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2025 Elliot Abramowitz – PCF Young Investigator Award

Mechanisms of RB1-Dependent Epigenomic Regulation of Prostate Cancer Neuroendocrine Plasticity

Rodrigo Romero, PhD          
The University of Texas MD Anderson Cancer Center

Mentors: Charles Sawyers, Julien Sage       

Description:

  • Although survival for patients with prostate cancer has improved due to next-generation androgen receptor signaling inhibitors (ARSIs), many eventually relapse with therapy-resistant disease. An emerging non-mutational mechanism of therapy resistance is lineage plasticity, in which prostate cancer cells lose prostate cell features and gain features of other lineages, most commonly neuroendocrine cells. 
  • Mutations in Retinoblastoma protein 1 (RB1) are strongly associated with both treatment-resistance and lineage plasticity in prostate cancer, allowing tumor cells to resist therapy and transition into neuroendocrine prostate cancer (NEPC). There is a critical need to investigate the mechanisms by which RB1 mutations drive neuroendocrine plasticity in prostate cancer, in order to develop effective treatments for NEPC.
  • Dr. Rodrigo Romero hypothesizes that RB1 loss alters the 3D structure and accessibility of DNA, enabling neuroendocrine plasticity through altered gene expression. 
  • In this project, Dr. Romero will use prostate cancer models to functionally assess how RB1 pathway alterations influence DNA states, gene expression, and the tumor microenvironment, to drive lineage plasticity and neuroendocrine transformation. He will also identify molecular interactors of RB1 to uncover the mechanisms by which RB1 regulates neuroendocrine plasticity at the molecular level.
  • If successful, these studies will define how RB1 alters cellular states that drive lineage plasticity and therapy resistance in prostate cancer and provide clinically relevant insights that can guide the development of new treatment strategies for NEPC. 

What this means to patients: RB1 is a tumor suppressor gene that is commonly lost as prostate cancer progresses, contributing to treatment resistance and the development of the altered tumor subtypes including aggressive NEPC. Dr. Romero’s project will define the molecular impact of RB1 gene alterations on prostate cancer biology and the development of NEPC, and identify new treatment strategies. These findings will enable new treatment paradigms for patients with aggressive prostate cancer and improve clinical outcomes for those who currently lack effective therapeutic options.