[Ian]

Low-dose Velcade may improve cancer virus therapy

by Ian on Tue Jun 17, 2014 4:25 am

There's a report out that low doses of Velcade might improve the effectiveness of cancer virus therapy (see below). The research was done, however, in models of brain and head and neck cancer, not multiple myeloma.

Would the findings of this study still apply to cancer virus therapies targeted at multiple myeloma like the one being investigated at the Mayo Clinic?

Here's the press release about the low-dose Velcade study:

Low Dose of Targeted Drug Might Improve Cancer-Killing Virus Therapy

• Viruses designed to kill cancer cells are being used in clinical trials to treat brain cancer and other malignancies.
• This study suggests that combining a particular targeted agent with a cancer-killing virus might improve the virus’s ability to kill cancer cells.
• The findings support the testing of this combination therapy in a clinical trial.

COLUMBUS, Ohio – Giving low doses of a particular targeted agent with a cancer-killing virus might improve the effectiveness of the virus as a treatment for cancer, according to a study led by researchers with The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

Viruses that are designed to kill cancer cells – oncolytic viruses – have shown promise in clinical trials for the treatment of brain cancer and other solid tumors. This cell and animal study 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,” says principal investigator Balveen Kaur, PhD, 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,” Kaur says.

Bortezomib inhibits the activity of proteasomes, structures in cells that break down and recycle proteins. Kaur notes 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, Kaur and her colleagues used a herpes simplex virus-type 1 oncolytic virus. Key technical findings include:

• One of the overexpressed heat-shock proteins, HSP90, facilitates oncolytic virus replication, enabling the virus to kill more tumor cells;
• In a glioma model, the combination treatment suppressed tumor growth by 92 percent relative to controls and improved survival (six of eight tumors had completely regressed by day 23 after treatment);
• Similar outcomes occurred in a head and neck cancer model.

“To our knowledge, this study is the first to show synergy between an oncolytic HSV-1-derived cancer killing virus and bortezomib,” Kaur says. “It offers a novel therapeutic strategy that can be rapidly translated in patients with various solid tumors.”

Funding from the National Institutes of Health (grants NS064607, CA150153, CA163205, NS045758, CA155521) and the Pelotonia Fellowship Program supported this research.

Other researchers involved in this study were Ji Young Yoo, Brian S. Hurwitz, Chelsea Bolyard, Jun-Ge Yu, Jianying Zhang, Karuppaiyah Selvendiran, Kellie S. Rath, Shun He, Deborah S. Parris, Michael A. Caligiuri, Jianhua Yu and Matthew Old, The Ohio State University; David Eaves and Zachary Bailey, Cincinnati Children's Hospital Medical Center; Timothy P. Cripe, Nationwide Children's Hospital.

http://cancer.osu.edu/mediaroom/releases/Pages/Low-Dose-of-Targeted-Drug-Might-Improve-Cancer-Killing-Virus-Therapy.aspx

[Beacon Staff]

Re: Low-dose Velcade may improve cancer virus therapy

by Beacon Staff on Tue Jun 17, 2014 5:55 am

Thanks for the heads up about this research, Ian.

Here is information about the journal article where the research described in the press release was published:

Ji Young Yoo et al, "Bortezomib-induced unfolded protein response increases oncolytic HSV-1 replication resulting in synergistic, anti-tumor effects", Clin Cancer Res. 2014 May 9. [early publication ahead of print]

Purpose: Bortezomib is an FDA-approved proteasome inhibitor, and oncolytic HSV-1 (oHSV) is a promising therapeutic approach for cancer. We tested the impact of combining bortezomib with oHSV for anti-tumor efficacy.

Experimental Design:The synergistic interaction between oHSV and bortezomib was calculated using Chou-Talalay analysis. Viral replication was evaluated using plaque assay and immune fluorescence. Western-blot assays were used to evaluate induction of ER stress and unfolded protein response (UPR). Inhibitors targeting Hsp90 were utilized to investigate the mechanism of cell killing. Anti-tumor efficacy in vivo was evaluated using subcutaneous and intracranial tumor xenografts of glioma and head and neck cancer. Survival was analyzed by Kaplan-Meier curves and two-sided log rank test.

Results: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 UPR (induction of hsp40, 70 and 90). 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 anti-tumor efficacy in multiple different tumor models in vivo.

Conclusions:The dramatic synergy of bortezomib and 34.5ENVE is mediated by bortezomib- induced UPR and warrants future clinical testing in patients.

http://clincancerres.aacrjournals.org/content/early/2014/05/09/1078-0432.CCR-14-0553.abstract (abstract only; full text only by subscription or for a fee)

The Mayo Clinic anti-myeloma virus study that Ian mentions is described and discussed in this Beacon forum thread: "Mayo Clinic measles vaccine study".