Brodeur Laboratory

Garrett M. Brodeur Laboratory

The Focus of the Brodeur Laboratory

The Brodeur lab focuses on understanding the molecular pathogenesis of neuroblastoma, a common childhood tumor, and utilizing this information for better patient management. Our primary goal is to identify the major genes, proteins and pathways responsible for malignant transformation and progression in neuroblastomas. This information, in turn, can be used to predict outcome and select the most appropriate intensity of therapy for patients. Ultimately, we hope to develop therapies that specifically target the proteins and pathways that individual tumors rely on for their survival and aggressive behavior. This in turn should lead to more effective and less toxic therapy for these patients. Also, the approaches we develop for molecular profiling and targeted therapy of neuroblastomas could easily be applied to many other pediatric and adult cancers. We remain focused on the genetics, genomics and epigenetics of neuroblastoma, but also on investigating the expression and function of selected genes play a critical role in neuroblastoma pathogenesis.

Our laboratory first identified amplification of the MYCN proto-oncogene as a change affecting about 20% of all primary neuroblastomas. We also showed the MYCN amplification was predictive of a poor outcome, regardless of age and stage, and this genomic change is now used to risk-stratify patients for different therapeutic intensities (low, intermediate or high), depending on the presence of absence of this feature. We also first identified deletion of distal 1p as a common change in high-risk neuroblastomas. Recently, we identified CHD5 as an important tumor suppressor gene that maps to the region of consistent deletion. Our lab contributed to the identification of 11q deletions as a marker of high-risk neuroblastomas that lacked MYCN amplification. We also collaborated with others at CHOP (Mosse and Maris) to identify ALK as the gene responsible for most cases of heritable neuroblastoma. Thus, we have been at the forefront of molecular profiling of neuroblastomas to identify the genes responsible for neuroblastoma predisposition, as well as identify genetically distinct subsets, and to use this information for risk stratification and therapy selection.

We have also focused on the role of receptor tyrosine kinases (RTKs) that are involved in neuroblastoma pathogenesis. We first demonstrated that high TrkA (NTRK1) expression was associated with younger age, lower stage and favorable outcome. Indeed, the expression of and dependence on TrkA may explain why some neuroblastomas differentiate (into ganglioneuromas) and others spontaneously regress, based on the presence or absence of the TrkA ligand, NGF, in the tumor microenvironment. Conversely, unfavorable neuroblastomas, especially those with MYCN amplification, frequently express TrkB and its ligand, BDNF. This represents an autocrine survival pathway for these tumors. However, in contrast to TrkA, where ligand exposure causes terminal differentiation, the TrkB/BDNF pathway causes neuroblastomas to be more invasive, metastatic, angiogenic and drug resistant. We are now studying novel inhibitors of TRK receptors, and the potential delivery of these and other RTK inhibitors using nanoparticles, in collaboration with Dr. Robert Levy and colleagues in Cardiology at CHOP. We have also begun to investigate the role of the RET receptor pathway in neuroblastoma survival, growth and differentiation.