Garrett M. Brodeur Laboratory
Led by Garrett M. Brodeur, MD researchers in the Brodeur Laboratory are focused on identifying the major genes, proteins and oncogenic pathways that are responsible for the malignant transformation and disease progression of neuroblastomas. The ultimate goal of the research conducted in this laboratory is to develop targeted cancer therapies to treat pediatric neuroblastomas that are more effective and less toxic than current neuroblastoma treatment options.
Ongoing studies in the Brodeur laboratory have shown that receptor tyrosine kinases (RTKs) play a role in the tumorigenesis of neuroblastomas. For example, receptor tyrosine kinase A (TrkA), which binds nerve growth factor (NGF), is frequently expressed on neuroblastomas that are associated with low-risk, better-outcome disease. In contrast, receptor tyrosine kinase B (TrkB), which binds brain-derived neurotrophic factor (BDNF), is over expressed on high-risk, treatment refractory neuroblastomas. Current research is aimed at elucidating the differences between TrkA and TrkB with the ultimate goal of using this knowledge to identify and develop targeted TrkB inhibitors to treat high-risk neuroblastomas.
In related studies, members of the Brodeur Laboratory are actively screening potential Trk inhibitors in neuroblastoma cell lines and animal models of disease. Two effective, low toxicity inhibitors of neuroblastoma have been identified (Entrectinib, LOXO-101). Currently, Entrectinib is being evaluated in a clinical trial as treatment for refractory neuroblastomas and other solid tumors that over express receptor tyrosine kinases.
Other studies in the Brodeur Laboratory on focused on elucidating the contribution of CHD5, a gene located on the distal portion of the short arm of chromosome 1, to the pathogenesis of high-risk neuroblastoma. Genomic analyses of children with neuroblastoma revealed that the short arm of chromosome 1 is frequently absent in high risk neuroblastomas. CHD5 was recently identified as an important tumor suppressor gene that maps to this region. Indeed, CHD5 functions as a tumor suppressor gene in a number of common adult cancers, in addition to neuroblastoma. New studies have been initiated to understand the molecular mechanisms by which CHD5 contributes to neuroblastoma tumorigenesis.
Additional studies, in collaboration with Dr. Michael Chorny, are focused on development of novel nanocarrier-based drug delivery strategies for tumor-targeted delivery of cancer drugs to treat neuroblastoma. Using ultra small-sized (<100nm) biodegradable particles containing an experimental cancer drug, these investigators were able to deliver 100 times the amount of drug to the tumor compared to the same dose given orally. As a result, they were able to induce long-term remissions (with no systemic toxicity) in mouse models of neuroblastoma. Different families of potent anticancer agents are currently being evaluated in the nanocarrier delivery system as potential new treatments for high-risk neuroblastomas.
Dr. Brodeur is also the Director of the Cancer Predisposition Program at CHOP. He is organizing an International Workshop on Pediatric Cancer Predisposition, sponsored by the American Association for Cancer Research (AACR). This workshop of thought leaders in the field from around the world will develop position papers for the major cancer predisposition syndromes affecting children. The papers will contain the major manifestations of the disorder, the genes known to be responsible, the relative cancer risk in children and adolescents (up to 20 years old), and the recommended cancer surveillance protocols for patients with these disorders.
Future studies will focus on targeted agents (e.g., TRK inhibitors) and targeted drug delivery using nanomedicines. Dr. Brodeur will also expand efforts to identify patients with heritable cancer predisposition and perform cancer surveillance protocols in order to detect tumors early when they should be more easily curable.