Chromatin Regulators in Prostate Cancer

Principal Investigator: 
Nicholas Brady, Ph.D.

Prostate cancer remains the second-leading cause of cancer-related death among American men. Over the past decade, tremendous advances in the understanding and treatment of the disease have led to significant improvements in patient survival. While nearly all patients with advanced prostate cancer respond to androgen deprivation therapy and androgen receptor (AR)-targeted therapies, castration-resistant prostate cancer (CRPC) inevitably develops. Most resistant tumors are dependent on the reactivation of the AR signaling pathway, through AR variants, overexpression, and mutations. However, 10-15% of CRPC tumors display an AR-low, androgen-independent phenotype that acquire alternative lineage programs, including the development of small cell neuroendocrine prostate cancer (NEPC). Shared genomic alterations between NEPC and prostate adenocarcinoma suggest that NEPC tumors arise clonally, however, significant epigenetic deregulation occurs during the transition process. In the last several years, we and others have identified potential drivers of the transition to NEPC, including loss of TP53 and RB1, as well as upregulation of MYCN (encoding the transcription factor N-Myc), EZH2, BRN2, and SOX2. While many recent studies have implicated these as drivers of lineage plasticity and NEPC, there is still much to learn about the downstream molecular and genomic changes that promote the acquisition of the neuroendocrine phenotype and the progression of prostate adenocarcinoma cells to NEPC following AR-targeted therapies.

The Brady Lab seeks to uncover how changes to chromatin states can drive the progression to NEPC and identify novel transcriptional regulators that cooperate with epigenetic changes to promote lineage plasticity. To address these goals, we utilize several different in vitro and in vivo models, including human prostate cancer cell lines, CRPC and NEPC patient-derived organoids, and transgenic mice. By applying next-generation sequencing approaches with single-cell resolution to these different models, we aim to shed light on the mechanistic underpinnings of treatment resistance and the molecular sequence of events underlying progression to NEPC.

Active Projects:

  • Regulation of chromatin states during progression to NEPC
  • Transcription factors that synergize with changes in chromatin accessibility


PI: Nicholas Brady, PhD

PI: Nicholas Brady, PhD

PI: Nicholas Brady, PhD
WCM JumpStart Program

PI: Nicholas Brady, PhD
WCM SPORE in Prostate Cancer Career Enhancement Program

Contact Information

Nicholas Brady, Ph.D.
Instructor in Pathology and Laboratory Medicine
Weill Cornell Medicine
Rockefeller University Campus

1188 York Avenue
Weiss 11th Floor
New York, NY 10065
(646) 962-8372

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700