Molecular biology and genetics of childhood cancer, especially neuroblastoma
Key words: neuroblastoma, MYCN, 1p36 deletion, tumor suppressor gene, CHD5, chromatin remodeling, TrkA, TrkB, Trk inhibitor, Trk signaling, nanotechnology.
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.
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)
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)
- Professor of Pediatrics at University of Pennsylvania School of Medicine (1993– present)
- M.D., Washington University (1975)
- B.A., Chemistry, St. Louis University (1971)
- 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. Vol 16(5) . 2010 Mar:1478-85.
- 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. Vol 100(9) . 2009 May:1471-82.
- 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. Vol 27(2) . 2009 Jan:289-97.
- 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. Vol 27(2) . 2009 Jan:298-303.
- 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. Vol 455(7215) . 2008 Oct:930-5.
- 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. Vol 100(13) . 2008 Jul:940-9.
- 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. Vol 6(5) . 2008 May:735-42.
- 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. Vol 26(6) . 2008 Feb:913-8.
- 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. Vol 66(12) . 2006 Jun:6050-62.