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.
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.
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