Targeting and Mechanistic Insights Underlying N-Myc Driven Neuroendocrine Prostate Cancer

About Targeting and Mechanistic Insights Underlying N-Myc Driven Neuroendocrine Prostate Cancer
  • Prostate tumors that express neuronal developmental markers can arise after the treatment of advanced prostate cancers with androgen deprivation therapy and are associated with an extremely poor prognosis and resistance to androgen receptor-targeting therapies.
  • Dr. Rickman and team are studying the roles of two proteins, N-MYC and Aurora-A, in prostate tumors with neuronal features and the clinical relevance of targeting these genes as a therapeutic strategy in these patients.
  • N-MYC is an oncogene that collaborates with Aurora-A to promote tumor growth. Both N-MYC and Aurora-A are overexpressed in prostate tumors following the acquisition of neuronal features, leading to the hypothesis that these proteins work together to drive this tumor phenotype.
  • The mechanisms by which N-MYC and Aurora-A drive prostate tumors with neuronal features will be determined by examining the genes that they regulate together and the effect of inhibiting Aurora-A on the function of N-MYC.
  • Usp proteins are hypothesized to be involved in interactions between N-MYC and Aurora-A. The team will test whether any Usp proteins are required for N-MYC functions in order to identify alternate molecules that can be therapeutically targeted to block this oncogenic pathway.
  • Finally, samples from a clinical trial evaluating the efficacy of the Aurora-A inhibitor MLN8237 will be examined to validate the clinical relevance of N-MYC/ Aurora-A in human prostate tumors with neuronal features. Whether N-MYC activity in tumors correlates with the presence of the neuronal phenotype, clinical responses to MLN8237, and lack of responses to the androgen receptor-targeting therapies, abiraterone or enzalutamide, will be determined.

What this means for patients: Prostate tumors that express markers of neuronal development represent a highly aggressive, treatment-resistant subtype of prostate cancer that can arise after androgen deprivation therapy. Dr. Rickman and team are studying the role of two genes, N-MYC and Aurora-A, in regulating the phenotype of these tumors, and how to therapeutically target these genes. If successful, this study will lead to new understandings of how this subtype develops and credential new treatment strategies for patients with this aggressive prostate cancer subtype.

Principal Investigator:

David Rickman, PhD (Weill Cornell Medical College)

Co-investigators:

Bernard Eilers, PhD (University of Wuerzburg); Mark Rubin, MD (Weill Cornell Medical College); Himisha Beltran, MD (Weill Cornell Medical College); Olivier Elemento, PhD (Weill Cornell Medical College); Myriam Kosai, MD (Weill Cornell Medical College)