Rani George Lab
The George laboratory seeks to 1) identify molecular targets that can be translated into novel therapies in the pediatric solid tumor neuroblastoma and 2) unravel the genetic perturbations that occur during development of the sympathetic nervous system and underlie neuroblastoma initiation and progression. Following our discovery of activating, inhibitor-sensitive somatic mutations in the ALK tyrosine kinase in neuroblastoma (Nature, 2008), we are investigating mechanisms of ALK activation and regulation, as well as strategies to inhibit ALK that can be employed therapeutically.
A second focus of the laboratory is exploring ways of inhibiting deregulated MYCN in neuroblastoma by targeting pathways that are synthetic lethal to its function. These studies stem from our 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 (Cancer Cell, 2012).
Finally, we are studying the role of the PHOX2B transcription factor, which is mutated in hereditary neuroblastoma, during development of the sympathetic nervous system. Studies include the effects of PHOX2B mutations on neuronal differentiation and protein-protein interaction networks of wild-type and mutated PHOX2B. The translational research program in the laboratory integrates cancer biology, high throughput analysis of human tumor samples and pre-clinical drug development. Our laboratory findings have informed the design and implementation of past and on going clinical trials for relapsed neuroblastoma and other solid tumors.