Studies in this laboratory over the past 20 years have focused on the role of insulin like growth factors (IGFs) in the growth and survival of childhood sarcomas, and more recently on the role of mTOR signaling in these tumors. The mTORC1 (mTOR-raptor) complex plays an important cellular role, integrating growth factor and stress signals to regulate cell cycle progression and survival. Dysregulated IGF and mTORC1 signaling is implicated in cellular transformation and progression of human cancer. As a consequence there are intense efforts to develop IGF-1 receptor inhibitors, and rapamycin analogs that selectively target mTORC1 complexes, as cancer chemotherapeutic agents. During the last period of funding we made two observations that have led to development of Aim 1. We showed that inhibition of mTORC1 by rapamycin induced a prolonged stress response that resulted in apoptosis only in cells lacking functional p53. Thus, potentially identifying a synthetic lethal interaction between mTORC1 and p53 that could be exploited therapeutically. The second observation was that exogenous insulin like growth factors, or high concentrations of insulin, were unique in protecting against rapamycin-induced apoptosis. Thus, the two observations suggest that concomitant inhibition of both mTORC1 and the IGF-1 receptor may result in changing the cellular response to rapamycin from cytostasis to apoptosis. This approach appears to be highly effective against IGF-1-driven osteosarcoma and Ewing sarcoma xenograft models in vivo when rapamycin is combined with an antibody that blocks IGF-1 binding to the receptor. However, the approach is not effective against IGF-2-driven rhabdomyosarcoma (RMS) xenografts. Thus, in Aim 1 we propose a series of experiments in vitro and in vivo to determine whether an antibody that blocks binding of both IGF-1 and IGF-2 to the IGF-1 receptor has a therapeutic advantage for treatment of these sarcomas.
Aims 2 and 3 focus on dysregulation of mTORC1 under conditions of hypoxia or DNA damage, and the consequences of maintained mTORC1 signaling under stress conditions. In `normal'untransformed cells hypoxia or DNA damage rapidly inhibit mTORC1 signaling. In contrast hypoxia does not down regulate mTORC1 signaling in RMS cells that are highly tolerant to hypoxia. We hypothesize that failure to regulate mTORC1 by DNA damage and hypoxia is due to expression of (Np73, a splice variant of TAp73 that acts as a dominant negative against all p53-family members. Our studies propose to map the signaling pathways that regulate mTORC1 under hypoxia and DNA damage, identify how these are dysregulated in RMS cells, and determine the biological consequences of aberrant mTORC1 signaling under these conditions. We speculate that maintenance of mTORC1 signaling protects cells from apoptosis under stress, but at the cost of increasing damage-induced mutations. Potentially, therefore modulating mTORC1 in RMS may enhance their sensitivity to hypoxic stress, and certain cytotoxic drugs that damage DNA, and reduce mutation frequency that leads to drug resistance or tumor progression.
Metastatic rhabdomyosarcoma is fatal for eighty percent of afflicted children and intensive radiation-chemotherapy has not advanced cure rates since 1984. Here we propose a novel strategy to treat metastatic rhabdomyosarcoma, and will test this in non-clinical models. The studies have the potential to radically alter outcome for these children, and reduce the debilitating sequellae of high dose radiation and chemotherapy.
|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|
|Cam, Maren; Bid, Hemant K; Xiao, Linlin et al. (2014) p53/TAp63 and AKT regulate mammalian target of rapamycin complex 1 (mTORC1) signaling through two independent parallel pathways in the presence of DNA damage. J Biol Chem 289:4083-94|
|Shen, Changxian; Oswald, Duane; Phelps, Doris et al. (2013) Regulation of FANCD2 by the mTOR pathway contributes to the resistance of cancer cells to DNA double-strand breaks. Cancer Res 73:3393-401|
|Shen, Changxian; Houghton, Peter J (2013) The mTOR pathway negatively controls ATM by up-regulating miRNAs. Proc Natl Acad Sci U S A 110:11869-74|
|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|
|Bid, Hemant K; London, Cheryl A; Gao, Jin et al. (2013) Dual targeting of the type 1 insulin-like growth factor receptor and its ligands as an effective antiangiogenic strategy. Clin Cancer Res 19:2984-94|
|Bid, Hemant K; Zhan, Jun; Phelps, Doris A et al. (2012) Potent inhibition of angiogenesis by the IGF-1 receptor-targeting antibody SCH717454 is reversed by IGF-2. Mol Cancer Ther 11:649-59|
|Katsumi, Yoshiki; Iehara, Tomoko; Miyachi, Mitsuru et al. (2011) Sensitivity of malignant rhabdoid tumor cell lines to PD 0332991 is inversely correlated with p16 expression. Biochem Biophys Res Commun 413:62-8|
|Cam, Hakan; Easton, John B; High, Anthony et al. (2010) mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1?. Mol Cell 40:509-20|
|Houghton, Peter J (2010) Everolimus. Clin Cancer Res 16:1368-72|
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