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.
|Dowless, Michele; Lowery, Caitlin D; Shackleford, Terry et al. (2018) Abemaciclib Is Active in Preclinical Models of Ewing Sarcoma via Multipronged Regulation of Cell Cycle, DNA Methylation, and Interferon Pathway Signaling. Clin Cancer Res 24:6028-6039|
|Gross, Amy C; Cam, Hakan; Phelps, Doris A et al. (2018) IL-6 and CXCL8 mediate osteosarcoma-lung interactions critical to metastasis. JCI Insight 3:|
|Saraf, Amanda J; Fenger, Joelle M; Roberts, Ryan D (2018) Osteosarcoma: Accelerating Progress Makes for a Hopeful Future. Front Oncol 8:4|
|Bandyopadhyay, Abhik; Favours, Edward; Phelps, Doris A et al. (2018) Evaluation of patritumab with or without erlotinib in combination with standard cytotoxic agents against pediatric sarcoma xenograft models. Pediatr Blood Cancer 65:|
|Waters, Andrew M; Ozkan-Dagliyan, Irem; Vaseva, Angelina V et al. (2017) Evaluation of the selectivity and sensitivity of isoform- and mutation-specific RAS antibodies. Sci Signal 10:|
|Zhou, Xinhui; Liu, Weijin; Hu, Xing et al. (2017) Regulation of CHK1 by mTOR contributes to the evasion of DNA damage barrier of cancer cells. Sci Rep 7:1535|
|Yu, Peter Y; Gardner, Heather L; Roberts, Ryan et al. (2017) Target specificity, in vivo pharmacokinetics, and efficacy of the putative STAT3 inhibitor LY5 in osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. PLoS One 12:e0181885|
|Jayabal, Panneerselvam; Houghton, Peter J; Shiio, Yuzuru (2017) EWS-FLI-1 creates a cell surface microenvironment conducive to IGF signaling by inducing pappalysin-1. Genes Cancer 8:762-770|
|Murphy, Brendan; Yin, Han; Maris, John M et al. (2016) Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis. Cancer Res 76:5798-5809|
|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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