- The Children's Hospital of Philadelphia
- Innovation Grants
Type of Childhood Cancer:
Neuroblastoma is one of the most common and deadly solid tumors of childhood. Several genetic changes have been identified neuroblastomas that almost certainly contribute to the development or behavior of these tumors. We identified deletion of the short arm of chromosome 1 (1p) as a common and characteristic change of more aggressive neuroblastomas. Deletions in tumors generally suggest that some important tumor suppressor gene (TSG) in the commonly deleted region needs to be removed or inactivated to allow the tumor to develop or to be aggressive. We hypothesize that CHD5 is the likely TSG deleted from 1p36 in neuroblastomas, and deletion or inactivation of CHD5 contributes to neuroblastoma development or behavior. In order to pursue further investigation of this gene and what it does in both normal development and in neuroblastomas, we need to do two things. First, we need to develop antibodies to CHD5 so we can study where the protein is expressed and what the protein does. Because CHD5 is part of a family of related proteins that has at least 9 members, these antibodies need to be able to recognize CHD5 and not cross-react with its closely related family members, CHD3 and CHD4. Second, we need to create a mouse model in which we knock out one copy of CHD5 in the germline of the mice. From this point, we can then study the consequences of missing one copy of the gene on normal development and the development of tumors, including neuroblastoma. We may need to knock out or inactivate both copies of the gene in order to see a full effect, or alternatively, we may need to knock it out only in certain tissues of the developing animal, such as the cells and tissues that give rise to neuroblastomas (sympathetic neurons, adrenal medulla). We propose making a single construct that will allow us to create all these variations. We can also breed these mice with the TH-MYCN transgenic mice to determine if neuroblastoma development is accelerated. The successful completion of these studies will provide sufficient preliminary data that should assure our ability to obtain longer term funding from an R01 research grant from the NIH to complete these and other studies. This in turn should provide a great deal of valuable information to help understand how neuroblastomas develop, what pathways are affected by 1p deletions, how to better subclassify patients to predict outcome, and ultimately how to approach the development of targeted therapy to treat neuroblastomas in a more effective and less toxic way.