Peptidic Inhibitors of N-myc for Treatment of Neuroblastoma
Abstract
This proposal will target neuroblastoma, a Fiscal Year 2014 Peer Reviewed Cancer Research Program Topic Area. It will address a gap in the treatment of neuroblastoma, thereby contributing to the well-being of military personnel and their beneficiaries. Neuroblastoma is the most common cancer found in children outside of the head and causes ~15% of all childhood cancer deaths. The goal of this project is to generate molecules that can be used as a treatment for neuroblastoma by interfering with the function of a protein called N-myc. N-myc acts like a switch inside cells -- it turns on genes that tell the cell to divide and grow. When left unchecked, this uncontrolled cell growth leads to cancer. It is thought that 20%-40% of neuroblastoma cases have an overabundance of N-myc, and these cases of neuroblastoma typically have the worst prognosis. In this project, we will test the idea that blocking N-myc function will turn off this switch, and by doing so, stop cells from growing and stop neuroblastoma cancers. The novelty in this proposal is not targeting N-myc itself, as N-myc s role in neuroblastoma has been recognized for years. N-myc belongs to a family of proteins called "transcription factors," and although there has been great interest in finding drugs against these transcription factors, drug development efforts have largely failed. These efforts have failed for numerous reasons including that the molecules: (1) cannot block the function of transcription factors, (2) are not stable in the body, or (3) cannot block the function of transcription factors inside the cells. The innovation of this proposal is that we believe that we have a technology to discover molecules that can target these transcription factors by solving these problems simultaneously. In this project, we propose to use our technology to engineer new drug-like molecules against N-myc that can block its function, and as a result, treat neuroblastoma patients. The ultimate goal would be a novel and effective mechanism for treating children with neuroblastoma that could cure their cancers. There are a number of benefits of targeting neuroblastoma with our molecules. First, by directly targeting N-myc, we can test if stopping N-myc s function in the cell would lead to highly effective neuroblastoma treatment. If successful, this project would therefore lay the foundation for further preclinical and eventual clinical studies. Second, by targeting N-myc directly, we avoid possible side effects that could arise from approaches that indirectly target N-myc function. An N-myc specific therapy should only affect cells possessing N-myc, specifically targeting neuroblastoma cells. Third, other types of cancers also have an overabundance of N-myc and the molecules developed here could also find use in treatment of these diseases. Lastly, in a broader context, if our approach in this project is successful, it can be applied and replicated to target other transcription factors that have long been recognized to play critical roles in cancer, leading to more specific and effective chemotherapeutics. The major source of risk for this specific project is that we will be unable to isolate molecules that stop N-myc function inside cells. However, our previous successes in engineering these types of molecules suggest that we should be successful in targeting N-myc. Additionally, we will try several approaches to generate these molecules, increasing the likelihood of success. Even if this project is successful, the path to a new drug typically takes 10-12 years of development and there are multiple risks including the molecule being toxic, generating an immune response, or just not functioning inside a human being. These risks are not unique to our molecules, are often not predictable, and are inherent in any drug development effort. Follow-up projects of testing our molecules in animals will help mitigate some of these risks. However, if t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510175
Entities
People
- Terry Takahashi
Organizations
- United States Army
- University of Southern California