The constitutive activation of Signal Transducer and Activator of Transcription 3 (STATS) is frequently detected in cell lines and patient samples of the three most frequently occurring childhood sarcomas, rhabdomyosarcoma, osteosarcoma, and Ewing's sarcoma. Constitutive STAT3 signaling participates in tumorigenesis by stimulating cell proliferation, mediating immune evasion, promoting angiogenesis, and conferring drug resistance. The central hypothesis of this project is that constitutive STATS signaling is required and critical for survival and tumorigenesis in these childhood sarcomas and as such, inhibition of STATS activity represents a viable approach for therapeutic intervention. This hypothesis is supported by our data demonstrating that a dominant negative form of STATS, STATS small interfering RNA (siRNA), and the small molecule allosteric STATS inhibitor LLL12 can inhibit proliferation and induce apoptosis of childhood sarcoma cell lines. We have developed an analog of LLL12, LY5, that exhibits several advantages including enhanced specificity for STATS, increased potency as evidenced by biologic activity at lower drug concentrations, greater solubility and predicted oral bioavailability, and a simpler method for synthesis. The objectives of this proposal are to build on these initial findings and identify the signals responsible for STATS activation in childhood sarcomas, and evaluate the efficacy of LY5 using a combination of studies with tumor cell lines, mouse models of childhood sarcomas (xenografts, orthotopic tumors and metastatic tumors), and a canine model of spontaneous osteosarcoma. Our long-term objective is to use combined therapy of a STATS-selective inhibitor with iGF-1R (Project 3) and NF-kappa B (Project 1) inhibitors and ultimately improve outcome for childhood sarcomas. The following specific aims will be studied: 1) Investigate the molecular mechanisms responsible for STATS activation in sarcoma cells;2) Evaluate the inhibitory efficacy of the novel STATS-selective small molecular inhibitor, LY5 on sarcoma cells in vitro and mouse sarcoma models in vivo;and 3) Determine the biologic activity and clinical toxicities of STATS inhibition in spontaneous canine osteosarcoma.
Constitutive activation of STATS is frequently detected in childhood sarcomas and blocking STATS activity inhibits tumor cell growth in vitro and suppresses tumor growth in mouse xenograft models. Constitutive STATS signaling is crucial to the survival of sarcoma cells and may serve as a therapeutic target. Therefore, the evaluation of targeted STATS therapy is relevant and significant to the childhood sarcoma treatments.
|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|
|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|
|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|
|Cam, Maren; Gardner, Heather L; Roberts, Ryan D et al. (2016) ?Np63 mediates cellular survival and metastasis in canine osteosarcoma. Oncotarget 7:48533-48546|
|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|
|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|
|Studebaker, Adam; Bondra, Kathryn; Seum, Star et al. (2015) Inhibition of MEK confers hypersensitivity to X-radiation in the context of BRAF mutation in a model of childhood astrocytoma. Pediatr Blood Cancer 62:1768-74|
|Forest, Amelie; Amatulli, Michael; Ludwig, Dale L et al. (2015) Intrinsic Resistance to Cixutumumab Is Conferred by Distinct Isoforms of the Insulin Receptor. Mol Cancer Res 13:1615-26|
|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|
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