Our Mission
The Brodeur lab focuses on understanding the molecular pathogenesis of neuroblastoma, a common childhood tumor, and utilizing this information for better patient management. The primary goal of the lab is to identify the major genes, proteins and pathways responsible for malignant transformation, maintaining the malignant state, and contributing to aggressive tumor behavior. The molecular profiling of neuroblastomas at the DNA, RNA and ultimately the protein levels should provide a more complete picture of each individual tumor and allow for the most accurate prediction of risk. This information should lead to the most appropriate selection of therapy, so that patients are neither undertreated nor overtreated. Patient profiling can identify individuals who are more susceptible to particular toxicities from certain therapies. Perhaps more importantly, the molecular profiling of tumors should identify critical targets to which novel therapies can be directed. These biologically based therapies should be more effective and less toxic than conventional chemotherapeutic agents.
Dr. Brodeur first identified deletion of the distal short arm of chromosome 1 as a characteristic feature of human neuroblastomas (Brodeur, Cancer 1977; Brodeur, Cancer Res. 1981). His group has continued to refine the map of the most commonly deleted region of 1p in neuroblastomas to subbands of 1p36 (White, PNAS 1995; White, Oncogene 2005). His laboratory is currently pursuing the positional cloning of the tumor suppressor gene (TSG) that is deleted from this region. He has narrowed the region of consistent deletion to about 1 megabase, which contains approximately 24 genes. He has characterized several of these genes in detail, and he is using structural and functional approaches to determine which is likely to be the neuroblastoma TSG. Furthermore, Dr. Brodeur has collaborated with Dr. John Maris to show that 1p deletion is a genetic predictor of poor outcome in neuroblastoma patients (Maris, Cancer Res. 1995; Maris, JCO 2000).
Dr. Brodeur played an integral role in the discovery of MYCN amplification in primary neuroblastomas and the association of MYCN amplification with advanced stages of disease and a poor prognosis (Brodeur, Science 1984; Seeger, NEJM 1985). His group also physically mapped the MYCN amplicon and demonstrated that MYCN is the only commonly expressed gene (Schneider, MCB 1992; Reiter, Genomics, 1996; Reiter, GCC 1998). He subsequently demonstrated that MYCN amplification and 1p deletion are associated with each other and characterize the most aggressive subset of neuroblastomas (Fong, PNAS 1989). Drs. Brodeur, White and Maris also played critical roles in describing the prevalence and significance of 11q and 14q deletions (Guo, Oncogene 1999; Thompson, MPO 2001). These two genetic features are associated with each other and characterize a subset of patients with intermediate prognosis that is genetically distinct from those with 1p deletion and MYCN amplification. Moreover, Dr. Brodeur has proposed a genetic evolutionary scheme that incorporates the above and other information to describe the relationship among tumors with good, intermediate and poor prognosis. From the clinical perspective, this information helps to predict outcome and select the appropriate intensity of therapy of patients with neuroblastoma (Brodeur, Nature Rev. Cancer 2003).
A remarkable feature of neuroblastomas is their propensity to spontaneously regress in infants (less than one year of age), or to mature into a benign ganglioneuromas. Alternatively, most tumors diagnosed over 1 year of age have unresectable or metastatic tumors that are very difficult to treat. Dr. Brodeur has determined that the Trk family of neurotrophin receptors probably plays a critical role in these disparate behaviors. He showed that TrkA, the receptor for nerve growth factor (NGF) is expressed on the majority of localized, favorable neuroblastomas, particularly from infants (Nakagawara, Cancer Res. 1992; Nakagawara, NEJM 1993; Eggert, Cancer Res. 2002). Trk-A expressing neuroblastoma cells placed in culture with NGF will differentiate, stop growing and can be kept alive for months. Conversely, the same cells in culture but deprived of NGF will undergo apoptosis (Nakagawara, EJC 1997). This behavior and response to the absence or presence of NGF recapitulates the spontaneous regression or differentiation of neuroblastomas in patients. In the former case, a lack of NGF in their microenvironment probably leads to developmentally programmed cell death and the spontaneous regression of the tumor. TrkA-expressing tumors that differentiate into a benign ganglioneuromas probably do so in response to NGF and other neurotrophic factors provided in their microenvironment. TrkC is also expressed in favorable neuroblastomas, and these tumors represent a subset of the TrkA expressing neuroblastomas (Yamashiro, Oncogene 1996).
Dr. Brodeur's group demonstrated that the most aggressive neuroblastomas, particularly those with MYCN amplification, express TrkB and its ligand brain-derived neurotrophic factor (BDNF) (Nakagawara, MCB 1994). Because these tumor cells also express and secrete the ligand, this presumably represents an autocrine survival pathway that leads to enhanced survival. He has also shown that the TrkB/BDNF pathway promotes tumorigenesis, angiogenesis and drug resistance, contributing significantly to the aggressive phenotype of these tumors (Eggert, MPO 2001; Ho, Cancer Res. 2002).
Currently, Dr. Brodeur is testing a Trk-specific tyrosine kinase (TK) inhibitor from Cephalon Inc. called CEP-701. This small molecule can block the autophosphorylation and subsequent signaling of Trk receptors, leading to apoptosis of Trk-expressing tumors in vitro as well as in vivo in a xenograft model (Evans, Clin. Cancer Res.1999; Evans, MPO 2001). He has collaborated with Dr. Maris to introduce this Trk TK inhibitor into clinical trials through a neuroblastoma clinical consortium. This represents the first example of a biological pathway identified as a potential target for neuroblastomas, and a specific, biologically-based agent that targets that pathway introduced into a clinical trial.