VCP protein inhibitor found to help virus kill liver tumors

August 24, 2017 by Bob Yirka, Medical Xpress report
Illustration showing how pharmaceuticals called VCP inhibitors enhance the therapeutic activity of cancer-killing M1 viruses. Credit: Haipeng Zhang, Guangmei Yan/Sun Yat-sen University

(Medical Xpress)—A team of researchers with members from several institutions in China has found that combining a VCP protein inhibitor with a virus that naturally targets liver cancer tumors made the virus much more potent. In their paper published in the journal Science Translational Medicine, the group describes their search for a way to improve the cancer fighting abilities of a natural virus, the protein inhibitor they found, and how well the two work together to kill cancer cells.

As scientists seek ways to prevent and treat , they sometimes look for natural remedies, including viruses—some actually target and kill cancer cells and are called . One such , called simply M1, has been found to target hepatocellular carcinoma (HCC) cells which are involved with liver cancer, the second leading cause of cancer deaths in men. M1 is carried by mosquitoes and causes a minor horse illness. But it also seeks out HCC cells and kills them.

Unfortunately, its potency, like other oncolytic viruses, is too low to be of much use as a cancer treatment—it does not kill enough cancer cells to slow tumor growth. But it is good at seeking out HCC cells, which is why the team in China embarked on a study of small molecules that might help M1 kill more . They looked at over 350 of them and found that one, Eeyarestatin I, which normally serves to inhibit the production of the protein VCP, had the effects the team was looking for. They created a compound that contained both the virus and the and found that when it was introduced into cancer cultures, M1 became approximately 3,600 times more potent.

The team next inoculated mice models and found that the M1 virus bolstered with Eeyarestatin I caused tumors to shrink, and in so doing, increased survivability. The team also tested the mix on monkeys and found nearly the same results. They have submitted a request to start a clinical trial for the compound and expect to begin testing in humans sometime next year.

Explore further: Clinical trial uses a genetically engineered virus to fight cancer

More information: Haipeng Zhang et al. Targeting VCP enhances anticancer activity of oncolytic virus M1 in hepatocellular carcinoma, Science Translational Medicine (2017). DOI: 10.1126/scitranslmed.aam7996

Oncolytic virotherapy is rapidly progressing through clinical evaluation. However, the therapeutic efficacy of oncolytic viruses in humans has been less than expected from preclinical studies. We describe an anticancer drug screen for compounds that enhance M1 oncolytic virus activity in hepatocellular carcinoma (HCC). An inhibitor of the valosin-containing protein (VCP) was identified as the top sensitizer, selectively increasing potency of the oncolytic virus up to 3600-fold. Further investigation revealed that VCP inhibitors cooperated with M1 virus–suppressed inositol-requiring enzyme 1α (IRE1α)–X-box binding protein 1 (XBP1) pathway and triggered irresolvable endoplasmic reticulum (ER) stress, subsequently promoting robust apoptosis in HCC. We show that VCP inhibitor improved the oncolytic efficacy of M1 virus in several mouse models of HCC and primary HCC tissues. Finally, this combinatorial therapeutic strategy was well tolerated in nonhuman primates. Our study identifies combined VCP inhibition and oncolytic virus as a potential treatment for HCC and demonstrates promising therapeutic potential.

Related Stories

Clinical trial uses a genetically engineered virus to fight cancer

August 15, 2017
Sanford Health is the first site in the United States to launch a clinical trial using a genetically-engineered virus that aims to destroy therapy-resistant tumors.

Cough virus kills liver cancer cells and hepatitis virus

November 16, 2016
A virus that causes childhood coughs and colds could help in the fight against primary liver cancer, according to a study.

Low dose of targeted drug might improve cancer-killing virus therapy

June 16, 2014
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 at The Ohio State University Comprehensive ...

Adenoviruses and the immune system join forces against cancer

February 16, 2017
Researchers of the Cancer Virotherapy Research Group of Bellvitge Biomedicine Research Institute (IDIBELL), led by Dr. Ramon Alemany, have developed an oncolytic virus capable of redirecting the patient's immune system against ...

Training viruses to be cancer killers

March 22, 2017
For decades, scientists and doctors have looked for ways to stop the damage that viruses cause to humans.

Recommended for you

Non-coding DNA reveals a route by which advanced prostate cancer resists treatment

June 15, 2018
Two research teams converge on epigenetic switches that feed treatment-resistant metastatic prostate tumors. This research highlights the value of exploring gene regulation and large-scale structural changes in the cancer ...

Researchers peer inside cells to spy on cancer's on-off switch

June 15, 2018
Forty years after researchers first discovered it in fruit flies, a once-obscure cluster of proteins called PRC2 has become a key target for new cancer-fighting drugs, due to its tendency—when mutated—to bind to and silence ...

PIM-2 protein kinase regulates T-cell activity differently than PIM-1 or PIM-3 isoform

June 15, 2018
The PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity, while PIM-1 and PIM-3 are positive regulators, report Medical University of South Carolina (MUSC) investigators in an article ...

Gene testing could identify men with prostate cancer who may benefit from immunotherapy

June 14, 2018
Scientists have identified a pattern of genetic changes that could pick out men with advanced prostate cancer who are likely to benefit from immunotherapy.

Without 'yoga and chardonnay' leukemia stem cells are stressed to death

June 14, 2018
Change is stressful. The change that a healthy blood stem cell undergoes to become a leukemia stem cell (LSC) is no exception—think of healthy blood stem cells as young professionals and the transformation into an LSC as ...

Statins found to enhance efficacy of chemotherapy drug in blood cancers

June 14, 2018
A team of researchers with members affiliated with several institutions in the U.S. has found that some statins could enhance the efficacy of a chemotherapy drug used to fight blood cancers in mouse models. In their paper ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.