Garrett M. Brodeur

faculty photo
Professor of Pediatrics
Pediatrician, The Children's Hospital of Philadelphia
Program Director, Child Health Research Career Development Award (CHRCDA) Institutional K12 Training Grant, The Children's Hospital of Philadelphia
Program Director, National Research Service Award (NRSA) Institutional T32 Training Grant, The Children's Hospital of Philadelphia
Associate Director for Pediatric Research, Abramson Cancer Center
Director, Cancer Predisposition Program, The Children's Hospital of Philadelphia
Chair, Pediatric Research Advisory Committee, The Children’s Hospital of Philadelphia
Department: Pediatrics

Contact information
The Children's Hospital of Philadelphia
Division of Oncology, 3018 CTRB
3501 Civic Center Boulevard
Philadelphia, PA 19104-4302
Office: (215) 590-2817
Fax: (215) 590-3770
Graduate Group Affiliations
B.A. (Chemistry)
St. Louis University, 1971.
Washington University, 1975.
University of Pennsylvania (Honorary), 1993.
Permanent link

Description of Research Expertise

Research Interests
Molecular biology and genetics of childhood cancer, especially neuroblastoma; pediatric cancer predisposition and surveillance

Key words: neuroblastoma, MYCN, 1p36 deletion, tumor suppressor gene, CHD5, chromatin remodeling, TrkA, TrkB, Trk inhibitor, Trk signaling, nanoparticle drug delivery, ALK, cancer predisposition

Description of Research
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.

Rotation Projects
1. Confirm role of CHD5 in forming a NuRD-type chromatin remodeling complex
2. Determine the proteins and chromatin modifications that regulate CHD5 expression
3. Identify the genes that are regulated by CHD5 (negatively or positively) using ChIP-Seq or microarray expression profiling
4. Assess the consequences of knocking out CHD5 on normal development and on tumor predisposition
5. Investigate differences between TrkA and TrkB structure, phosphorylation in response to ligand, protein associations, signaling and gene regulation
6. Study the effects of Trk inhibition by small molecules or downstream signaling inhibitors on neuroblastoma survival and growth, in vitro and in vivo
7. Explore the use of nanotechnology to deliver conventional chemotherapy, biologically targeted agents, and regulators of gene expression (shRNA, RNAi)

Lab personnel
Venkatadri Kolla, PhD Sr. Research Associate;
Tiangang Zhuang, PhD Research Associate;
Mayumi Higashi, MD-PhD Research Associate;
Haiyan Xiao, BS Research Technician;
Koumudi Naraparaju Student (Drexel);
Jane E. Minturn, MD-PhD Assistant Professor;
Radhika Iyer, PhD Research Associate;
Jennifer L. Mangino, MD Heme-Onc Fellow;
Anisha M. Simpson, BS Research Associate;
Jee-Hye Choi Student (Penn)

Description of Itmat Expertise

My lab has been focused on identifying the genes, proteins and pathways responsible for malignant transformation and progression of human neuroblastoma. We are also interested in developing more effective, less toxic therapy for neuroblastoma and other pediatric solid tumors. We have identified several genes that play critical roles in this regard, including MYCN gene amplification, CHD5 deletion and epigenetic inactivation, and germline ALK activation in hereditary neuroblastoma. We also identified the importance of TrkA in favorable neuroblastoma and TrkB in unfavorable neuroblastoma. We provided the preclinical data to launch phase 1 clinical trials for two TRK inhibitors, Lestaurtinib and Entrectinib. Finally, we have collaborated with Dr. Michael Chorny and colleagues to formulate and test novel nanoparticle drug delivery vehicles that are highly effective in animal models.

