Drugging the Aurora Kinase A Interactome in Neuroblastoma
Abstract
Principal Investigator: This award will be essential in supporting Dr. Mukherjee s career goals to become an independent investigator and group leader in oncology pharmacology, with a specific focus on neuroblastoma, which is a Fiscal Year 2018 (FY18) Peer Reviewed Cancer Research Program (PRCRP) Topic Area. As stated in the research development plan, Dr. Mukherjee will complete tutorials in cancer biology, rational drug design, and clinical oncology from her mentors at UCSF to allow her to translate her biochemistry and pharmacology experience toward a career in preclinical drug discovery and development that is directly applicable to the clinic. Scientific Objective, Rationale for Proposed Project, and Clinical Application: The goal of this proposal is to innovate targeted therapeutics for neuroblastoma using small molecule inhibitors. Specifically, we aim to optimize inhibitors that lead to the destruction of a commonly overexpressed protein that drives neuroblastoma called MYCN. The first generation of inhibitors has been shown to not only lead to degradation of MYCN, resulting in neuroblastoma cell death, but also to function by a new mechanism that has yet to be exploited to the full extent. We will optimize these inhibitors to promote the efficacy in killing tumor cells while diminishing the toxic side effects. In addition, we propose to use the compounds to gain mechanistic understanding of how the overexpression of MYCN can affect the expression and regulation of other proteins that may adversely affect the outcome of these cancers. Since CD532 has been licensed to industry for development and clinical trials, the proposed research to understand how CD532 works will directly benefit neuroblastoma patients who will eventually receive CD532 as a treatment. In addition, this proposal aims to understand how cells may become resistant to CD532 after prolonged treatment. Identification of mutations and what biological processes they affect will provide biomarkers that can be measured in patients during CD532 treatment. Currently, preclinical tests are ongoing in preparation for clinical trials with which should begin in one year. This study will advance neuroblastoma research and patient care as we develop a first-in-class inhibitor for MYCN-driven disease. Benefit for Military Beneficiaries: Because of the potential broad applicability across cancers beyond neuroblastoma (the FY18 PRCRP topics which would have significant benefit for the children of military Service members and Veterans), these studies also have repercussions across an array of pediatric cancers and adult cancers that are driven by the MYC transcription factors. This study will fill critical gaps in treatment, which are directly relevant to military families, Veterans, and active duty Service members.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910275
Entities
People
- Sucheta Mukherjee
Organizations
- United States Army
- University of California, San Francisco