Neuroblastoma is an important pediatric cancer as it contributes disproportionately to childhood disease-related morbidity and mortality. We have recently discovered that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. This project will extend our work focused on the overriding hypothesis that ALK is a critical neuroblastoma oncogene and that activation of this cell surface kinase is a tractable therapeutic target. We propose three Specific Aims to validate this hypothesis and extend this work towards new therapeutic strategies in the clinic. First, we will characterize the full spectrum and frequency of germline and somatic DNA alterations (mutation, amplification, translocation) leading to ALK activation using a fully annotated set of 1500 sporadic neuroblastoma tumors obtained at diagnosis, all with available matched germline DNA, and a large set of human neuroblastoma derived cell lines. Second, we will identify the functionally relevant ALK mutations that contribute to the neuroblastoma oncogenic phenotype and examine how these mutations differentially activate downstream signaling pathways. We will determine the malignant transforming properties of all mutations identified in Aim 1 by forcibly over expressing ALK mutants to neural crest-derived retinal pigment epithelial cells (RPE1). To understand the mechanism for malignant transformation, we will survey the downstream signaling pathways activated in ALK mutant and wild-type cells. Finally, we will determine the varying sensitivity of different ALK mutations to pharmacologic inhibition, work that should provide the impetus for developing therapeutic strategies aimed at inhibiting ALK-mediated signaling in the clinic. Preclinical evaluations of anti-tumor efficacy will be designed to quickly develop the rationale necessary to move discoveries in this project to early Phase clinical trials in children with neuroblastoma.
Neuroblastoma remains a challenging childhood health problem as our attempts to cure more patients has resulted in only very modest improvements in cure rates, but with the associated cost of extensive morbidity in survivors. Our work discovering the genetic etiology of human neuroblastoma provides the first evidence for oncogenic activation of ALK via mutation of the kinase domain. This project will result in important steps forward in developing rational therapeutic strategies aimed at inhibiting ALK- mediated signaling for this often-devastating childhood cancer.
|Wood, Andrew; Krytska, Kateryna; Ryles, Hannah T et al. (2016) Dual ALK and CDK4/6 inhibition demonstrates on-target synergy against neuroblastoma. Clin Cancer Res :|
|Krytska, Kateryna; Ryles, Hannah T; Sano, Renata et al. (2016) Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma. Clin Cancer Res 22:948-60|
|MossÃ©, Yael P (2016) Anaplastic Lymphoma Kinase as a Cancer Target in Pediatric Malignancies. Clin Cancer Res 22:546-52|
|Infarinato, Nicole R; Park, Jin H; Krytska, Kateryna et al. (2016) The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma. Cancer Discov 6:96-107|
|Bresler, Scott C; Weiser, Daniel A; Huwe, Peter J et al. (2014) ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell 26:682-94|
|MossÃ©, Yael P; Lim, Megan S; Voss, Stephan D et al. (2013) Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study. Lancet Oncol 14:472-80|
|Carpenter, Erica L; MossÃ©, Yael P (2012) Targeting ALK in neuroblastoma--preclinical and clinical advancements. Nat Rev Clin Oncol 9:391-9|
|Carpenter, E L; Haglund, E A; Mace, E M et al. (2012) Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma. Oncogene 31:4859-67|
|Light, Jennifer E; Koyama, Hiroshi; Minturn, Jane E et al. (2012) Clinical significance of NTRK family gene expression in neuroblastomas. Pediatr Blood Cancer 59:226-32|
|Devoto, Marcella; Specchia, Claudia; Laudenslager, Marci et al. (2011) Genome-wide linkage analysis to identify genetic modifiers of ALK mutation penetrance in familial neuroblastoma. Hum Hered 71:135-9|
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