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Paddock 2013

Created By: Kaylin Braden
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A modified Newcastle disease virus that targets and kills all types of prostate cancer cells and leaves normal cells untouched shows promise as a cancer treatment that avoids the side effects which normally accompany hormonal treatment and chemotherapies, says a team of veterinary scientists in the US.

Corresponding author Subbiah Elankumaran, an Associate Professor of Virology, at Virginia-Maryland Regional College of Veterinary Medicine, and colleagues, are due to report their findings in an April edition of the Journal of Virology; a pre-print issue of which was released online on 25 January.

Oncolytic Viruses
[1] Researchers first became interested in the treatment potential of oncolytic viruses nearly two decades ago. These viruses target and kill tumor cells while leaving normal healthy cells intact.

"Onco" means cancer, and "lytic" means to burst open, which describes the effect that oncolytic viruses have on targeted cells. Once the virus gains entry to the host cancer cell it hijacks the cell machinery so it mistakenly copies the viral acids instead of its own nucleic acids.

[2] Eventually the cell becomes so full of virus copies that it bursts, releasing its surrogate progeny to infect other host cells, and so the anti-cancer "infection" spreads, eliminating cancer cells.

But what looks promising on the lab bench is proving difficult to translate into clinical success. For example, a key problem is getting the oncolytic virus to enter deep tumors and penetrate enough cancer cells to be effective, without having repeatedly to inject huge quantities into the host.

Newcastle Disease Virus (NDV)
Newcastle disease virus (NDV) is a virus that kills chickens (it is an "avian paramyxovirus") but is harmless to humans. It is also an oncolytic virus that targets tumor cells and has shown promise in human clinical trials for various types of cancer.

Normal healthy cells have an antiviral system based on interferon that becomes active when NDV enters the cell, thus preventing the virus from taking over the cell and replicating.

Cancer cells have defective interferon antiviral systems, which NDV exploits, allowing it to take over diseased cells and use them as replicating machines.

But the clinical trial results with NDV have not been good enough because successful treatment requires many large injections of the virus, probably because not enough of the virus managed to reach the solid tumors and so the infection did not spread very well to other cancer cells.

"Despite encouraging Phase I/II clinical trials with NDV, further refinements for tumor specific targeting are needed to enhance its therapeutic index", write the authors.

What if the virus could be made to target host cells more efficiently?

Modifying Cell Fusion Property of NDV
In their study, Elankumaran and colleagues addressed the problem by changing the way the virus fuses to the host cell.

NDV is a type of virus that gains entry into host cells by fusing or blending its envelope with the membrane of the host cell, making small holes in it and releasing its contents into the cell.

This is done with the aid of a fusion protein that is activated by being "cleaved" by any number of molecules called cellular proteases.

The researchers modified NDV's fusion protein so it could be activated only by prostate specific antigen (which is a protease):

"We engineered the F protein of NDV and generated a recombinant NDV (rNDV), whose F protein is cleavable exclusively by prostate specific antigen (PSA)," write the authors, who then tested the result in the lab:

"The rNDV replicated efficiently and specifically in prostate cancer (CaP) cells and three-dimensional prostaspheres but failed to replicate in the absence of PSA," they note.

Retargeted NDV Potentially Offers Major Advantages
In a statement to the press, Elankumaran says the modified virus is now ready for preclinical tests on animals, and possibly phase I human trials.

The researchers are hopeful because as the "retargeted" virus only interacts with prostate cancer cells, it should reduce the amount of virus needed for treatment.

Retargeted NDV potentially offers major advantages over other cancer treatments, says Elankumaran.

[3] First, because it targets only prostate cancer cells and not normal healthy cells, it avoids the various unpleasant side effects of conventional cancer therapies. In previous trials, even with very large doses of naturally occuring NDV strains, "only mild flu-like symptoms were seen in cancer patients," says Elankumaran.

Second, it offers an alternative for hormone-refractory patients (whose disease progresses despite hormone therapy), without the side effects of testosterone suppression that follows hormone treatment.

Current estimates suggest 1 in 6 men will be diagnosed with prostate cancer during their lifetime, and the disease kills about 1 man in 36.

If the cancer has not spread (usually this is to the bone), men with hormone-refractory prostate cancer have a median survival of around 68 months. This shortens to around 40 months if the cancer has spread to the bone.

In February 2012, US researchers reported how a strain of measles virus engineered to kill cancer cells prolonged survival in a model of medulloblastoma that is disseminated in the fluid around the brain.
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