Garrett M. Brodeur

faculty photo
Professor of Pediatrics
Department: Pediatrics
Graduate Group Affiliations

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
Education:
B.A. (Chemistry)
St. Louis University, 1971.
M.D.
Washington University, 1975.
MA
University of Pennsylvania (Honorary), 1993.
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Description of Research Expertise

Research Interests
Molecular biology and genetics of childhood cancer, especially neuroblastoma; Pediatric cancer predisposition and surveillance; Nanoparticle drug delivery

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

Description of Research
Prior Research Interests
Identification of MYCN Amplification as a Prognostic Marker for Neuroblastomas. We first demonstrated that MYCN amplification occurred in about 22% of primary neuroblastomas, and amplification is strongly associated with advanced stage, adverse prognostic factors and poor outcome. This was the first example of an oncogene shown to have prognostic significance in a human cancer, introducing the concept of molecular profiling to predict outcome and tailor the intensity of therapy. Assessment of neuroblastomas for MYCN amplification is currently done throughout the world on all newly diagnosed tumors, and it remains one of the most potent predictors of poor outcome in this disease.

Cloning and Characterization of the Tumor Suppressor Gene, CHD5, Deleted from 1p36. We were the first to identify and clone CHD5, the fifth member of the chromodomain-helicase-DNA binding family, as a candidate tumor suppressor gene deleted from 1p36 in neuroblastomas and possibly other tumors. We showed that high CHD5 expression was strongly associated with favorable prognostic features and outcome. We further demonstrated that CHD5 functioned as a tumor suppressor gene in vitro and in vivo in a mouse xenograft model of neuroblastoma. In addition, we showed that the CHD5 promoter was frequently methylated in tumors with 1p36 deletion, transcriptionally silencing the remaining allele in these tumors. CHD5 likely functions as part of a NuRD-type chromatin remodeling complex. Finally we showed the CHD5 expression was required for normal spermatogenesis and chromatin condensation, regulating the substitution of histone for protamine at stage 9, step 9 of spermiogenesis.

Demonstration of the roles of TrkA and TrkB in Neuroblastoma Behavior. We were the first to demonstrate that TrkA, the receptor for nerve growth factor (NGF), is expressed on most favorable tumors, and the NGF/TrkA pathway may be involved in the spontaneous regression or differentiation seen in favorable NBs, especially in infants. Conversely, TrkB and its primary ligand, brain-derived neurotrophic factor (BDNF), are expressed in many unfavorable NBs, and the autocrine activation of this pathway contributes to aggressive behavior, such as enhanced survival, invasion, metastasis, angiogenesis and drug resistance. Therefore, targeting this pathway with selective Trk receptor inhibitors, alone or in combination with other agents, should be an effective and relatively nontoxic approach to treat aggressive NBs.

Development and implementation of TRK-Targeted Therapy for Neuroblastomas. TrkB and its ligand, BDNF, are overexpressed in over half of high-risk neuroblastomas and contributes to its aggressive phenotype, including invasion, metastasis, angiogenesis and drug resistance. We have worked with several pharmaceutical companies to develop TRK-selective inhibitors as a form of targeted therapy for neuroblastomas. We first developed CEP-701 (Lestaurtinib) as a TRK-selective inhibitor, and our preclinical work (Evans AE et al, Cancer Res, 1999) led to a phase 1 clinical trial in neuroblastomas. Half of the patients receiving a pharmacologically adequate dose had durable responses lasting a mean of 10+ months (some lasting over 2 years) with essentially no clinical toxicity. We are now testing entrectinib and larotrectinib, second-generation TRK inhibitors that far more potent and selective than prior inhibitors we have tested.


Current Research Interests
Nanoparticle (NP) Drug Delivery. We are working closely with Drs. Michael Chorny and Ivan Alferiev at CHOP. Our goal is to develop more effective, less toxic therapy for pediatric cancers, especially solid tumors like neuroblastoma. Although agents targeting specific genes, proteins and pathways are needed, targeted drug delivery could dramatically improve efficacy and decrease toxicity. We are developing several novel approaches for nanoparticle design and formulation. Furthermore, we are using several robust animal models of neuroblastoma (flank, orthotopic, and PDX xenografts; transgenic TH-MYCN mice) for testing nanocarrier formulations. This work has led to two recent publications, demonstrating our successful collaboration to study nanocarrier delivery of a PLA-PEG NP carrying SN38 co-drug with tocopherol succinate. Indeed, we have improved on this formulation, as described in a third paper that has recently been accepted (see below). This proposal extends our efforts to optimize nanocarrier drug delivery by development of single-component, multivalent nanomedicines containing camptothecin derivatives SN38 or SN22 for enhanced delivery of cancer therapeutics to pediatric solid tumors like neuroblastoma and sarcomas.

Cancer Predisposition. I am currently the Director of the Cancer Predisposition Program at CHOP, which fulfills a longstanding interest in pediatric cancer predisposition. My interest began with my interest in neuroblastoma predisposition, which culminated in the identification of activated ALK as the gene responsible for most cases (Mosse, et al. Nature, 2008). As Chair of the AACR Pediatric Cancer Working Group, I organized an international workshop on Pediatric Cancer Predisposition and Surveillance with 65 participants from 11 countries to develop consensus protocols for cancer surveillance for the 60 most common predisposition syndromes. This resulted in 18 publications in Clinical Cancer Research (http://clincancerres.aacrjournals.org/pediatricseries). I am deeply committed to expanding our clinical and research efforts in pediatric cancer predisposition and surveillance, and to make our program at CHOP this space. I am also mentoring two junior faculty at CHOP who have each focused on specific subpopulations of patients with cancer predisposition (Jennifer Kalish and BWS/Overgrowth syndromes, Suzanne MacFarland and GI cancer predisposition syndromes). My lab is interested in the identification of novel cancer predisposition genes, determination of genotype-phenotype associations, development of enhanced surveillance techniques, and identification of epigenetic mechanisms leading to cancer predisposition.


Rotation Projects
1. Explore the use of nanotechnology to deliver conventional chemotherapy, biologically targeted agents, and regulators of gene expression (shRNA, RNAi)
2. Identification of cancer predisposition genes, genotype-phenotype correlations, enhanced cancer surveillance

Lab personnel
Venkatadri Kolla, PhD Sr. Research Associate;
Koumudi Naraparaju, Medical Research Technician;
Peng Guan, Medical Research Technician;
Ferro Nguyen, Medical Research Technician;
Suzanne P. MacFarland, MD, Instructor in Pediatrics (Oncology);
Laren Perry, University of Pennsylvania student/Vagelos program

Description of Clinical Expertise

Dr. Brodeur is Director of the Pediatric Cancer Predisposition Program at CHOP. He Organized the first AACR-sponsored International Workshop on Pediatric Cancer Predisposition and Surveillance in October 2016. He is currently engaged in research to identify novel cancer predisposition genes and syndromes, as well as assess existing genes and syndromes for genotype-phenotype associations.

Selected Publications

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

Ambros P F, Ambros I M, Brodeur GM, 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 GM, 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 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 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 GM, 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 GM: 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 GM, 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 GM, 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 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 GM, 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: 06/06/2018
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