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

• Published in: Molecular cancer therapeutics 2024-01, Vol.23 (1), p.24-34
• Main Authors: Sharma, Monika, Barravecchia, Ivana, Teis, Robert, Cruz, Jeanette, Mumby, Rachel, Ziemke, Elizabeth K, Espinoza, Carlos E, Krishnamoorthy, Varunkumar, Magnuson, Brian, Ljungman, Mats, Koschmann, Carl, Chandra, Joya, Whitehead, Christopher E, Sebolt-Leopold, Judith S, Galban, Stefanie
• Format: Article
• Language: English
• Subjects: Animals; Brain Stem Neoplasms - drug therapy; Brain Stem Neoplasms - genetics; Brain Stem Neoplasms - pathology; Child; CNS Cancers; Diffuse Intrinsic Pontine Glioma - drug therapy; Diffuse Intrinsic Pontine Glioma - genetics; Diffuse Intrinsic Pontine Glioma - metabolism; DNA - therapeutic use; Dna Damage And Repair; DNA Repair; Drug Targets; Humans; Mice; Neoplasm Recurrence, Local; Signal Transduction; Small Molecule Agents; Small Molecule Therapeutics
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-23-0026

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.