Thrombospondin-1 mimetics are promising novel therapeutics for MYC-associated medulloblastoma.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Tiffany S Y Chan, Daniel Picard, Cynthia E Hawkins, Mei Lu, Stefan Pfister, Andrey Korshunov, Martine F Roussel, Robert J Wechsler-Reya, Jack Henkin, Eric Bouffet, Annie Huang
• Journal: Neuro-oncology advances (Neurooncol Adv) 2021 Jan-Dec Vol. 3 Issue 1 Pg. vdab002 ISSN: 2632-2498 [Electronic] England
• PMID: 33629064 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.