The ultimate goal of this Program Project is to develop novel therapeutic approaches for advanced childhood sarcoma. While over 70% of children with sarcoma are considered cured, the outcome is still poor for those with advanced or metastatic disease. Specifically, the 5-year event free survival rates are 30 percent or less in children with advanced or metastatic Ewing sarcoma, osteosarcoma or rhabdomyosarcoma and intensive chemo-radiotherapy has not significantly altered this outcome. As additional cytotoxic drugs alone are unlikely to increase cure rates, alternative and complimentary approaches should be explored. This Program centers around three separate but integrated signaling pathways shown to be active in childhood sarcomas. The projects will characterize the interrelationship of these pathways and identify combinatorial inhibitory approaches most likely to yield biologic activity in the clinical setting. Project 1 will define the role of the classicalNF-?B pathway in regulating metabolism of sarcomas through a shift to the glycolytic pathway. Our, and other, data indicate that NF-?B signaling impacts STAT3 signaling and that components of the NF-?B pathways interact with mTOR to modulate cellular metabolism. Project 2 focuses on how STAT3 signaling regulates the proliferation and survival of sarcoma cells, and on the development LY5, a highly selective allosteric inhibitor of STAT3. We show that both NF-?B and IGF signaling pathways regulate STAT3 in sarcoma cells. Project 3 will examine intrinsic and acquired resistance to IGF-targeted therapies with respect to proliferation, survival and angiogenesis. Our data demonstrate that IGF-1 protects against apoptosis induced by mTORC1 inhibition and will explore the role of STAT3 and NF-?B in protection from apoptosis. The Program is supported by three shared resources. Core A (Administration and Biostatistics) coordinates communication, program interactions, and provides a centralized mechanism for biostatistical support. Core B (Xenograft and Cell Line) provides unique mouse models of childhood sarcoma and expertise. And Core C (Comparative Animal Core) supplies expertise in histopatholgy, fresh canine tumor specimens, and access to dogs with spontaneous osteosarcoma for preclinical testing of novel therapeutics.
Dose intensive chemo-radiotherapy has not improved survival for children with advanced or metastatic sarcoma. This Program integrates investigators with expertise in cell signaling, sarcoma biology, medicinal chemistry and pediatric drug development, and incorporates unique models of sarcoma for preclinical testing thereby facilitating the identification of novel therapeutic strategies most likely to impact outcome in childhood sarcoma.
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|Bid, Hemant K; Phelps, Doris A; Xaio, Linlin et al. (2016) The Bromodomain BET Inhibitor JQ1 Suppresses Tumor Angiogenesis in Models of Childhood Sarcoma. Mol Cancer Ther 15:1018-28|
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|Wu, Xiaojuan; Xiao, Hui; Wang, Ruoning et al. (2016) Persistent GP130/STAT3 Signaling Contributes to the Resistance of Doxorubicin, Cisplatin, and MEK Inhibitor in Human Rhabdomyosarcoma Cells. Curr Cancer Drug Targets 16:631-8|
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|Phelps, Doris; Bondra, Kathryn; Seum, Star et al. (2015) Inhibition of MDM2 by RG7388 confers hypersensitivity to X-radiation in xenograft models of childhood sarcoma. Pediatr Blood Cancer 62:1345-52|
|Adamson, Peter C; Houghton, Peter J; Perilongo, Giorgio et al. (2014) Drug discovery in paediatric oncology: roadblocks to progress. Nat Rev Clin Oncol 11:732-9|
|Singh, Mamata; Leasure, Justin M; Chronowski, Christopher et al. (2014) FANCD2 is a potential therapeutic target and biomarker in alveolar rhabdomyosarcoma harboring the PAX3-FOXO1 fusion gene. Clin Cancer Res 20:3884-95|
|Bid, Hemant K; Roberts, Ryan D; Cam, Maren et al. (2014) Ã½Ã½Np63 promotes pediatric neuroblastoma and osteosarcoma by regulating tumor angiogenesis. Cancer Res 74:320-9|
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