Scientists at the Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC–James) report that giving low doses of a particular targeted agent with an oncolytic virus might improve the effectiveness of the virus as a treatment for cancer.

Oncolytic viruses have shown promise in clinical trials for the treatment of brain cancer and other solid tumors. This cell and animal study (“Bortezomib-induced unfolded protein response increases oncolytic HSV-1 replication resulting in synergistic, antitumor effects”) suggests that combining low doses of the drug bortezomib with a particular oncolytic virus might significantly improve the ability of the virus to kill cancer cells during oncolytic virus therapy. The research is published in the journal Clinical Cancer Research.

“These findings pave the way for a treatment strategy for cancer that combines low doses of bortezomib with an oncolytic virus to maximize the efficacy of the virus with little added toxicity,” said principal investigator Balveen Kaur, Ph.D., professor and vice chair of research, department of neurological surgery and radiation oncology, and a member of the OSUCCC–James Translational Therapeutics Program. “Because bortezomib is already approved by the Food and Drug Administration, a clinical trial could be done relatively quickly to test the effectiveness of the drug-virus combination.”

Bortezomib inhibits the activity of proteasomes, structures in cells that break down and recycle proteins. Dr. Kaur noted that blocking these “cellular recycling plants” activates a cellular stress response and increases the expression of heat shock proteins. This reaction, which can lead to bortezomib resistance, makes the cells more sensitive to oncolytic virus therapy with little additional toxicity.

For this study, Dr. Kaur and colleagues used a herpes simplex virus-type 1 oncolytic virus—HSV-1 (oHSV), 34.5ENVE.

“Combination treatment with bortezomib and oHSV, 34.5ENVE, displayed strong synergistic interaction in ovarian cancer, head & neck cancer, glioma, and malignant peripheral nerve sheath tumor (MPNST) cells. Bortezomib treatment induced ER stress, evident by strong induction of Grp78, CHOP, PERK, and IRE1α (Western blot analysis) and the [unfolded protein response] (induction of hsp40, 70, and 90),” wrote the investigators. “Bortezomib treatment of cells at both sublethal and lethal doses increased viral replication (p value <0.001), but inhibition of Hsp90 ablated this response, reducing viral replication and synergistic cell killing. The combination of bortezomib and 34.5ENVE significantly enhanced antitumor efficacy in multiple different tumor models in vivo."

According to the scientists, “The dramatic synergy of bortezomib and 34.5ENVE is mediated by bortezomib-induced UPR and warrants future clinical testing in patients.”

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