Going forward, my lab will focus in two areas: 1) development and testing of novel nanomedicines o treat pediatric (and adult) solid tumors; and 2) genes responsible for pediatric cancer predisposition. We will formulate and test novel nanomedicines using both biocompatible polymeric nanoparticles (NPs) and single-component, multivalent nanomedicines. We will test prodrug and codrug constructs that enhance hydrophobicity and NP retention, as well as single component nano medicines that have greater tumor penetration. We will first test in animal models of neuroblastoma (flank xenograft, orthotropic, transgenic), as well as animal models of sarcomas and brain tumors. We will identify and characterize novel genes involved in pediatric cancer predisposition. We will also explore genotype-phenotype correlations, epigenetic modifications that affect penetrance and expressly, and optimize cancer surveillance protocols.

Selected Publications

Iyer Radhika, Evans Audrey E, Qi Xiaoxue, Ho Ruth, Minturn Jane E, Zhao Huaqing, Balamuth Naomi, Maris John M, Brodeur Garrett M: Lestaurtinib enhances the antitumor efficacy of chemotherapy in murine xenograft models of neuroblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 16(5): 1478-85, Mar 2010.

Ambros P F, Ambros I M, Brodeur G M, Haber M, Khan J, Nakagawara A, Schleiermacher G, Speleman F, Spitz R, London W B, Cohn S L, Pearson A D J, Maris J M: International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. British journal of cancer 100(9): 1471-82, May 2009.

Cohn Susan L, Pearson Andrew D J, London Wendy B, Monclair Tom, Ambros Peter F, Brodeur Garrett M, Faldum Andreas, Hero Barbara, Iehara Tomoko, Machin David, Mosseri Veronique, Simon Thorsten, Garaventa Alberto, Castel Victoria, Matthay Katherine K, : The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27(2): 289-97, Jan 2009.

Monclair Tom, Brodeur Garrett M, Ambros Peter F, Brisse Hervé J, Cecchetto Giovanni, Holmes Keith, Kaneko Michio, London Wendy B, Matthay Katherine K, Nuchtern Jed G, von Schweinitz Dietrich, Simon Thorsten, Cohn Susan L, Pearson Andrew D J, : The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27(2): 298-303, Jan 2009.

Mossé Yaël P, Laudenslager Marci, Longo Luca, Cole Kristina A, Wood Andrew, Attiyeh Edward F, Laquaglia Michael J, Sennett Rachel, Lynch Jill E, Perri Patrizia, Laureys Geneviève, Speleman Frank, Kim Cecilia, Hou Cuiping, Hakonarson Hakon, Torkamani Ali, Schork Nicholas J, Brodeur Garrett M, Tonini Gian P, Rappaport Eric, Devoto Marcella, Maris John M: Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455(7215): 930-5, Oct 2008.

Fujita Tomoyuki, Igarashi Jun, Okawa Erin R, Gotoh Takahiro, Manne Jayanthi, Kolla Venkatadri, Kim Jessica, Zhao Huaqing, Pawel Bruce R, London Wendy B, Maris John M, White Peter S, Brodeur Garrett M: CHD5, a tumor suppressor gene deleted from 1p36.31 in neuroblastomas. Journal of the National Cancer Institute 100(13): 940-9, Jul 2008.

Cole Kristina A, Attiyeh Edward F, Mosse Yael P, Laquaglia Michael J, Diskin Sharon J, Brodeur Garrett M, Maris John M: A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene. Molecular cancer research : MCR 6(5): 735-42, May 2008.

Schneiderman Jennifer, London Wendy B, Brodeur Garrett M, Castleberry Robert P, Look A Thomas, Cohn Susan L: Clinical significance of MYCN amplification and ploidy in favorable-stage neuroblastoma: a report from the Children's Oncology Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26(6): 913-8, Feb 2008.

Wang Qun, Diskin Sharon, Rappaport Eric, Attiyeh Edward, Mosse Yael, Shue Daniel, Seiser Eric, Jagannathan Jayanti, Shusterman Suzanne, Bansal Manisha, Khazi Deepa, Winter Cynthia, Okawa Erin, Grant Gregory, Cnaan Avital, Zhao Huaqing, Cheung Nai-Kong, Gerald William, London Wendy, Matthay Katherine K, Brodeur Garrett M, Maris John M: Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy number. Cancer research 66(12): 6050-62, Jun 2006.

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Last updated: 11/07/2017
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