Abstract C150: Targeted inhibition of homologous recombination and nonhomologous end joining in diffuse intrinsic pontine gliomas to prevent tumor recurrence

Abstract

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. Based on 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 demonstrate 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. Since 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 ATM 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. Citation Format: Ivana Barravecchia, Monika Sharma, Robert Teis, Jeanette Cruz, Rachel Mumby, Elizabeth Ziemke, Carlos Espinoza, Brian Magnuson, Mats Ljungman, Carl Koschmann, Christopher Whitehead, Judith Sebolt-Leopold, Stefanie Galban. Targeted inhibition of homologous recombination and nonhomologous end joining in diffuse intrinsic pontine gliomas to prevent tumor recurrence [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C150.