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  • hellacious_too hellacious_too Jan 22, 2013 1:12 PM Flag

    Biobombs Blast Cancer

    This is an article from "The WHY Files The Science Behind the News" Google "Biobombs Blast Cancer" to read entire article.
    In addition to Reovirus, the article mentions Onyx 15 and OncoVex's trial in Melanoma

    Fighting cancer with virus

    The war on cancer goes on and on, and despite limited victories — mainly when tumors are discovered early — the death toll refuses to slacken. One of the more promising innovations uses something seen 100 years ago: Some viruses kill tumors.

    Nothing in nature rivals the virus for entering a cell, duplicating itself, and then exploding the cell to release thousands of brand-new virus particles. This enter-duplicate-kill-release process relies on biological tools perfected through millions of years of evolution.

    And it can be compelling, says Timothy Cripe, chief of hematology and oncology at Nationwide Children’s Hospital in Columbus, Ohio. Cripe, who advocates intensive testing of cancer-fighting viruses, says, “If you look at a virus spreading through a culture dish or animal model after one injection and see the tumor melt away, that’s powerful. It has a lot of promise.”

    Outsiders may deem it insane to deliberately infect people with viruses, but this happens by accident all the time. A viral infection may begin with aching, swelling, malaise and mild fever. Although some viruses can be fatal or debilitating, often, we notice little or nothing, or recover fully.

    Viruses — and their human hosts — are that variable.

    Viruses now under consideration in the struggle against cancer include herpes simplex, the cause of cold sores; measles, cause of epic epidemics through history, and reovirus, a widespread infection that, handily enough, causes no known disease.

    A crisis of lysis?

    Still, curing disease with an agent that causes disease reminds us of the bad old days when radium or mercury were considered medicine, and Cripe acknowledges some skepticism among his colleagues. “The whole field is still an area where people who are not involved say it’s interesting, but I will believe it when I see it. When we get the first FDA approval, that will be proof of principle. This is at least going to be another tool in the armamentarium for fighting cancer.”

    In the past few years, researchers have shown, in lab dishes and lab animals, that viruses can home in on tumor cells and kill them by exploding – the process of lysis. Tack on “onco-” for cancer, and we meet the “oncolytic viruses.”

    No oncolytic virus has yet attained FDA approval, but there are many signs of progress:

    A preliminary test of a virus/vaccine combination against advanced melanoma, in 50 patients, had “stunning results,” says Howard Kaufman, associate dean of Rush Medical College in Chicago. Eight patients recovered completely and four partially responded to the treatment. The results were so good that the researchers launched a larger, phase III trial that could provide evidence needed for Food and Drug Administration approval.

    A 2012 study1 showed that injecting a reovirus into the blood caused it to “hitchhike” on blood cells and spread through 10 bowel cancer patients. Intravenous delivery, if it works generally, is much simpler than trying to inject every tumor.

    A virus called Onyx 015 added no toxicity to standard chemotherapy in 40 head and neck patients2. Sixty-three percent of the patients responded, compared to 35 percent who would be expected to respond to chemo alone.

    A preliminary test of reovirus3 against head and neck cancers showed the combined potential of virus plus chemotherapy. The cancers shrank in about one-third of patients who could be evaluated, and disease stabilized in another third, and all signs of cancer disappeared in one patient. “We saw really very impressive response rates,” said Kevin Harrington, oncologist at The Royal Marsden hospital in London, via press release. “These are patients whose cancers had grown despite a great deal of previous treatment. … We’d expect that the average response rate to chemotherapy alone might be as low as single digits figures and the average survival would be somewhere between three to four months.” In the study, average survival was seven months.......

    Choosy, choosy!

    Traditional cancer treatment is as selective as a shotgun: Radiation and chemotherapy attack fast-dividing cells found in tumors, and in the gut, bone marrow and hair follicles.

    The inevitable side effects — hair loss, nausea, weight loss, treatment-induced leukemia — don’t just make patients miserable for the duration. They also limit treatment options.

    And so the holy Grail in cancer treatment is selectivity: Identifying and killing tumor cells, without harming normal cells.

