

Lucia Nappi, MD, PhD

Lucia Nappi, MD, PhD

Mentors: Martin Gleave, MD; Amina Zoubeidi, PhD

Description:

  • The mechanisms of resistance to androgen receptor (AR)-targeted therapies in prostate cancer are not fully understood. One mechanism of AR-targeted therapy resistance, is lineage plasticity, in which prostate cancer cells lose prostate cell features and gain features of other cell types such as neuroendocrine cells. Understanding the mechanisms that enable lineage plasticity is critical, and will enable the development of new treatments for these lethal forms of prostate cancer.
  • Dr. Lucia Nappi is studying molecular mechanisms of prostate cancer lineage plasticity.
  • Dr. Nappi is conducting a neoadjuvant (pre-surgery) precision medicine clinical trial, in which patients with high-risk localized prostate cancer are treated with AR-targeted therapy for 8 weeks followed by one of four therapy protocols based on their tumor genomic profile, for additional 16 weeks. Patients will then undergo radical prostatectomy and assessment for the degree of remaining tumor.
  • Pre-treatment biopsy and post-treatment surgical samples will be evaluated for gene expression and epigenetic profiles. Gene expression signatures and epigenetic patterns associated with treatment response or resistance in any of the four precision medicine treatment groups will be investigated. Those indicative of lineage plasticity will be specifically evaluated.
  • The PAM50 classifier is used to identify major molecular subtypes of breast cancer based on gene expression profiles, and may be useful in prostate cancer. Whether PAM50 classification is associated with epigenetic patterns, lineage plasticity, and with treatment response or resistance in patients on this trial will be investigated.
  • If successful, this project will result in validation of a precision medicine treatment paradigm, as well as biological insights into early molecular events associated with development of treatment resistance and lineage plasticity.

What this means to patients: Dr. Nappi is investigating mechanisms of treatment resistance and response in patients with high-risk localized prostate cancer in a neoadjuvant precision medicine clinical trial. This study will uncover mechanisms associated with lineage plasticity and early signatures of treatment resistance, enabling refinement of future precision medicine approaches.