Center for Environment-Mediated Drug Resistance in Pediatric Cancer

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The mission of the Center, to be designated the EMDR Center, is to conduct fundamental inquiries on mechanisms responsible for EMDR in order to identify inhibitors of EMDR pathways, to promote their testing in clinical trials in children with ALL and neuroblastoma, and to share the knowledge acquired and the technology developed with the scientific community. Through extensive collaboration, the 7 investigators of the EMDR Center will test the fundamental hypothesis that the bone marrow provides a unique microenvironment for ALL and neuroblastoma cells which allows them to survive the injuries induced by drugs and promotes the establishment of drug-resistant cells that are responsible for disease recurrence and treatment failure. Accordingly, the secondary hypothesis is that blocking specific pathways responsible for EMDR with inhibitors will prevent the emergence of these drug-resistant cells. These hypotheses will be tested through 3 interrelated research projects that will examine 3 specific leading pathways of EMDR in childhood ALL and neuroblastoma. All projects will combine experiments in co-cultures of tumor cell lines and bone marrowderived stromal cells and in murine models. Projects will then validate their observations in bone marrow samples from patients with ALL and neuroblastoma, to be made available through the EMDR Center. The data generated will be used to promote the implementation of phase l/ll clinical trials, to be conducted by 2 pediatric clinical trials consortia headquartered at CHLA. Projects will explore new concepts such as the effects of glycosylation, methylation and tumor microenvironmental fuels on the development of EMDR, generate new mouse models and data sets, and develop new technology in drug screening that will be shared with the scientific community through the NCI-TMEN. Furthermore, the EMDR Center will benefit from closely interacting with several academic entities at CHLA, USC and COH, and at the same time will substantially contribute to expanding their research focus on the tumor microenvironment.