Blockade of p53 and Aurora A in Therapy Resistant Neuroblastoma

High-risk MYCN-amplified neuroblastoma is typically responsive to therapy at diagnosis, becoming resistant to chemotherapy/radiation at relapse.  Mirroring human disease, the well established TH-MYCN mouse model of neuroblastoma, developed in our lab, is responsive to conventional chemotherapy.  To cure MYCN-amplified high-risk neuroblastoma, we propose to:

1) Develop mouse models which accurately reflect the genetics and behavior of relapsed, chemotherapy refractory disease. I have developed a drug-resistant version of the TH-MYCN model by crossing it with mice defective in p53, leading to a defective response to chemotherapy, and mirroring a similar defect in resistant childhood disease. I plan to characterize the response of this model to conventional chemotherapy as well as novel, targeted therapies including that described below.
 
2) Develop of novel and clinically tolerable therapies which target drug-resistant neuroblastoma. I propose to use cutting-edge chemistry to direct targeted therapy against the Aurora A protein, known to be critically important both in driving cell growth, and in maintaining high MYCN levels.  I have already generated a new class of Aurora A inhibitors which block both Aurora functions (current drugs only block cell growth) which we predict will have improved activity against MYCN amplified neuroblastoma.