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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA165995-01A1
Application #
8516641
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (J1))
Project Start
2013-06-05
Project End
2018-05-31
Budget Start
2013-06-05
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$317,283
Indirect Cost
$36,093
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
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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; Manchanda, Parmeet K et al. (2013) RAC1: an emerging therapeutic option for targeting cancer angiogenesis and metastasis. Mol Cancer Ther 12:1925-34