Pediatric high-grade gliomas (pHGGs) are some of the most aggressive brain tumors, responsible for over 40% of all childhood tumor-related deaths. Although the molecular landscape of pHGG has been characterized, pHGG lack effective molecular targeted therapies. The epidermal growth factor receptor (EGFR), a common oncogenic driver in cancer, is amplified or mutated in two out of four specific subsets of pHGGs: those characterized by histone 3 (H3) and isocitrate dehydrogenase (IDH) wild-type status plus diffuse midline gliomas, particularly when bithalamic. However, it has previously been unknown whether aberrant EGFR can be successfully targeted pharmacologically to help treat pHGGs.

In the first study of its kind, we tested the anti-tumor activity of ERAS-801, a highly brain-penetrant EGFR inhibitor developed by our laboratory in a patient-derived orthotopic xenograft mouse model of H3/IDH wild-type pHGG with EGFR amplification. Excitingly, we observed that mice treated with ERAS-801 demonstrated both dramatically slower tumor growth and >100% longer survival (median survival of over 60 days) compared to vehicle-treated mice (median survival less than 25 days). Furthermore, treatment with ERAS-801 affords better tumor control than radiation, and combining ERAS-801 with radiation demonstrates a synergistic effect on tumor control and mouse survival.

These preliminary data have led us to hypothesize that EGFR inhibition predominantly slows down the growth of pHGGs with EGFR alterations and that the exquisite sensitivity seen of pHGGs in response to ERAS-801 stems from high apoptotic priming (i.e., proximity to the apoptotic cliff). We intend to use ERAS-801 as a meaningful treatment strategy for H3/IDH wild-type pHGGs and diffuse midline gliomas with EGFR alterations. Strong preliminary data indicate a role for EGFR inhibition by ERAS-801 for treating pHGGs that harbor EGFR amplification or mutations, thus serving as both an adjunct to radiation or as an alternative treatment option entirely. Accordingly, our work can allow patients to avoid the neurotoxicity of radiation at a young age and even provide those who are too young for radiation with life-prolonging therapy.