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

  • Mol Cancer Ther. 2023 Sep 19. doi: 10.1158/1535-7163.MCT-23-0026.
Monika Sharma  1 ,  Ivana Barravecchia  1 ,  Robert Teis  1 ,  Jeanette Cruz  1 ,  Rachel Mumby  1 ,  Elizabeth K Ziemke  2 ,  Carlos E Espinoza  3 ,  Varunkumar Krishnamoorthy  1 ,  Brian Magnuson  4 ,  Mats Ljungman  5 ,  Carl Koschmann  2 ,  Joya Chandra  6 ,  Christopher E Whitehead  7 ,  Judith S Sebolt-Leopold  2 ,  Stefanie Galban  1
Affiliations
  • 1. University of Michigan Medical School, Ann Arbor, MI, United States.
  • 2. University of Michigan-Ann Arbor, Ann Arbor, MI, United States.
  • 3. University of Michigan-Ann Arbor, Ann Arbor, United States.
  • 4. University of Michigan-Ann Arbor, Ann Arbor, Michigan, United States.
  • 5. University of Michigan-Ann Arbor, Ann Arbor, Mi, United States.
  • 6. The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
  • 7. Mekanistic Therapeutics, Ann Arbor, MI, United States.
PMID: 37723046 DOI: 10.1158/1535-7163.MCT-23-0026
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 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. 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.

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