Targeting DNA Repair and Survival Signaling in Diffuse Intrinsic Pontine Gliomas to Prevent Tumor Recurrence

Authors

Monika Sharma
Ivana Barravecchia
Robert Teis
Jeanette Cruz
Rachel Mumby
Elizabeth K Ziemke
Carlos E Espinoza
Varunkumar Krishnamoorthy
Brian Magnuson
Mats Ljungman
Carl Koschmann
Joya Chandra
Christopher E Whitehead
Judith S Sebolt-Leopold
Stefanie Galban

Publication Date

1-3-2024

Journal

Molecular Cancer Therapy

Abstract

Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. On the basis of these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrated that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Because radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of Ataxia Telangiectasia Mutated to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG. Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease.

Keywords

Humans, Child, Mice, Animals, Diffuse Intrinsic Pontine Glioma, Neoplasm Recurrence, Local, DNA Repair, Signal Transduction, DNA, Brain Stem Neoplasms

Comments

Supplementary Materials

PMID: 37723046