August 20, 2010

Cells' demise provides clues about cancer

Derek Parker From: The Australian
August 21, 2010

APOPTOSIS may sound like an unfortunate malady.

In fact, it may be the secret to understanding the development of cancer and devising better cancer therapies.

Ultimately, it may provide an alternative to invasive surgery or debilitating chemotherapy.

Research into apoptosis is taking place worldwide, with several large drug companies pouring money into the area, but critical work is being undertaken in Australia.

"The key is to look at how cancer cells differ from healthy cells," says Andreas Strasser, of the molecular genetics of cancer division at Melbourne's Walter and Eliza Hall Institute.

"We need to understand how cells function and, even more importantly, how they die.

"Apoptosis is the study of programmed cell death and it is taking us into very promising areas of research, including towards a whole new generation of anti-cancer drugs."

All healthy cells in the body have genes that can cause or program them to die. Cell suicide and replenishment are crucial to all living organisms and play critical roles in the body's development even before birth.

But many cancer cells can override or ignore their programmed death machinery. They grow, mutate and multiply at a rate enabling them to take over and eventually destroy their host.

There's also good evidence that subversion of the cell death machinery is necessary for the transformation of normal cells into cancer cells.

Although the principle of apoptosis was recognised in the 19th century, much of the fundamental work in translating the idea into possible therapies can be traced to a 1988 paper published by WEHI researchers David Vaux, Suzanne Cory and Jerry Adams.

They showed that a cancer-causing gene, Bcl-2, inhibits apoptosis. The finding was the critical breakthrough in the field.

Little wonder that as a postdoctoral researcher Strasser was excited by the opportunity to continue the work. And followed up the research in a 1990 paper he co-authored with Alan Harris and Cory. It demonstrated that blocking apoptosis in mice could cause cancer. It also revealed that combined abnormalities in cell death and the control of cell division co-operated in tumour development.

"The field of cancer biology has come to the realisation that a cancer is caused by a string of abnormalities, maybe five or six, in critical cellular processes, including a lack of cell death," he says. "If we can reliably overcome or restore one or even several of the processes in that string, it would be a major advance for cancer therapy."

Strasser's WEHI team recently announced findings that could lead to a new class of anti-cancer drugs.

"Until now, everybody believed that a failure of damaged cells to undergo suicide allowed mutated cells to proliferate, which contributes to tumour development," he says. "That's certainly true, but we discovered that, in certain settings, the opposite can also hold, that the body's natural cell-suicide program can fuel tumour development."

Specifically, their experiments with mice showed this could happen if cellular DNA was damaged, say, by repeated exposure to low doses of radiation. When the body attempts to replace the damaged tissue it drives tumour development because the damaged cells will divide quickly, promoting tumour development.

The critical issue, Strasser notes, is whether a gene called Puma is present. His group found that if mice with the Puma gene were given a low dose of radiation it destroyed about 80 per cent of the mature white blood cells.

This means stem cells in the bone marrow must work extra hard to replace the white cells, many of which may themselves be damaged. The result: leukaemia, cancer of the blood or bone marrow.

"The surprise was that mice that don't carry the Puma gene are fully protected from this type of tumour development," says Strasser. "Puma is essential for the death of cells that have damaged DNA. If mice don't have the Puma gene when they receive low doses of radiation the white blood cells aren't destroyed, so they don't force stem cells to become activated to replenish the blood system."

This suggests the risk of cancer is increased in people who experience cycles of tissue destruction followed by tissue repopulation by stem cells. Such a process may account for the liver cancers frequently associated with viral infections, such as hepatitis C, or alcohol-related liver damage.

The finding also helps explain why secondary cancers sometimes arise in patients who were cured of their primary cancer. The secondary cancer was triggered by the DNA damaged from the original life-saving chemotherapy.

To transform its research into therapeutic products, WEHI has entered into a collaborative agreement with US medical giants Genentech and Abbott. The agreement involves funding support for WEHI, as well as data sharing between the parties.

The present focus of research is to develop drugs targeted at a specific protein that would activate the suicide process in existing cancer cells or in other cells likely to become cancerous if genetic activity overrode their programmed cell death.

Early phase clinical trials with people are under way in several places across the world using a compound called ABT-263, which is showing promising signs.

Apoptosis is also revealing other strategies for dealing with cancer, according to Paul Ekert of the Children's Cancer Centre at the Murdoch Childrens Research Institute in Melbourne.

"Building on the basic work from WEHI, we've been looking at how the apoptosis pathways are activated, or how activation fails in response to signals that originate from outside the cell," he explains. "We want to understand the biochemical processes [that] underpin how signals originate and are transmitted."

In particular, this research is examining the role of a family of genes called the Hox genes, which appears to regulate critical aspects of the apoptosis pathway.

"Originally we were simply using the Hox gene to create large numbers of cells for experimentation purposes," Ekert says. "But then we began to think about how it could be manipulated for possible therapeutic purposes."

According to Ekert, the idea is to inhibit the division of some cells while not affecting others.

This could be especially relevant to treating leukaemia-type cancers, although the applications could be broad.

"The way signals from the outside of the cells regulate apoptosis pathways is still something of a black box, where you can see things going in and things coming out, but you don't know much about what happens inside," Ekert says. "We are starting to lift the lid."

He is collecting proof-of-principle data as the basis for early-stage testing.

Another area of apoptosis research focuses on the nature of the suicide trigger.

"There are cells [that] require constant signals to stay alive and they die when those signals cease," says John Silke of the biology department at La Trobe University, where he heads a team looking at apoptosis-related proteins.

"There are others [that] require a particular signal to activate the suicide trigger," says Silke.

"Understanding those processes would go a long way to understanding not just cancer but a whole gamut of cell-related diseases."

This research has already led to a drug, at present in phase one trials in the US, he says. The drug mimics a natural protein that activates apoptosis, amplifying the signal so cells commit suicide.

"There's still a long way to go, but there is the potential to focus on specific types of cells, avoiding the system damage generated by approaches like chemotherapy," Silke says.

"It would be like using a sniper rifle rather than a hand grenade."

For his part, Strasser underlines the importance of fighting cancer at the fundamental level: "It's a matter of understanding your enemy."

As he notes, cancer cells are an excellent example of so-called generational evolution.

"Our medium-term goal is to be able to disrupt that process, to give the body of a person with cancer a good fighting chance."

His long-term goal?

"To fight cancer at the time in the early stages of its development, hopefully preventing it from becoming a danger in the first place."


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