TY  - JOUR
AU  - Chan, Tiffany S Y
AU  - Picard, Daniel
AU  - Hawkins, Cynthia E
AU  - Lu, Mei
AU  - Pfister, Stefan
AU  - Korshunov, Andrey
AU  - Roussel, Martine F
AU  - Wechsler-Reya, Robert J
AU  - Henkin, Jack
AU  - Bouffet, Eric
AU  - Huang, Annie
TI  - Thrombospondin-1 mimetics are promising novel therapeutics for MYC-associated medulloblastoma.
JO  - Neuro-oncology advances
VL  - 3
IS  - 1
SN  - 2632-2498
CY  - Oxford
PB  - Oxford University Press
M1  - DKFZ-2021-00462
SP  - vdab002
PY  - 2021
AB  - Medulloblastoma (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.
KW  - AKT (Other)
KW  - MYC (Other)
KW  - PI3K (Other)
KW  - TSP-1 (Other)
KW  - medulloblastoma (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:33629064
C2  - pmc:PMC7890793
DO  - DOI:10.1093/noajnl/vdab002
UR  - https://inrepo02.dkfz.de/record/167615
ER  -