Drugging the AXIN/GSK/MYCN Complex through an Allosteric Transition in Aurora Kinase A in Neuroblastoma and Medulloblastoma
Abstract
The cancer-causing genes MYC and MYCN are major causes of the childhood neural tumor neuroblastoma and the pediatric brain tumor medulloblastoma. Until recently, these molecules have been considered undruggable because of their inaccessible biological structure and properties. We recently described a molecule that does indeed target MYCN in neuroblastoma and medulloblastoma tumors through a vulnerable interaction with the Aurora Kinase A molecule. The scientific objectives of the proposed research are to (1) explore the basic biology of neuroblastoma and medulloblastoma through study of known cancer drivers, specifically the molecules MYC, MYCN, Aurora Kinase A, and AXIN; (2) to better understand the mechanism of action of a new class of drugs designed to specifically target MYC and MYCN by acting through intermediary molecules Aurora Kinase A and AXIN. My long-term goal is to continue to develop new therapies to treat the deadly pediatric cancers neuroblastoma and medulloblastoma through efforts, eventually in my own independent lab. Funds from the Department of Defense and the research and career development plan outlined in this proposal will allow further progress towards my chosen goal by providing a fiscal framework and foundation from which to perform these studies. By the end of the funding period, we hope to uncover additional "Achilles heel" interactions with key cancer-causing proteins that we can eventually exploit to generate novel therapies for children with both neuroblastoma and medulloblastoma. Further, since we are studying cancer drivers common to many adult and pediatric tumors, we predict that the knowledge and novel therapies that emerge from these studies will be applicable to a large number of different cancer types. The outlined studies will also lay out additional rationale for further development of CD532, a newly synthesized compound described in our lab this year, which we hope to eventually advance to clinical trials either in its current form or after several rounds of optimization. Military Relevance: Because of the potential broad applicability across cancers beyond medulloblastoma and neuroblastoma (which, as pediatric cancers and Peer Reviewed Cancer Research Program congressionally directed research topics, would have efficacy primarily for the children of military Service members and Veterans), we predict that these studies will also have significant repercussions across an array of MYCN and MYC-driven cancers. These studies will fill critical gaps in treatment that are directly relevant to military families, Veterans, and active duty Service members.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510166
Entities
People
- William Gustafson
Organizations
- United States Army
- University of California, San Francisco