TMOD-19. Determining mechanisms that drive PPM1D-mutant specific vulnerabilities and resistance in DMG

Diffuse Midline Gliomas (DMGs) are universally fatal pediatric brain tumors. The current standard of care is radiation therapy, which provides only a transient benefit. The genetic landscape of DMG has revealed mutual exclusivity between TP53-mutant and PPM1D-mutant tumors, likely due to functional redundancy. While both TP53 and PPM1D mutations participate in DMG formation, different mechanisms of p53 pathway suppression may present unique therapeutic opportunities. We hypothesize that PPM1D-mutant tumors retain a suppressed yet functional p53 which can be reactivated under therapy stress. Targeting other complementary pathways and PPM1D-specific targets could help attain better overall outcomes. Moreover, PPM1D-mutant tumors frequently co-occur with sub-clonal PI3K pathway activating mutations leading to our hypothesis that they help accelerate tumorigenesis and confer therapy resistance. To investigate this, we have generated isogenic DMG IUE mouse models of Trp53-mutant, PPM1D-mutant, and PIK3CA-mutant (in the context of both Trp53- and PPM1D-mutant) to uncover shared and unique functions of these mutations. Ongoing studies are aimed to elucidate the differential response to radiation therapy using a combination of in vitro assays and transcriptomic profiling in each condition. We aim to test whether Trp53- and PPM1D-mutant DMG models display differences in response to CHK1 inhibition, which is a direct target of PPM1D phosphatase activity and regulator of DNA damage response and cell cycle progression. Similarly, experiments are focused on the use of PI3K/AKT/mTOR inhibitors, examining their in vitro and in vivo ability to improve response to DNA damaging agents in PPM1D-mutant DMGs. We expect to reveal PPM1D and PIK3CA specific targets that can be pursued to improve the outcomes for PPM1D-mutant DMG patients. This will help strategize specific targeted therapeutic approaches in combination with radiation to better treat PPM1D-mutant DMGs.