Abstract 3966: Targeting DNA repair and survival signaling in diffuse intrinsic pontine gliomas to prevent tumor recurrence

Abstract

Abstract Therapeutic resistance remains a major obstacle in the successful clinical management of Diffuse Intrinsic Pontine Glioma (DIPG), a high-grade pediatric tumor arising in the brain stem. Currently available therapies do not prevent tumor recurrence in nearly all patients diagnosed with this devastating disease. Innovative combinatorial therapies that penetrate the blood brain barrier and effectively lead to long-term control of tumor growth are desperately needed. Using RNA sequencing, we identified mechanisms of resistance of DIPG to radiotherapy (RT) standard of care. Not surprisingly, RT leads to upregulation of DNA repair and PI3K-mTOR signaling. Our team has rationally designed a brain-penetrant small molecule that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. This molecule, MTX-241F, developed at the University of Michigan, is an excellent candidate to target the compensatory escape mechanisms leading to radioresistance and drug evasion of DIPG. Due to achievement of micromolar levels of MTX-241F in mouse brain tissue, we anticipate that this development candidate will be highly efficacious and considerably more effective than predecessor combination therapies tested against DIPG. Preliminary studies carried out in patient derived DIPG neurospheres show that MTX-241F exhibits promising signs of single agent activity efficacy and radiosensitizing activity in the combination setting. The physiochemical properties of MTX-241F include remarkably high exposure in the brain, indicating efficient blood brain barrier penetrance. Since radiotherapy results in double strand breaks which are repaired by both homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have also tested the combination of MTX-241F with an inhibitor of ATM, to achieve blockade of HR and NHEJ, respectively in the absence or presence of radiotherapy. When the HR blockers were combined with MTX-241F and radiotherapy synthetic lethality was observed in clonogenic assays, providing impetus to explore combination of HR blockers with this novel first-in-class kinase inhibitor and radiotherapy in clinically relevant models of DIPG. In summary, our data provide proof of concept evidence to support the rapid clinical development of MTX-241F for the treatment of DIPG. Future studies have been designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease. Citation Format: Monika Sharma, Rachel Mumby, Varunkumar Krishnamoorthy, Brian Magnuson, Mats Ljungman, Chris Whitehead, Judith Sebolt-Leopold, Stefanie Galban. Targeting DNA repair and survival signaling in diffuse intrinsic pontine gliomas to prevent tumor recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3966.