Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis.

in Cancer cell by Derek Dang, Akash Deogharkar, John McKolay, Kyle S Smith, Pooja Panwalkar, Simon Hoffman, Wentao Tian, Sunjong Ji, Ana P Azambuja, Siva Kumar Natarajan, Joanna Lum, Jill Bayliss, Katie Manzeck, Stefan R Sweha, Erin Hamanishi, Matthew Pun, Diya Patel, Sagar Rau, Olamide Animasahun, Abhinav Achreja, Martin P Ogrodzinski, Jutta Diessl, Jennifer Cotter, Debra Hawes, Fusheng Yang, Robert Doherty, Andrea T Franson, Allison R Hanaford, Charles G Eberhart, Eric H Raabe, Brent A Orr, Robert J Wechsler-Reya, Brandon Chen, Costas A Lyssiotis, Yatrik M Shah, Sophia Y Lunt, Ruma Banerjee, Alexander R Judkins, John R Prensner, Carl Koschmann, Sebastian M Waszak, Deepak Nagrath, Marcos Simoes-Costa, Paul A Northcott, Sriram Venneti

TLDR

  • This study discovers a previously unknown vulnerability in group-3 medulloblastomas, which can be targeted using a cuproptosis-inducing agent. The findings suggest a potential new treatment approach for this aggressive pediatric brain cancer.

Abstract

MYC-driven group-3 medulloblastomas (MBs) are malignant pediatric brain cancers without cures. To define actionable metabolic dependencies, we identify upregulation of dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenase complex (PDC) in a subset of group-3 MB with poor prognosis. DLAT is induced by c-MYC and targeting DLAT lowers TCA cycle metabolism and glutathione synthesis. We also note upregulation of isocitrate dehydrogenase 1 (IDH1) gene expression in group-3 MB patient tumors and suppression of IDH1 epigenetically reduces c-MYC and downstream DLAT levels in multiple c-MYC amplified cancers. DLAT is a central regulator of cuproptosis (copper-dependent cell death) induced by the copper ionophore elesclomol. DLAT expression in group-3 MB cells correlates with increased sensitivity to cuproptosis. Elesclomol is brain-penetrant and suppresses tumor growth in vivo in multiple group-3 MB animal models. Our data uncover an IDH1/c-MYC dependent vulnerability that regulates DLAT levels and can be targeted to kill group-3 MB by cuproptosis.

Overview

  • This study aims to define actionable metabolic dependencies in group-3 medulloblastomas (MBs), a subset of pediatric brain cancers without cures.
  • Researchers identify upregulation of dihydrolipoyl transacetylase (DLAT) in a subset of group-3 MB with poor prognosis, induced by c-MYC.
  • The study also explores the correlation between DLAT expression and cuproptosis sensitivity in group-3 MB cells, and the potential of cuproptosis inducer elesclomol to suppress tumor growth in vivo.

Comparative Analysis & Findings

  • The study finds that DLAT is induced by c-MYC in group-3 MB and that its overexpression is associated with poor prognosis. The data also demonstrate that IDH1 gene expression is upregulated in group-3 MB patient tumors.
  • Suppression of IDH1 epigenetically reduces c-MYC and downstream DLAT levels in multiple c-MYC amplified cancers, suggesting a regulatory interaction between IDH1 and c-MYC.
  • DLAT expression in group-3 MB cells correlates with increased sensitivity to cuproptosis, a copper-dependent cell death pathway. Elesclomol, a cuproptosis inducer, is brain-penetrant and suppresses tumor growth in vivo in multiple group-3 MB animal models.

Implications and Future Directions

  • The study identifies IDH1/c-MYC dependent vulnerability that regulates DLAT levels, providing a potential therapeutic target for group-3 MB treatment.
  • Future studies should investigate the optimal dosing and administration of elesclomol as a potential treatment for group-3 MB.
  • The study opens up new avenues for exploring the therapeutic potential of cuproptosis-inducing agents in pediatric brain cancers, particularly those with poor prognosis.
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