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.
Cancer is the second most common cause of death among children. Drug resistance is a major roadblock in attempts to increase the cure rate in these patients and a better understanding of the role of the microenvironment in drug resistance will result in the identification of specific targets for intervention. If successful, inhibition of EMDR will provide a new paradigm and result in improved survival not only for children with ALL and neuroblastoma but also for all cancer patients.
|Borriello, Lucia; Seeger, Robert C; Asgharzadeh, Shahab et al. (2016) More than the genes, the tumor microenvironment in neuroblastoma. Cancer Lett 380:304-14|
|Yue, Chanyu; Shen, Shudan; Deng, Jiehui et al. (2015) STAT3 in CD8+ T Cells Inhibits Their Tumor Accumulation by Downregulating CXCR3/CXCL10 Axis. Cancer Immunol Res 3:864-70|
|Bergfeld, Scott A; Blavier, Laurence; DeClerck, Yves A (2014) Bone marrow-derived mesenchymal stromal cells promote survival and drug resistance in tumor cells. Mol Cancer Ther 13:962-75|
|Borriello, Lucia; DeClerck, Yves A (2014) [Tumor microenvironment and therapeutic resistance process]. Med Sci (Paris) 30:445-51|
|Priceman, Saul J; Shen, Shudan; Wang, Lin et al. (2014) S1PR1 is crucial for accumulation of regulatory T cells in tumors via STAT3. Cell Rep 6:992-9|
|Yang, Chunmei; Lee, Heehyoung; Jove, Veronica et al. (2013) Prognostic significance of B-cells and pSTAT3 in patients with ovarian cancer. PLoS One 8:e54029|
|Ara, Tasnim; Nakata, Rie; Sheard, Michael A et al. (2013) Critical role of STAT3 in IL-6-mediated drug resistance in human neuroblastoma. Cancer Res 73:3852-64|
|Yang, Chunmei; Lee, Heehyoung; Pal, Sumanta et al. (2013) B cells promote tumor progression via STAT3 regulated-angiogenesis. PLoS One 8:e64159|
|Xin, Hong; Lu, Rongze; Lee, Heehyoung et al. (2013) G-protein-coupled receptor agonist BV8/prokineticin-2 and STAT3 protein form a feed-forward loop in both normal and malignant myeloid cells. J Biol Chem 288:13842-9|
|Fang, Hua; Declerck, Yves A (2013) Targeting the tumor microenvironment: from understanding pathways to effective clinical trials. Cancer Res 73:4965-77|