The outcome of the research proposed here will be to define the use of a new set of drugs against a newly defined molecular target in neuroblastoma. Molecularly targeted therapeutics have been very successful for treatment of several other cancers, notable examples being the use of Gleevec in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST), of Iressa and Tarceva in non-small cell lung cancer (NSCLC), of Sutent in renal cell carcinoma (RCC), and Herceptin and Tykerb in breast cancer. Our goal is to define a similar approach for successfully treating neuroblastoma, a deadly childhood cancer.

Key to this approach is the recent discovery in the Partnering Principal Investigator's (PI's) laboratory that a gene called ALK is mutated in many cases of neuroblastoma. The ALK gene codes for a molecule that is in the same family as the targets for Gleevec, Sutent, Iressa, etc. This is exciting, because it opens the possibility of developing a Gleevec-like drug for neuroblastoma. Defining how to attack neuroblastoma effectively in this way is the primary goal of this proposal.

We combine the expertise of a pediatric oncologist who is an expert in understanding hereditary predisposition and progression of neuroblastoma (Dr. Mossé) with a structural biologist/biochemist who is an expert in understanding mechanisms of molecules like the ALK gene product (Dr. Lemmon). Dr. Mossé will analyze neuroblastomas for the type of ALK mutations found, and Dr. Lemmon's studies will determine how these mutations cause the ALK gene product to become activated inappropriately. Together, the two PIs will also analyze how ALK mutations affect signaling to promote cell growth. There are several ALKtargeted inhibitors that are in clinical development for other diseases. Dr. Lemmon will use structural approaches to determine how these drugs block ALK activity and, in turn, will determine which drugs will be most effective for which mutated forms of ALK. With this combination of approaches, we will link the occurrence of ALK mutations in neuroblastoma to a molecular understanding of how best to reverse their tumorigenic consequences.

Neuroblastoma remains a devastating clinical problem, and continues to be a leading cause of childhood cancer morbidity and mortality despite dramatic increases in chemoradiotherapy. Through the research proposed here, we will determine how to apply Gleevec-like ALK inhibitors to patients with ALK-dependent neuroblastomas, leading to a change in the standard of care for these patients.