Our laboratory is focused on studying neuroblastoma, an embryonically derived pediatric tumor of the peripheral sympathetic nervous system. We are interested in the following general areas: 1) identifying molecular targets that can be translated into novel therapies in metastatic neuroblastoma, and 2) unraveling the genetic perturbations that occur during development of the sympathetic nervous system and underlie neuroblastoma initiation and progression.

We identified activating, somatic mutations in the ALK tyrosine kinase receptor in neuroblastoma that are sensitive to small molecule inhibitors. Our laboratory is currently investigating mechanisms of ALK receptor activation and regulation in this disease with the ultimate goal of developing strategies to inhibit ALK-driven pathways. The anti-apoptotic role of the activated ALK kinase is an active area of investigation in our laboratory.

A second focus of the laboratory is exploring ways of inhibiting deregulated MYCN, an oncogenic transcription factor that is frequently amplified in high-risk neuroblastoma, by targeting pathways that are synthetic lethal to its function. These studies stem from the finding that mutated ALK accelerates MYCN-induced neuroblastoma by activating key signaling cascades and that combined inhibition of ALK and downstream signaling leads to tumor regression and prolongation of survival.

Thirdly, we are studying the early perturbations that occur during sympathetic neuronal development, specifically focusing on mutant ALK and PHOX2B, both of which have been observed in familial neuroblastoma. Native ALK is mainly expressed in the developing central and peripheral nervous systems and is thought to function as a dependence receptor to trigger apoptosis. Using ALK-driven transgenic animal models that develop neuroblastoma and those that are deficient in ALK, we are dissecting the early molecular changes that occur during tumorigenesis. The effects of PHOX2B mutations on neuronal differentiation and alterations in protein-protein interaction networks are also being investigated.

The translational research program in our laboratory integrates cancer biology, pre-clinical drug development and clinical trials targeting molecular aberrations in neuroblastoma. Our laboratory research has informed the design and implementation of clinical trials for relapsed neuroblastoma and other solid tumors.