Abstract:
:Oncolytic viruses constitute a promising therapy against malignant gliomas (MGs). However, virus-induced type I IFN greatly limits its clinical application. The kinase mammalian target of rapamycin (mTOR) stimulates type I IFN production via phosphorylation of its effector proteins, 4E-BPs and S6Ks. Here we show that mouse embryonic fibroblasts and mice lacking S6K1 and S6K2 are more susceptible to vesicular stomatitis virus (VSV) infection than their WT counterparts as a result of an impaired type I IFN response. We used this knowledge to employ a pharmacoviral approach to treat MGs. The highly specific inhibitor of mTOR rapamycin, in combination with an IFN-sensitive VSV-mutant strain (VSV(DeltaM51)), dramatically increased the survival of immunocompetent rats bearing MGs. More importantly, VSV(DeltaM51) selectively killed tumor, but not normal cells, in MG-bearing rats treated with rapamycin. These results demonstrate that reducing type I IFNs through inhibition of mTORC1 is an effective strategy to augment the therapeutic activity of VSV(DeltaM51).
journal_name
Proc Natl Acad Sci U S Aauthors
Alain T,Lun X,Martineau Y,Sean P,Pulendran B,Petroulakis E,Zemp FJ,Lemay CG,Roy D,Bell JC,Thomas G,Kozma SC,Forsyth PA,Costa-Mattioli M,Sonenberg Ndoi
10.1073/pnas.0912344107subject
Has Abstractpub_date
2010-01-26 00:00:00pages
1576-81issue
4eissn
0027-8424issn
1091-6490pii
0912344107journal_volume
107pub_type
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