Suppression of antiviral innate immunity by sunitinib enhances oncolytic virotherapy.

Abstract

The use of lytic viruses to preferentially infect and eliminate cancer cells while sparing normal cells is a promising experimental therapeutic approach for treating cancer. However, the efficacy of oncolytic virotherapy is often limited by two innate immunity pathways, the protein kinase PKR and the 2'-5'-oligoadenylate (OAS)/RNase L systems, which are widely present in many but not all tumor cell types. Previously, we reported that the anticancer drug, sunitinib, an inhibitor of VEGF-R and PDGF-R, has off-target effects against both PKR and RNase L. Here we show that combining sunitinib treatments with infection by an oncolytic virus, vesicular stomatitis virus (VSV), led to the elimination of prostate, breast, and kidney malignant tumors in mice. In contrast, either virus or sunitinib alone slowed tumor progression but did not eliminate tumors. In prostate tumors excised from treated mice, sunitinib decreased levels of the phosphorylated form of translation initiation factor, eIF2-α, a substrate of PKR, by 10-fold while increasing median viral titers by 23-fold. The sunitinib/VSV regimen caused complete and sustained tumor regression in both immunodeficient and immunocompetent animals. Results indicate that transient inhibition of innate immunity with sunitinib enhances oncolytic virotherapy allowing the recovery of tumor-bearing animals.

• Authors: Babal K Jha, Beihua Dong, Carvell T Nguyen, Irina Polyakova, Robert H Silverman
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 21 Issue 9 Pg. 1749-57 (Sep 2013) ISSN: 1525-0024 [Electronic] United States
• PMID: 23732991 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indoles
• Pyrroles
• eIF-2 Kinase
• Endoribonucleases
• 2-5A-dependent ribonuclease
• Sunitinib

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Renal Cell (pathology, therapy)
• Cell Line, Tumor
• Combined Modality Therapy
• Endoribonucleases (antagonists & inhibitors, metabolism)
• Female
• Immunity, Innate (drug effects)
• Indoles (administration & dosage, pharmacology)
• Kidney Neoplasms (pathology, therapy)
• Male
• Mammary Neoplasms, Experimental (pathology, therapy)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Oncolytic Virotherapy
• Oncolytic Viruses (immunology, metabolism, physiology)
• Prostatic Neoplasms (pathology, therapy)
• Pyrroles (administration & dosage, pharmacology)
• Sunitinib
• Vesiculovirus (genetics, physiology)
• eIF-2 Kinase (antagonists & inhibitors, metabolism)