Drug Activates A Protein Which in-turn Helps Viruses Kill Cancer Cells
Scientists at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have been studying viruses with the aim of developing a viral therapy to treat glioblastomas, a type of aggressively growing brain cancer. One such virus is parvovirus H-1 which causes no harm in humans, but they can attack and kill cancer cells. A clinical trial has been conducted since 2011 at the Heidelberg University Neurosurgery Hospital to test the safety of treating cancer patients with this virus.
“We obtained impressive results in preclinical trials with parvovirus H-1 in brain tumors,” says Dr. Antonio Marchini, a virologist at DKFZ. “However, the oncolytic effect of the viruses is weaker in other cancers. Therefore, we are searching for ways to increase the therapeutic
potential of the viruses.”
In doing so, the virologists also tested valproic acid, a compound belonging to a group of drugs called HDAC inhibitors
. These inhibitors raise the transcription of many genes that have been chemically silenced. Valproic acid is commonly used to treat epilepsy and has also proven effective in treating specific types of cancer.
The researchers initially used a combination of parvoviruses and valproic acid to treat tumor cells
that had been obtained from cervical and pancreatic carcinomas and raised in the culture dish. In both types of cancer, the drug raised the rate of virus-induced cell death; in some cases, the cancer cells were even completely eliminated.
The results obtained in cultured cells were confirmed in cervical and pancreatic tumors that had been transplanted to rats. After the animals were treated with a combination of parvoviruses and valproic acid, in some cases the tumors regressed completely and animals remained free of recurrences over a one-year period. In contrast, animals treated with the same virus dose without the drug displayed no regression, not even when a 20-times higher dose of viruses was administered.
The virologists were also able to unravel the molecular mechanism by which valproic acid assists parvoviruses in fighting cancer: Treatment with the drug activates a viral protein called NS1, which is toxic. This helps the viruses replicate more rapidly and kill cancer cells more effectively
. The findings were published in the EMBO Molecular Medicine
“The synergistic effect
of a combination of parvoviruses and valproic acid enables us to deliver both the viruses and the drug at low doses, which prevents severe side effects
,” Marchini explains. “The results are encouraging us to carry out further tests of this combination therapy
. We believe it has the potential to arrest tumor growth in severe cases of cancer.”