Targeted Virus Compels Cancer Cells to Eat Themselves

M.D. Anderson Cancer Center ^ | 5/4/2006 | Press Release

[Neville72]

An engineered virus tracks down and infects the most common and deadly form of brain cancer and then kills tumor cells by forcing them to devour themselves, researchers at The University of Texas M. D. Anderson Cancer Center report this week in the Journal of the National Cancer Institute.

The modified adenovirus homed in on malignant glioma cells in mice and induced enough self-cannibalization among the cancer cells - a process called autophagy - to reduce tumor size and extend survival, says senior author Seiji Kondo, M.D., Ph.D., associate professor in the Department of Neurosurgery at M. D. Anderson.

"This virus uses telomerase, an enzyme found in 80 percent of brain tumors, as a target," Kondo says. "Once the virus enters the cell, it needs telomerase to replicate. Normal brain tissue does not have telomerase, so this virus replicates only in cancer cells."

Other cancers are telomerase-positive, and the researchers showed in lab experiments that the virus kills human prostate and human cervical cancer cells while sparing normal tissue.

In addition to demonstrating the therapeutic potential of the virus, called hTERT-Ad, Kondo says the international research team also clarified the mechanism by which such conditionally replicating adenoviruses (CRAs) infect and kill cancer cells.

Autophagy is a protective process that cells employ to consume part of themselves when nutrients are scarce or to destroy some of their organelles to recycle their components. A double membrane forms around the material to be consumed, then everything inside is digested.

Kondo and colleagues showed that hTERT-Ad (short for human telomerase reverse transcriptase promoter regulated adenovirus) infected the glioma cells and induced autophagy by inactivating a molecular pathway - the mammalian target of rapamycin (mTOR) pathway - that is known to prevent cellular self-cannibalization.

The result was a huge difference in tumor volume among mice with subcutaneous malignant glioma that got hTERT-Ad and those that received a different, non-replicating virus. Average tumor size in the hTERT-Ad group was 39 cubic millimeters, while those receiving the other virus had an average tumor volume of 200 cubic millimeters.

Among mice with malignant gliomas in the brain, those treated with three injections of hTERT-Ad on average lived 53 days. Those receiving the control adenoviruses lived on average 29 days. Two of the hTERT-Ad mice survived 60 days and had no detectable brain tumors.

Analyses of dead cancer cells showed telltale signs of autophagy: bits of virus in the cell nucleus and autophagic vacuoles - cavities with residual digested material.

The cells showed no sign of having been killed by apoptosis - a much better known process of programmed cell death. A normal biological defense mechanism that systematically kills defective cells, apoptosis is suppressed or dysfunctional in cancer cells. Many cancer therapies focus on restoring or enhancing apoptosis to combat the disease.

"We believe that autophagy, but not apoptosis, mediates the principal anti-tumor effect of conditionally replicating adenoviruses," Kondo says.

Cells killed by apoptosis show specific damage to the cell nucleus and DNA, with other cellular organelles preserved, Kondo explains. Cells killed by autophagy have little damage to the nucleus but heavy degradation of the cells' organelles.

Apoptosis and autophagy should be viewed as type 1 and type 2 versions of programmed cell death, Kondo says. In a Nature Reviews Cancer paper last September, Kondo and colleagues reviewed therapies and molecules that cause or inhibit the self-cannibalization process and compared autophagy and apoptosis, which has been more heavily studied.

To improve cancer therapeutics, Kondo and colleagues concluded that it is vital to identify molecules that regulate autophagy in cancer cells and to understand how autophagy is associated with cell death, a relatively new field in cancer research.

The research group is following up the malignant glioma findings by studying ways to improve the efficiency of viral infection of cancer cells.

In addition to Kondo, other co-authors who contributed to this study include, from M. D. Anderson Cancer Center: Hideaki Ito, M.D., Ph.D.; Hiroshi Aoki, M.D., Ph.D.; Yasuko Kondo, M.D., Ph.D.; Eiji Iwado, M.D.; Arifumi Iwamaru, M.D., Ph.D.; Keishi Fujiwara, M.D., Ph.D.; Kenneth R.Hess, Ph.D.; Frederick F. Lang, M.D.; and Raymond Sawaya, M.D.; and from the Medical School of Hannover in Hannover, Germany: Florian Kühnel, Ph.D., Stefan Kubicka, M.D., and Thomas Wirth.

