DMG-64. PI3 Kinase and Checkpoint Inhibition: A Potentially Novel Therapeutic Strategy for Diffuse Intrinsic Pontine and Diffuse Midline Glioma

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) and Diffuse Midline Glioma (DMG) are rare, fast-growing pediatric brain tumors, with no effective treatments. These tumors are resistant to chemotherapy, radiation, and immunotherapy/checkpoint inhibition. The catalytic subunit of the phosphoinositol 3 kinase (PI3K) is a genetic dependency factor necessary for growth of both DIPG and DMG. GCT-007 is a novel, small molecule PI3K inhibitor developed to inhibit growth of adult glioblastoma (GBM). GCT-007 in combination with the check point drug anti-PD1 has demonstrated significant promise in two mouse models of adult GBM. Our current goal is to create a therapeutic approach that targets anti-tumor response for DIPG. Our hypothesis has been that inhibiting PI3K will cause growth arrest, autophagy, and an increased likelihood of immune recognition. Experimentally, human DIPG lines and mouse GBM were incubated with GCT-007 for at least 48 hours. Cell proliferation was significantly reduced. GBM cells were stained for MHC II, PD-L1, CD74, and CD80, and flow cytometry was used to measure relative increased cell surface expression of each. GCT-007 was compared to other PI3K inhibitors with cells containing either wild type or DIPG/DMG mutant variants of PI3K. GCT-007 decreased DIPG cell viability with IC50’s ranging between 0.7–13.8 μM. and resulted in increased expression of PD-L1, CD74, CD80, and MHCII in GBM. Compared with other PI3K inhibitors (Paxalisib and Buparlisib), GCT-007 showed greater efficacy in inhibiting PI3K and showed an increase in potency. Taken together, these results demonstrate that GCT-007 is potentially an effective, brain penetrate, anti-DIPG therapy that targets the dependence on PI3K. DIPG and DMG are known to lack expression of PD-L1, while GCT-007 treated GBM cells show a dose-dependent increase in PD-L1, CD74, CD80, and MHC II. Thus, combination strategies using immune checkpoint inhibitors and GCT-007 may provide a potent strategy against DIPG/DMG.