Children with disseminated neuroblastoma have a very high risk of treatment failure and death despite receiving greatly intensified chemotherapy, underscoring the need to design novel molecular therapies for this disease, which constitutes the long-term goal of our proposal. However, recent efforts to discover promising molecular targets in this aggressive pediatric malignancy have revealed a very low somatic mutation rate, and the majority of high-risk tumors do not harbor druggable oncogenic proteins activated by somatic mutations, demonstrating that personalized therapeutic strategies will require insights well beyond those afforded by resequencing tumor DNA alone. This multiple principal investigator project will build on our recent genome- wide association study (GWAS) discovery of a robust genetic association at the LMO1 gene locus, which encodes a LIM-domain-only (LMO) transcriptional cofactor. Together, our published and unpublished preliminary data support a major oncogenic role for LMO1 in the most aggressive subset of neuroblastomas, and suggest the following central hypothesis: LMO1 is required for the initiation and maintenance of the malignant phenotype in a substantial subset of high-risk neuroblastoma cases. We propose to test this original concept in two integrated Specific Aims using the multi-PI leadership mechanism to bring together complementary research skills and resources available in the Maris and Look laboratories.
In Aim 1, we will focus on how polymorphisms at the LMO1 locus alter regulatory mechanisms of the LMO1 gene in developing sympathetic nervous system cells to promote the initiation of neuroblastoma using genetic and epigenetic approaches in human-derived tissues and genome editing in the zebrafish model system.
In Aim 2, we will focus on the mechanism by which LMO1 overexpression is somatically deregulated during malignant neuroblastic clonal evolution, and will seek to discover the key cellular networks that maintain the highly proliferative and metastatic phenotype characteristic of neuroblastomas high levels of LMO1 expression. The innovation of this project resides in the combined use of robust human (epi)genetic approaches with a novel and highly manipulable zebrafish model of neuroblastoma to address a fundamental problem with high clinical relevance. Our results will establish the requirement for LMO1 in neuroblastoma initiation, growth and survival. The work proposed here will serve as a roadmap for the investigation of GWAS discoveries in cancer and other human diseases, providing a paradigm for determining their mechanistic and clinical relevance.

Public Health Relevance

The proposed multi-PI research project is relevant to public health because the methods used here to uncover how LMO1 functions as an oncogene in neuroblastoma, based on the integration of genome-wide association and functional genomics experimentation, will be important for the field of cancer research in general, and the pediatric cancer neuroblastoma in particular. The proposed research is highly relevant to the NIH mission and the urgent unmet need of developing rational evidence-based strategies to reduce the health burden of neuroblastoma and other cancers. This approach will also serve as a roadmap for the analysis of the cellular phenotypes and molecular pathways altered by newly discovered susceptibility loci in many types of human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA180692-01A1
Application #
8888225
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mietz, Judy
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zimmerman, Mark W; Liu, Yu; He, Shuning et al. (2018) MYC Drives a Subset of High-Risk Pediatric Neuroblastomas and Is Activated through Mechanisms Including Enhancer Hijacking and Focal Enhancer Amplification. Cancer Discov 8:320-335
Cimmino, Flora; Avitabile, Marianna; Diskin, Sharon J et al. (2018) Fine mapping of 2q35 high-risk neuroblastoma locus reveals independent functional risk variants and suggests full-length BARD1 as tumor-suppressor. Int J Cancer 143:2828-2837
Rajbhandari, Presha; Lopez, Gonzalo; Capdevila, Claudia et al. (2018) Cross-Cohort Analysis Identifies a TEAD4-MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma. Cancer Discov 8:582-599
Zhu, Shizhen; Zhang, Xiaoling; Weichert-Leahey, Nina et al. (2017) LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis. Cancer Cell 32:310-323.e5
Zhang, Xiaoling; Dong, Zhiwei; Zhang, Cheng et al. (2017) Critical Role for GAB2 in Neuroblastoma Pathogenesis through the Promotion of SHP2/MYCN Cooperation. Cell Rep 18:2932-2942
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Oldridge, Derek A; Wood, Andrew C; Weichert-Leahey, Nina et al. (2015) Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism. Nature 528:418-21