[butternut_squash_bisque]

Gee whiz, if this happened to liberals, there'd be no cells left in their empty heads.

[Ingtar]

Why does this scare me as much as it gives hope?

[heartwood]

In case it gets out of the brain and attacks normal cells that do have telomerase? Because somebody could make a contagious vaccine like this?

[sr4402]

Why does this scare me as much as it gives hope?

What happens if the virus gets out and mutates?

[heartwood]

er "vaccine" should be "virus"

[Danae]

!!!!!!!!!!!!!!
WOW
!!!!!!!!!!!!!!

This is a TREMENDOUS breakthrough in looking for the cure for cancer!
HUGE!

[Danae]

They use the Virus type of life for to do this because Viruses are VERY specific in nature. They are little databases that can literally ONLY enter certain cells under certain conditions. Think of it as a key in a lock, only the correct key can open it and get in. Once the door is open the virus can enter. In this case the Virus has been PROGRAMED to do a specific task. To cause a hormonal reaction in a specific type of cell with a specific component. Telomerase. The reason it it works is because it can do both. Likely there are other specifics that they did not go into for the sake of brevity in the article. The Virus CAN NOT by its very nature effect other cells because those cells are different. This is the culmination of YEARS if not decades of research into that SPECIFIC type of cell, its components, and of course the manufacture of the Virus. It is a tremendously time consuming project. It is nothing short of amazing.

[mysterio]

If it only targets cancer cells, it's great. Apoptosis is quite different from regular cell death (necrosis). Necrosis causes the membrane to burst and release the organelles (and lysozymes) into the intercellular space, which can damage surrounding cells. Apoptosis looks like the cell is just boiling away to nothing from the inside, and nontargeted cells would be safe.. It's literally programmed cell death. Pretty effective therapy, when you think about it.

[Neville72]

A quick question since you seem quite knowlegable on this topic. How far ranging is this advance? Is this something to cheer about specifically because it may soon help brain cancer patients OR is this technique applicable to a wide variety of cancers?

Thanks.

[mysterio]

More than likely, the virus would be only able to attach to cancer cells. Cancer cells have a different membrane glycoprotein, if I recall correctly from college. Every cell the virus attached to would undergo apoptosis (programmed cell death), so the virus would be unable to replicate. The cell would die before it could become a virus producing factory. Plus, the viruses are probably replication negative anyway. They can probably only replicate in a specific type of cell that isn't present in the human body. My lab uses viruses in research that are unable to replicate. So far not one has regained its wild type replication ability.

So this should be very safe.

[diamond6]

bttt

[Danae]

It is both. It's a breakthrough for this SPECIFIC type of cancer, but with similar research into other types of cancers it may be useful with a wide variety of cancers.

This works because they figured out the 'shape of the key' if you will. It is tremendously complex, and takes a great deal of time and a huge depth of knowledge into the specific type of cancer cell they are targeting. They also have to know the specific and detailed attributes of each type of cancer they are targeting. So literally each 'key' is going to be different for each one. But the path they took to get the first one may well be one they can use to get to others! Surely it may work with other. For some it may not be possible.

This works because they figured out how to target the cell, using Telomerase, found the key to get into the cell, and they figured out how to trigger the hormonal reaction inside the cell causing it to eat itself basically. All of these things have to be present for it to work. Each type of cancer cell is going to have different properties, which is what enables the SPECIFIC targeting of that cell and only that cell. You begin to see the problem I think now. It is HUGELY complex. They likely chose this type of cancer because preview research had identified the inherent properties of one thing or another. Research often does this. They call it standing on the shoulders of Giants.

This is the culmination of decades of research by a great many people. Nothing short of miraculous. Can they repeat it? I would bet on it, I just would not bet on WHEN. If and when research comes up with a practical decoder ring for DNA, and specific maps of what each molecule of it does, then you will see this kind of thing just explode. To some degree they can do it now, it's just slow.

[geezerwheezer]

With the upcoming, new, "super warp speed" computers coming on line (IBM's Blue) I hope it will help these researchers in their wonderful efforts to fight cancer. It is a very complex fight, and my hat is off to all of them. Dedication and determination are not in short supply for them, and we all owe a great debt of gratitude to their efforts.

[rawhide]

Wow, amazing science!