Therapeutic Strategies for MYCN-Amplified Neuroblastoma
Abstract
Scientific Objective and Rationale: Our proposal has the potential to advance one of the Fiscal Year 2015 Peer Reviewed Cancer Research Program Topic Areas -- Neuroblastoma. This tumor of the nervous system has a poor prognosis that becomes dire when the tumor cells contain several copies of the MYCN gene. Despite intensive treatment that includes chemotherapy, surgery, radiation, and stem cell transplantation, patients with advanced MYCN-amplified neuroblastoma, who account for over half of those with neuroblastoma, have a very low survival rate, and once the tumor relapses, the number of curative treatment options dwindles to zero. To revise this outlook, we are developing a novel treatment strategy for patients with high-risk neuroblastoma that is based on the activity of MYCN in tumor cells. Thus far, we have generated two agents that suppress MYCN expression at different levels and have the potential to eradicate MYCN-amplified neuroblastoma without the risk of serious toxicity: covalent CDK7 inhibitors and conformation disrupting Aurora Kinase A inhibitors. We now propose to test new versions of these inhibitors in laboratory models of high-risk neuroblastoma. In addition to models of newly diagnosed tumors, we plan to study these compounds in a model that mimics relapsed neuroblastoma. Ultimate Applicability of the Research: By tailoring our treatment strategy to specific aspects of the abnormal MYCN gene, we are, in a sense, developing "precision medicine" directed to the key genetic lesion in patients with this high-risk tumor. Demonstration that our new agents can cause decreased tumor growth, or even complete eradication, will be the first step toward moving these agents into Phase 1 trials in patients with MYCN-amplified neuroblastoma. Because any experimental therapy has the potential to induce life-threatening toxicity, we have taken steps to ensure that the compounds selected for clinical testing will have acceptable toxicity profiles in animal models of high-risk neuroblastoma. Importantly, targeted treatments similar to ours are already under investigation by the pharmaceutical industry in adult patients, ensuring rapid transition to pediatric trials of the most promising compounds identified through our research. By the completion of this project (3 years), we anticipate that we will identify at least one if not two compounds from each class of our novel agents that can be taken forward for clinical development and testing. How Our Research Will Benefit Active Duty Service Members, Their Families, and/or other Military Beneficiaries: No child is exempt from developing high-risk neuroblastoma, including those with families serving in the military. Although the diagnosis and treatment of neuroblastoma exact a heavy emotional and financial toll on all families, the impact is likely to be greater in military families, who often have one or more members on active duty. The stresses imposed by prolonged hospital admissions for intensive treatment or its complications and the need to travel far from home to seek specialized care and experimental treatments following relapse cannot be overemphasized. Even among survivors of this disease, the opportunities for military service or jobs in the private sector may be greatly reduced due to the life-long debilitation caused by several side effects that often arise in children treated with radiation and high-dose chemotherapy. These include but are not limited to cardiac disease, stunted growth, hypothyroidism, and hearing loss. This scenario becomes even bleaker when one realizes that pharmaceutical companies have little interest in developing treatments for a childhood disease that offers few prospects of financial compensation, in contrast to adult cancers. Thus, federal funding is the only recourse for addressing the tragically unmet need of developing novel therapies for children with high-risk neuroblastoma. Our novel inhibitors that target t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610251
Entities
People
- William Gustafson
Organizations
- United States Army
- University of California, San Francisco