    Viral selectivity can take many forms. For example, a virus can be engineered so its genes do not work in normal cells, or it can make tiny bits of RNA that regulate which genes work and which lie dormant. Or they can, like reovirus, multiply only in cells with a “ras” mutation.

    Interfering with interferon

    Ras, named for its discovery in rat sarcoma, is a cellular switch that activates numerous growth signaling pathways that are normally used when a cell grows or divides. These growth pathways are also critical to making more virus and more tumors, says Cripe. “To turn the cell into a virus factory, a virus has to turn on a bunch of genes for making nucleic acids, proteins and enzymes. The virus wants the cell to rev up, so the virus can use the same things a cell needs to grow and divide.”

    Among other effects, a ras mutation interferes with the interferon network, which normally protects cells by slowing this production of proteins and DNA. “The interferon pathway was named because it interferes with virus infection,” Cripe says. “Once the interferon protein is expressed, it forces a lot of other genes to turn on and shut down those growth pathways.”

    Credit: Wikimedia Commons

    Interferon was touted as a wonder drug in the 1980s, and although it’s no magic bullet against cancer, several interferons are on the market for treating diseases like cancer and multiple sclerosis.

    Reovirus, an oncolytic virus now under intense study, can enter most cells, but it only reproduces if a ras mutation has closed the interferon pathway. As a result, the virus’s “kitchen” is stocked with plenty of those essential proteins and nucleic acids.

    And thus the ras defect, found in up to two-thirds of tumor cells, makes those cells vulnerable to reovirus.

    Selectivity can work in other ways, says Kaufman, who directs the Rush University Cancer Center. “Oncolytic viruses can infect a wide range of cells, and probably do, but some viruses [including OncoVEX, which he is studying in melanoma] have been rendered a little less powerful. In order for them to really divide and kill the cell, they need a big pool of nucleic acid [used to make DNA or RNA]; they can’t assemble it themselves.”

    Although most normal cells lack such a supply of nucleic acids, “cancer cells are abnormal to begin with,” he says, “and there is a large pool of nucleic acid because they have to divide so often. The virus can take advantage of that; if they are only able to grow inside a cancer cell, those are the cells they kill, and that’s why the oncolytic virus is more specific than radiation or chemotherapy.”

    Although the OncoVEX-melanoma trial will not use chemotherapy, oncolytic viruses seem ideal for combination therapy, as they have, by all accounts, minimal side effects (typically including fever and aching). Clinical tests already under way are comparing the activity of oncolytic viruses, combination therapy, and chemotherapy alone.

    The question of resistance

    Cancer cells are brilliant at evading our weapons; when chemo or radiation works, tumor cells often evolve resistance. The same could happen with oncolytic virus, says Cripe. “If the virus depends on a particular receptor [to enter the cell], it can [find a way to] turn that receptor off. But it only takes one infectious virus particle to kill a cell, and if every cell that is infected gets killed, the tumor cells don’t have the opportunity to mutate and develop resistance. Tumor cells may or may not be receptive to a given virus, but if they are, it’s unlikely they can change, as they will get killed.”

    The situation differs from chemotherapy, Cripe says. “If chemotherapy inhibits an enzyme, one cell may figure out how to overcome this. With a virus, it’s all or nothing.” Tumor cells will not see the virus, so they will have no reason to mutate. “If they see the virus, it will kill them,” Cripe says.

    But cancer teaches that miracle cures never seem miraculous in the long run. Magic bullets can miss their target. Progress takes time. And, as oncologists remind themselves, “cancer is smarter than we are.”


    – David J. Tenenbaum

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    • Of particular note are these remarks about reovirus

      - “To turn the cell into a virus factory, a virus has to turn on a bunch of genes for making nucleic acids, proteins and enzymes. The virus wants the cell to rev up, so the virus can use the same things a cell needs to grow and divide.”

      Reovirus, an oncolytic virus now under intense study, can enter most cells, but it only reproduces if a ras mutation has closed the interferon pathway. As a result, the virus’s “kitchen” is stocked with plenty of those essential proteins and nucleic acids.

      And thus the ras defect, found in up to two-thirds of tumor cells, makes those cells vulnerable to reovirus.-

 
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