Although cure rates for childhood cancers have steadily improved, survival rates for sarcoma cancers over the last decade have reached a plateau. For these children with advanced disease, prognosis for a 5- year survival remains dismally low. Eradicating the remaining cases of childhood sarcomas will require additional knowledge of the underlying mechanisms driving advanced disease so as to potentially develop novel therapeutic strategies. The N F - K B signaling pathway is commonly altered in human cancers and shown to contribute to the initiation and progression of tumorigenesis. N F - K B is therefore considered as an attractive therapeutic target in the treatment of solid and hematopoietic cancers and several classes of inhibitor compounds are currently being developed. Our laboratory recently established a link between N F - KB signaling and rhabdomyosarcoma and similar findings were reported in osteosarcoma, suggesting that N F - K B signaling may contribute to the development of childhood sarcomas. How this occurs and whether N F - K B inhibition is efficacious in these tumors is the basis of this proposal. Our published and preliminary data suggest that activation of N F - K B in sarcomas is mediated by the canonical (classical) N F - K B pathway, and that non-canonical (alternative) signaling, which is usually active in normal differentiated tissue, is downregulated in transformed cells. We also show that sarcomas associate with mitochondrial dysfunction. These data are suggestive that sarcomas exhibit a metabolic shift, reminiscent of the Warburg effect. Since we show that alternative N F - K B signaling regulates mitochondria and oxidative phosphorylation through PGC-1 p, while classical NF-KB signaling along with mTOR and STATS coordinate the induction of glycolytic genes, indicate that NF-KB contributes to sarcomagenesis by altering cellular metabolism through promotion of the Warburg effect. To test this hypothesis, the following three specific aims will be performed: 1) Determine the disease relevance of PGC-1 (3 regulation by N F - K B in the Warburg effect;2) Elucidate the significance of N F - K B crosstalk with mTOR, STATS in altering metabolism of sarcomas, and 3) Test the therapeutic benefit of inhibiting classical N F - K B in mouse models of sarcomas. Results from these studies, and those described in separate projects of this P01 application, are likely to yield significant mechanistic insight into the therapeutic benefit of targeting NF-KB for the treatment of childhood sarcomas.

Public Health Relevance

Constitutive signaling of N F - K B is associated with a number of solid and hematopoietic cancers, but less is known for childhood sarcomas, where for the more aggressive cases there is no cure. Data in rhabdomyosarcomas indicate that these cancers undergo metabolic alterations. Since metabolic dysfunction may be a driving force of tumorigenesis, studies will determine the relevance of NF-KB as a contributing factor in the metabolic shift in soft tissue cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA165995-02
Application #
8745054
Study Section
Special Emphasis Panel (ZCA1-RPRB-C)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$293,834
Indirect Cost
$33,208
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
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

Showing the most recent 10 out of 22 publications