Targeting drivers of tumor heterogeneity to block the progression to neuroendocrine prostate cancer

PROJECT SUMMARY/ABSTRACT
Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the
treatment of men with advanced prostate cancer, acquired resistance ultimately ensues. Lineage plasticity has
been proposed as one mechanism of therapeutic resistance whereby patients with resistant disease develop
AR-negative, androgen signaling-indifferent prostate tumors that lose their luminal identity and display
neuroendocrine features (neuroendocrine prostate cancer, NEPC). While NEPC tumors share many genetic
alterations with prostate adenocarcinoma, the potential drivers of lineage plasticity remain understudied. Using
a novel genetically-engineered mouse model that faithfully recapitulates the transition to NEPC, I have
established an organoid-based allograft platform that is amenable to gene editing technologies. Using single-cell
based approaches, Furthermore, I have identified a previously undescribed tumor subpopulation with a unique
transcriptional regulator that may represent an transition between adenocarcinoma and NEPC. For the proposed
studies, I will modulate the expression levels of the identified transcriptional regulator using CRISPR-based gene
editing or overexpression strategies in prostate organoids and determine how the transition to NEPC is affected.
I will also assess the sensitivity of this tumor subpopulation to clinically-relevant treatment options, including
androgen withdrawal and AR-targeted therapy. Finally, I will reveal how targeting epigenetic modifiers changes
the composition of tumor subpopulations and reverses the development of therapeutic resistance. Alongside
these scientific aims, I will use the period of support to enhance my skillset and develop as an independent
researcher. Through a comprehensive plan, including workshops, course work, clinical case conferences, and
attendance at seminars and scientific conferences, I plan to develop a deeper understanding of bioinformatics
at the single cell level, expand my exposure to critical barriers facing clinicians and prostate cancer patients, and
successfully continue my transition to an independent research position. The environment at Weill Cornell
Medicine, and among its closely aligned neighboring institutions, is ideal for me to complete the proposed studies
and will help foster my continued research and career development success.

Grant Number: 5K22CA269707-02
NIH Institute/Center: NIH
Principal Investigator: Nicholas Brady