Science & Research

Targeting cancer

Scientists at the Manitoba Institute of Cell Biology are investigating ways to manipulate a cancer cell into killing itself

The image above is a snapshot of a cancer cell. Proteins called BNIP3 (represented by the red dots) are found in the DNA (blue) and mitochondria (green) within a cell. When starved of oxygen, the BNIP3 within a cell can trigger a process that leads to cell death
The image above is a snapshot of a cancer cell. Proteins called BNIP3 (represented by the red dots) are found in the DNA (blue) and mitochondria (green) within a cell. When starved of oxygen, the BNIP3 within a cell can trigger a process that leads to cell death.
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About the Manitoba
Institute of Cell Biology

Teaming up to fight
breast cancer

BY JOEL SCHLESINGER
Winnipeg Health Region
Wave, March / April 2014

The road to discovery is rarely straight and narrow.

More often than not, it is filled with twists and turns that must be navigated before the final destination is reached.

Dr. Spencer Gibson understands this better than most.

As the Director of the Manitoba Institute of Cell Biology, a joint research institute of CancerCare Manitoba and the University of Manitoba, Gibson is responsible for guiding one the country's top cancer research centres. He also conducts his own research into the disease, with support from his six-member team.

As a result, Gibson understands first-hand the unpredictable nature of cancer research.

"There is a saying in science that if you answer a good question, you'll create 10 more," says Gibson. "You never know whether that finding will turn out to be important down the road."

The work taking place in Gibson's lab at the institute illustrates the point.

Until recently, the treatment of cancer was largely limited to surgery to remove the tumour or chemotherapy to eradicate it from the body. That started to change in the late 1980s and early 1990s when a third approach was enlisted, thanks to advances in the study of cancer's genetics and the development of what are commonly referred to as targeted therapies.

Essentially, targeted therapies involve the use of certain drugs to affect the function of genes and proteins within a cell. Such therapies can, for example, be used to selectively inhibit the growth of cancer cells or induce a cancer cell to kill itself, a process known as apoptosis.

It is in this area that Gibson and his team - which includes Elizabeth Henson, Yongqiang Chen, Rebecca Dielschneider, Hannah Eisenstat, Shumei Ma, and Sara Beiggi - are concentrating their efforts and resources.

"We all have genes that give us instruction on what cells are supposed to do and how they're supposed to react to the environment," says Gibson, who is also a professor in the Departments of Biochemistry and Medical Genetics and Immunology in the Faculty of Medicine at the University of Manitoba, and is a Margaret A. Sellers Chair at CancerCare Manitoba. "Understanding the biology behind the cancer cells gives us the necessary context to develop therapies that can kill a cancer cell, and not the normal cells surrounding the cancer. That is one of the major challenges in cancer therapy today."

With this in mind, Gibson and his team are pursuing two lines of inquiry that could eventually lead to treatments for cancer. The first involves a protein known as BNIP3.

Researchers the world over have long been interested in the role BNIP3 plays in the life and death of cells. In fact, it was an early area of interest of Dr. Arnold Greenberg, who helped guide the institute as its director until shortly before his death in 2001. Research on BNIP3 continued under Gibson, who became a member of the institute in 2000, and took an interesting turn about 10 years ago.

At the time, one of Gibson's team members - Elizabeth Henson - was observing the behaviour of normal brain cells as part of a research project. As she studied the cells under her microscope, she started to notice something unusual about the location of the protein.

Typically, BNIP3 is found in the mitochondria of a cell. But Henson found significant amounts of the protein in the nucleus of the cell, something that had not been noticed before.

Henson says it didn't take long for her to realize this was potentially significant. "I thought, 'This is something unusual. This is something we should pay attention to.'"

She reported her observation to Gibson. He, too, was surprised by the observation. And curious.

Since the initial observation in 2004, Gibson and his team have conducted a number of studies into the BNIP3 and published several papers. Through their work, they have learned more about how BNIP3 interacts with different genes and chemicals in the body, sometimes to promote cell death, other times to promote cell survival.

As Gibson explains, cells need oxygen to survive. When they are robbed of it - a condition called hypoxia - they try to survive by a process called autophagy.

Essentially, autophagy means to "eat oneself." And in a low-oxygen environment, that's just what a cell will do. Because the cell is starved for oxygen, it starts digesting itself as a source of energy until the oxygen supply is restored. It's akin to how our bodies use fat cells when we are starved of food.

This is where the BNIP3 protein comes into play.

The mitochondria is an organelle within the cell that processes oxygen into energy. When the cell is stressed, the BNIP3 protein triggers "uncontrolled" autophagy, which leads to cell death.

Interestingly, says Gibson, this does not happen when BNIP3 is located in the nucleus of a cancer cell. In fact, it does the opposite, blocking genes that could trigger cell death.

