Brodeur Laboratory


Current Laboratory Research in the Brodeur Lab Falls into Two Main Areas:

Role of CHD5 in neuroblastoma pathogenesis


Our lab 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). About one-third of all neuroblastomas have deletion of the distal 1p that includes 1p36, and about 80-90 percent of established neuroblastoma cell lines have this deletion. Deletion of 1p36 is strongly associated with MYCN amplification and aggressive tumor behavior. It is independently predictive of event-free survival in neuroblastomas lacking MYCN amplification. Thus, it is likely that one or more tumor suppressor genes (TSGs) reside at this locus, and loss of one or both copies of this gene contributes to the pathogenesis of aggressive neuroblastomas. We have 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). We then used positional cloning approaches to identify the tumor suppressor gene (TSG) that is the target of these deletions (Okawa, Oncogene 2008). We have identified a gene encoding the chromodomain-helicase-DNA-binding protein 5 (CHD5) as the TSG that is deleted from this region (Thompson, Oncogene 2003; Fujita, JNCI 2008). We are currently characterizing the structure and function of CHD5 in forming a chromatin-remodeling complex (Nucleosome Remodeling and Deacetylation, or NuRD), in comparison to the CHD4-NuRD complex. We have shown that low CHD5 expression is associated with 1p deletion and unfavorable outcome, but inactivating mutations of the remaining allele are rare. Our preliminary evidence suggests that the promoter of the remaining allele is methylated, silencing the expression of this gene, but other potential mechanisms of epigenetically silencing gene expression are being pursued.

    Specific Projects:
  • Determine the prevalence, regulation and clinical significance of CHD5 expression in primary neuroblastomas
  • Determine if CHD5 forms a NuRD-type chromatin remodeling complex
  • Determine if CHD5 is regulated by microRNAs
  • Identify the genes that CHD5 regulates using microarray expression profiling
  • Examine the important regulatory domains of the CHD5 promoter
  • Investigate the effect of CHD5 knockout in a mouse model and determine the effect on normal and tumor development
    Supported by:
  • NIH-NCI (R01-CA39771): Molecular Genetic Analysis of Human Neuroblastoma
  • Alex’s Lemonade Stand Innovation Grant: CHD5 Inactivation in Neuroblastomas
    United States Patent:
  • 7,553,659
  • Brodeur, GM
  • June 30, 2009
  • CHD5 encoding nucleic acids, polypeptides, antibodies and methods of use thereof
    Technologies Available for Licensing:
  • CHOP 03/0162 - CHD5, a New Member of the Chromodomain Gene Family, is Preferentially Expressed in the Nervous System
Role of TRK receptors in neuroblastoma behavior (Brodeur, Clin Cancer Res 2009)
TRK Receptors

Neuroblastomas have the propensity to spontaneously regress in infants (less than one year of age), or to mature into a benign ganglioneuroma. Unfortunately, most tumors diagnosed over 1 year of age have unresectable or metastatic tumors that are very difficult to treat. We have determined that the TRK family of neurotrophin receptors probably plays a critical role in these disparate behaviors. TrkA, the receptor for nerve growth factor (NGF), is expressed in the majority of localized, favorable neuroblastomas, particularly from infants (Nakagawara, Cancer Res, 1992; Nakagawara, NEJM, 1993; Eggert, Cancer Res, 2002). TrkA 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, which may depend on the presence or absence of NGF in the tumor microenvironment. TrkC is also expressed in favorable neuroblastomas, and these tumors represent a subset of the TrkA expressing, favorable neuroblastomas (Yamashiro, Oncogene, 1996).

We have also 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. We have also shown that the TrkB/BDNF pathway promotes tumorigenesis, angiogenesis and drug resistance, contributing significantly to the aggressive phenotype of these tumors (Eggert, Cancer Res, 2002; Ho, Cancer Res, 2002). More recently, we began investigating the role of the RET receptor pathway in the survival, growth and differentiation of neuroblastomas. Currently, we are testing a TRK-specific receptor tyrosine kinase (RTK) 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). We have introduced this RTK inhibitor into clinical trials through a neuroblastoma clinical consortium (Minturn, Cancer Chemo Pharmacol, 2011). This represents the first example of a targeted therapy introduced into clinical trial based on preclinical evidence in neuroblastoma.

    Specific Projects:
  • Determine why the consequences of activating TrkA or TrkB in neuroblastomas are different (protein associations, signaling pathways, genes induced, etc.)
  • Examine the consequences of TrkA isoform expression in neuroblastomas
  • Test the utility of TRK receptor inhibitors as targeted therapy of neuroblastoma in animal models and in clinical trials
  • Explore the utility of delivery of receptor tyrosine kinase inhibitors using passively and actively targeted nanoparticles
  • Investigate the role of RET expression and activation in neuroblastoma differentiation, and the interaction between RET and TRK receptors
    Supported by:
  • NIH-NCI (R01-CA94194): Effect of Trk Expression and Inhibition in Neuroblastoma

  • NIH-NCI (P01-CA97323): Biology and Therapy of Human Neuroblastoma
  • V Foundation Innovation Award: Nanoparticle Delivery of TRK Inhibitors in Neuroblastomas
    Technologies Available for Licensing:
  • CHOP 03/0023 - Human Neurotrophic Factor Receptor TrkB