Despite major modifications in therapy over the last few decades, the long-term cure rate in children with advanced neuroblastoma, a tumor of the sympathetic nervous system, is still far from satisfactory. We recently discovered activating somatic mutations in the ALK receptor tyrosine kinase gene in primary neuroblastomas. Neuroblastoma cells harboring ALK mutations were found to be dependent on mutant ALK for their survival and were exquisitely sensitive to inhibition by small molecule compounds. The central hypothesis of this proposal is that ALK, when activated by certain mutations, can sustain the growth and survival of neuroblastoma cells and thus could provide a novel "druggable" target in patients with high-risk neuroblastoma. The applicant, who is a New Investigator, will test this hypothesis by addressing key issues that are fundamental to validating a potential drug target, to identifying secondary targets to enhance the effects of ALK inhibition, and to developing methods to prevent or forestall drug resistance. Both in vitro and in vivo models will be utilized in these studies.
Aim 1 tests the prediction that ALK mutations can be either passengers or drivers and that only drivers leading to kinase activation will be sensitive to pharmacological inhibition. It also seeks to identify novel, highly selective ALK kinase inhibitors with potent activity in ALK-driven neuroblastoma cells.
Aim 2 will pursue preliminary evidence that the PI3K/PTEN/AKT and the RAS/ERK pathways serve as the principal downstream signaling pathways triggered by mutant ALK and that combined inhibition of these pathways, together with ALK, would enhance the cytotoxicity of targeted therapy directed to neuroblastoma cells.
Aim 3 tests whether resistance to ALK kinase inhibitors emerges in ALK-driven NB cells because of mutations within the kinase itself or aberrant activation of genes that induce resistance by usurping the signaling pathways normally employed by mutant ALK. The long-term goal of this proposal is to develop novel therapeutic options from insights into ALK-mediated transformation that can be tested in early phase trials in children with high-risk neuroblastoma.!

Public Health Relevance

Neuroblastoma is the most common extracranial solid tumor of children, and the leading cause of cancer deaths in children 1-4 years of age. We have recently discovered critical mutations in the tyrosine kinase receptor, ALK, in neuroblastoma tumors that provide a novel focus for targeted therapy. This proposal seeks to further characterize these mutations, to test inhibitor compounds directed against ALK and its downstream signaling pathways, and to decipher the mechanisms of resistance to ALK inhibitors with the ultimate goal of developing drugs that may improve the survival of children with this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA148688-04
Application #
8598861
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Arya, Suresh
Project Start
2011-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2014
Total Cost
$326,813
Indirect Cost
$140,063
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Moore, Nathan F; Azarova, Anna M; Bhatnagar, Namrata et al. (2014) Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma. Oncotarget 5:8737-49
Chipumuro, Edmond; Marco, Eugenio; Christensen, Camilla L et al. (2014) CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell 159:1126-39
Jamin, Yann; Glass, Laura; Hallsworth, Albert et al. (2014) Intrinsic susceptibility MRI identifies tumors with ALKF1174L mutation in genetically-engineered murine models of high-risk neuroblastoma. PLoS One 9:e92886
Azarova, Anna M; Gautam, Gargi; George, Rani E (2011) Emerging importance of ALK in neuroblastoma. Semin Cancer Biol 21:267-75