"In normal cells, when you have a stress that will lead to killing, BNIP3 is in the mitochondria and will drive the cell death response," explains Gibson.

But cancer cells have apparently figured out a way to avoid BNIP3's killing function by pushing the protein to the nucleus. "When it (BNIP3) is there (in the nucleus), it can suppress genes that would allow these cells to die under stress," he says.

Moreover, these cancer cells tend to get stronger under the protection of BNIP3. "In other words, these cells have a greater ability to survive under stress," says Gibson. "And what doesn't kill you makes you stronger."

In this way, BNIP3 has a dual purpose, killing or protecting cells, depending on whether it is in the mitochondria or in the nucleus.

This simple fact has important implications for cancer research. Understanding how BNIP3 functions - what causes it to move to the nucleus or stay in the mitochondria - could lead to a potential treatment for cancer.

"Cancer cells have devised mechanisms to get around BNIP3's killing activity. So if we understand how it kills, then we can use the fact that these cancer cells have a lot of this protein around to trigger the death response in the cells," says Gibson.

A second line of inquiry that Gibson is working on also illustrates the unexpected turns cancer research can take.

The project is rooted in some work Gibson performed on a protein called TNF-related apoptosis-inducing ligand, or TRAIL for short. This protein is also known for starting a chemical reaction that can kill cells. Researchers suspected they could use it to target cancer cells. And so, a few years ago Gibson conducted a clinical trial designed to test whether certain chemical compounds could be used to trigger and maintain TRAIL's killing capabilities.

With other researchers at the institute and CancerCare Manitoba, Gibson worked with a compound called valproic acid. An anti-seizure medication, valproic acid had shown promise in early research as a potential drug that could increase the effectiveness of the TRAIL killing.

As it turned out, Gibson and the research group did find valproic acid to be effective when given to leukemia patients, but they didn't get the results they were looking for.

The main problem was that the therapy left patients too weak. They simply couldn't endure valproic acid in the high doses required for it to be effective.

But the study also revealed something else.

"What we saw was the killing of leukemia cells wasn't actually through TRAIL," he says. "What we discovered was that it was working through a different mechanism in which proteins were actually being chopped up."

This different mechanism centred on the lysosome, an organelle in the cell that contains a number of enzymes and acts as the cell's digestive system.

As it turns out, lysosomes are more prevalent in cancer cells than normal cells. They're also more fragile. This is interesting because it reveals a potential soft spot in a cancer cell's armour.

In order to survive, says Gibson, a cancer cell needs to have energy. "It takes a lot of coordination and work for a cell to proliferate. To do that, they (cancer cells) use the natural processes that happen in a cell to degrade and reuse proteins that are in the cell to survive," he says.

"What we have discovered is that these structures (lysosomes) tend to be weaker. So if we can put a chemical in there that destroys these lysosomes and allows the (enzymes) to leach out, the cell dies," he says, partly because the lysosomes can't do their job on behalf of the cancer cell, but also because the enzymes that leach out destroy functioning proteins within the cancer cell.

It's the kind of discovery that could lead some day to a new class of treatment, says Gibson. But he also emphasizes that there is still a lot of work to do.

The next step involves testing certain drugs to see how effective they are in destroying lysosomes in the lab. "Where we are at right now is that we think this (using a drug to destroy lysosomes) kills cancer cells. So we need to make sure that it does kill the cells and that it kills all types of cancer cells."

And that is not always as simple as it sounds.

"Cancer is smart. We've had cures for cancer in the past where it kills cancer cells in the lab really well. Put it in the patient and you might get a modest effect."

In order to develop an effective treatment, Gibson says it is important to understand what happens inside a cell when a drug is applied and to anticipate potential roadblocks.

"What are the processes that happen in a cell that's not going to make this work? Are there protective mechanisms that are going to affect how (a given) drug would actually work?"

Getting the answers to these questions and others will allow Gibson and his team to develop as many as three or four potential drug combinations that can be tested. If successful in the lab, the next step would be to test one or more of the potential drug therapies on animals. If a drug or drugs prove successful, the next step would be a clinical trial involving cancer patients.

"To get to a clinical trial, we're looking at about three to five years from now."

In pursuing these lines of inquiry, Gibson and his team are helping to unravel the mystery surrounding the life and death of cancer cells.

"Science is very complicated, and the reason it's that way is because - I hate to say this - we don't really know that much," he says. "As we discover one thing, it gets linked to something else, increasing our understanding of the disease. Over time, this will accelerate the transfer of our discoveries to the cancer patient so we will have effective treatments."

Joel Schlesinger is a Winnipeg writer.

Wave: March / April 2014

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Wave is published six times a year by the Winnipeg Health Region in cooperation with the Winnipeg Free Press. It is available at newsstands, hospitals and clinics throughout Winnipeg, as well as McNally Robinson Books.

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