Identification of proteins interacting with ALK in neuroblastoma.

Neuroblastoma is a tumor of the peripheral sympathetic nervous system that accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastoma, prevalent in the majority of patients, is rapidly progressive and even with intensive chemotherapy relapse is common. Therefore, novel strategies that exploit genetic alterations in this aggressive cancer need to be sought.  We have reported previously unknown mutations that affect key portions of the ALK gene and indicate that ALK has potential as a novel therapeutic target in neuroblastoma. We also found that neuroblastoma cells with the oncogenic ALK mutations are sensitive to small molecule inhibitor compounds and that most of the neuroblastoma cell lines harboring oncogenic ALK mutations are dependent on the mutated ALK gene for survival. To understand more about the role of ALK in neuroblastoma, we plan to identify proteins interacting with ALK using a high-throughput genetic screen utilizing binding proteins in human genome. Once these interacting proteins are identified from the screen, the interactions will be verified in human neuroblastoma cell lines. Furthermore, a series of assays in cell lines will be conducted to investigate the roles these proteins play in neuroblastoma.  The overall goal of this project is to find genes and pathways that are regulated by these ALK mutations. This will lead to an understanding of the mechanisms responsible for the uncontrolled proliferation and acquisition of cancer-like properties by cells with mutant ALK and also provide additional targets against which to devise new therapies for neuroblastoma.