NT-17 * TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) WITH AN ONCOLYTIC MEASLES VIRUS IN COMBINATION WITH INHIBITORS OF THE PI3-KINASE PATHWAY

Abstract

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a highly malignant pediatric brainstem tumor with less than 10% of patients surviving beyond 2 years. Surgical resection of this diffusely infiltrative tumor is not possible, radiation therapy is palliative not curative, and chemotherapy is ineffective. Clearly, more effective therapy for DIPG is necessary. The genomic analyses on tissue samples from biopsy and autopsy have frequently implicated amplification in the PI3K-mTOR pathway signaling in DIPG tumors. The vaccine strain of measles virus (MV) has been shown to be an effective oncolytic therapy in brain tumors in murine xenograft models. METHODS AND RESULTS: Flow cytometry showed that human DIPG cells abundantly express the CD46 receptor on the membrane that is preferentially utilized by MV for cellular entry. MV efficiently infects DIPG cells, replicates in these cells, and causes the formation of multinucleated syncytia. MV kills DIPG cells in dose and time dependent manner with more than 70% cell death observed at MOI of 0.5 after 96hrs. The mTORC1 inhibitor, rapamycin, and the Akt inhibitor, MK2206, individually attenuated the proliferation of DIPG cells (p < 0.05). Importantly, the killing of DIPG cells by MV was synergistically increased when used in combination with rapamycin or MK2206, as determined by the Chou-Talalay equation (synergism if combination index (CI) < 1). The CI values for MV-rapamycin and MV-MK2206 treatments were 0.4 and 0.8 respectively, at EC50. Cells treated with MV in combination with the inhibitor produced 10-times more virus than cells treated with the virus alone. The switch from apoptosis caused by MV alone to autophagy seen when inhibitors are used may be responsible for the increased virus titer. CONCLUSION: Measles virus has therapeutic potential in the treatment of DIPG tumors and the efficacy may be improved by simultaneously targeting the Akt-mTOR pathway.