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000167615 1001_ $$00000-0001-7703-475X$$aChan, Tiffany S Y$$b0
000167615 245__ $$aThrombospondin-1 mimetics are promising novel therapeutics for MYC-associated medulloblastoma.
000167615 260__ $$aOxford$$bOxford University Press$$c2021
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000167615 520__ $$aMedulloblastoma (MB) comprises four subtypes of which group 3 MB are the most aggressive. Although overall survival for MB has improved, the outcome of group 3 MB remains dismal. C-MYC (MYC) amplification or MYC overexpression which characterizes group 3 MB is a strong negative prognostic factor and is frequently associated with metastases and relapses. We previously reported that MYC expression alone promotes highly aggressive MB phenotypes, in part via repression of thrombospondin-1 (TSP-1), a potent tumor suppressor.In this study, we examined the potential role of TSP-1 and TSP-1 peptidomimetic ABT-898 in MYC-amplified human MB cell lines and two distinct murine models of MYC-driven group 3 MBs.We found that TSP-1 reconstitution diminished metastases and prolonged survival in orthotopic xenografts and promoted chemo- and radio-sensitivity via AKT signaling. Furthermore, we demonstrate that ABT-898 can recapitulate the effects of TSP-1 expression in MB cells in vitro and specifically induced apoptosis in murine group 3 MB tumor cells.Our data underscore the importance of TSP-1 as a critical tumor suppressor in MB and highlight TSP-1 peptidomimetics as promising novel therapeutics for the most lethal subtype of MB.
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000167615 650_7 $$2Other$$aAKT
000167615 650_7 $$2Other$$aMYC
000167615 650_7 $$2Other$$aPI3K
000167615 650_7 $$2Other$$aTSP-1
000167615 650_7 $$2Other$$amedulloblastoma
000167615 7001_ $$aPicard, Daniel$$b1
000167615 7001_ $$aHawkins, Cynthia E$$b2
000167615 7001_ $$aLu, Mei$$b3
000167615 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b4$$udkfz
000167615 7001_ $$0P:(DE-He78)8d9c904a6cea14d4c99c78ba46e41f93$$aKorshunov, Andrey$$b5$$udkfz
000167615 7001_ $$aRoussel, Martine F$$b6
000167615 7001_ $$aWechsler-Reya, Robert J$$b7
000167615 7001_ $$aHenkin, Jack$$b8
000167615 7001_ $$aBouffet, Eric$$b9
000167615 7001_ $$aHuang, Annie$$b10
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