Elucidating the Regional Responses to ONC201 in H3K27M-mutant Pediatric High-grade Glioma
Mentor: Dr. Carl Koschmann
Pediatric brain tumors have become the leading cause of cancer-related deaths among pediatric patients. Diffuse midline gliomas with the H3K27M mutation are associated with poorer prognosis compared to wild type tumors. ONC201 is a bitopic DRD2 antagonist that has shown clinical efficacy in multiple human solid tumors, including anecdotal clinical and radiographic responses in pediatric patients treated with the small molecule (Chi et al., 2019; Hall et al., 2019). Dr. Koschmann and his colleagues began noting that patients with thalamic H3K27M may be having an exceptional response. Given this observation, I began working with Dr. Koschmann and multiple other clinical sites to clarify the efficacy and mechanism of ONC201 in thalamic H3K27M-mutant glioma. I performed an analysis of recurrent and non-recurrent thalamic H3K27M-mutant glioma patients treated with ONC201 on active clinical trials. Median PFS or OS have not been reached for non-recurrent patients with median follow up of 21.9 months (8.6-26.6) from diagnosis, surpassing historical OS of 13.5 months.
These data represent the first evidence of an effective targeted therapy in this patient population, outside of focal radiation. However, the mechanism driving this phenotype has not been established, and no previous work has addressed the impact of dopamine signaling on regional therapeutic response in H3K27M-pHGG. Thus, there is a critical need to determine the mechanism underlying exceptional response to ONC201 in thalamic H3K27M-pHGG patients. In the absence of such knowledge, the ability to maximize ONC201 therapeutic benefit in future trials will be difficult. The goal of my summer research is to establish a mechanistic rationale behind the observed ONC201 efficacy in thalamic patients. Our hypothesis is that microenvironmental dopaminergic signaling in the thalamus contributes to exceptional clinical response. Previous work in HCT116 cells has established that ONC201 induces the integrated stress response in tumor cells and upregulates ATF4, CHOP, and DR5 (Kline et al, 2016).
Effective targeted therapies against H3K27M will help a significant proportion of children/young adults with HGG, especially if leveraged with understanding of the environmental/regional context. Our integrative experimental approach will establish the mechanism behind the phenotypes we have recently discovered and open new windows for therapies targeted to H3K27M-mutant pediatric HGG.
