Targeting N-Myc-Driven Castrate-Resistant Prostate Cancer
Abstract
Applicability of the Research: There have been several recent advances in our understanding of advanced prostate cancer. This knowledge has led to the development of new highly potent hormonal therapies (e.g., abiraterone and MDV3100) that are now entering widespread clinical use. However, despite significant responses, all patients ultimately develop resistance. Neuroendocrine prostate cancer (NEPC) does not respond well to hormonal intervention; it frequently metastasizes to visceral organs and carries a poor prognosis with an average survival of less than 1 year. NEPC is a critically important group where no drugs have been shown to have significant improvements for patients and where the average survival is 7 months after diagnosis. Since transformation of NEPC is thought to be accelerated by the use of hormonal therapy, there is concern that with the recent Food and Drug Administration approval of potent androgen receptor (AR)-targeted therapies for the treatment of metastatic prostate cancer, the incidence of AR-negative NEPC will escalate. NEPC is characterized by N-Myc and Aurora-A amplification. Aurora-A and N-Myc associate in NEPC and jointly drive a NEPC-specific gene expression program through a mechanism that has yet to be fully characterized. We will study how N-Myc, together with its targetable co-factor EZH2, induces the neuroendocrine phenotype and regulates its critical downstream targets. We will gain insights of the Aurora-A-mediated N-Myc stability and use this knowledge to identify inhibitors to target N-Myc in NEPC. This proposal has high potential for rapid clinical translation and potential to impact the care of patients with advanced prostate cancer. Findings from this project already led the opening of a Phase 1 clinical trial for EZH2 inhibitors led by our collaborator Dr. H. Beltran. We believe that these important insights on Aurora-A and N-Myc will allow us to develop a novel treatment strategy and combination for men with NEPC and spur the development of potent second-generation compounds to disrupt the Aurora-A/N-Myc complex. Career Goals in Prostate Cancer Research: Dr. Dardenne s long-term scientific interest and goal is to perform translational- and patient-oriented research and translate basic findings in the regulation of oncogenic transcription factors to patient benefits. The proposed research plan will prepare him to make valuable contributions to the understanding of prostate cancer. Dr. Dardenne will greatly benefit by the multidisciplinary and multi-institutional team that will contribute to this project and will develops all the skills which are essential for him of ultimately becoming an independent investigator. Contributions to Advancing the Field of Prostate Cancer Research: This study will also help advance the field of prostate cancer research by improving our understanding of the biologic mechanisms underlying tumor resistance, which will directly lead to the development of new biomarkers and therapeutic strategies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710103
Entities
People
- Etienne Dardenne
Organizations
- United States Army
- Weill Cornell Medicine