Cancer Stem Cells
Dr. Paola Marignani is searching for new treatments. More precisely, the Dalhousie Medical School researcher wants a new combination of drugs to target cancer in a new and different way.…
Dr. Paola Marignani is searching for new treatments. More precisely, the Dalhousie Medical School researcher wants a new combination of drugs to target cancer in a new and different way.
“Many of the drugs we have in the clinic today block oncogenes that were discovered 15 or 20 years ago,” says Dr. Marignani, pictured at right. “We can’t just keep using the same drugs over and over again in different combinations. We need to find new targets and new drugs.”
Her key target is LKB1, a protein that has multiple functions throughout the body, including tumour suppression. LKB1 is often found to be missing or mutated in breast cancer, lung cancer, pancreatic cancer and other forms of the disease. “If you lose LKB1 or its mutated, it sets up protein signalling pathways for disaster,” says Dr. Marignani. “It would be like an intersection that once had stop signs and is now without any. Eventually an accident is going to happen.”
To understand what happens when LKB1 is lost and mutated, her team used re-engineered mice without the ability to express the protein. That led them to finding a combination of compounds that shuts down aggressive, metabolically active HER2-positive breast cancers — a common form of the disease — in the rodents.
Dr. Marignani is using a two-pronged approach by testing the new compounds in combination with Herceptin®, which has become the standard of care for HER2-positive breast cancer. “We know Herceptin® is effective,” says Dr. Marignani. “We can use the discovery we made in mice to strategically attack the cancers from multiple branches using new drugs in combination with the standard treatment of care, and see what happens.”
So far, she is cautiously optimistic. “The animals tolerate the drug combination, which is very important, and early data suggests the tumours are not progressing.”
Beyond shutting down tumour growth, Dr. Marignani and her team want to find ways to stop cancer from recurring by killing off the cancer stem cells that resist the original treatment.
“There is always the possibility that there are some cancer stem cells hiding out, just waiting, that have developed resistance to the treatment that killed off the bulk of the cancer,” she explains. “We have seen that our drug combination reduced the proteins that drive recurrence. We did not anticipate this would happen because there was no evidence in the literature. In our current study, we need to consider whether stem cells play a role in cancer recurrence in our model and look for pathways that are active in those cells. We don’t know yet. We’re working on it.”
With fine tuning of her animal-model preclinical work done, Dr. Marignani hopes to move into a Phase 1 clinical trial, testing the safety of the drug combination in humans. But she emphasizes that the work is in the early stages.
“It is important that we look for new treatment possibilities even though the current treatments are reasonably good. Targeting oncogenes has served us well, however it is time we expand our toolbox. We can do better.”
International stem cell scientists, led in Canada by Dr. John Dick and in the Netherlands by Dr. Gerald de Haan, have found the switch to harness the power of cord blood and potentially increase the supply of stem cells for cancer patients needing transplants.…
International stem cell scientists, led in Canada by Dr. John Dick and in the Netherlands by Dr. Gerald de Haan, have found the switch to harness the power of cord blood and potentially increase the supply of stem cells for cancer patients needing transplants.
The findings, published today in Cell Stem Cell, could provide a way to make more stem cells from cord blood, which is increasingly available through public cord blood banking.
“Stem cells are rare in cord blood and often there are not enough present in a typical collection to be useful for human transplantation,” says Dr. Dick, Senior Scientist, Princess Margaret Cancer Centre, University Health Network (UHN), in a media release.
“Our discovery shows a method that could be harnessed over the long term into a clinical therapy and we could take advantage of cord blood being collected in various public banks that are now growing across the country.”
The Dick-de Haan teams found that when a stem cell divides it makes progenitor cells that retain key properties of being able to develop into any one of the 10 mature blood cell types, but they have lost the stem cell’s key ability to self-renew.
Working with mice and human models of blood development, the teams identified microRNA (mirR-125a), a genetic switch that is normally on in stem cells and controls self-renewal, gets switched off in the progenitor cells.
“Our work shows that if we artificially throw the switch on in those downstream cells, we can endow them with stemness and they basically become stem cells and can be maintained over the long term,” says Dr. Dick.
This is just the latest discovery by Dr. Dick. He isolated a human blood stem cell in its purest form and was the first to identify cancer stem cells in leukemia and colon cancer.
Dr. de Haan is Scientific Co-Director, European Institute for the Biology of Ageing, University Medical Centre Groningen, the Netherlands.
Dr. Dick talks about their research at here.
A “Dream Team” of top Canadian scientists, led by two outstanding figures in stem cell research, is launching a new attack on brain cancers.…
A “Dream Team” of top Canadian scientists, led by two outstanding figures in stem cell research, is launching a new attack on brain cancers.
The team, announced today in Toronto, will receive $11.7 million over four years from Stand Up To Cancer Canada (SU2C), Genome Canada, the Canadian Institutes of Health Research, the Cancer Stem Cell Consortium, and Ontario Institute for Cancer Research.
Dr. Peter Dirks, a neurosurgeon at Toronto’s SickKids Hospital who first identified cancer stem cells in brain tumours, leads the team while Dr. Sam Weiss, director of the University of Calgary’s Hotchkiss Brain Institute is co-leader. A member of the Canadian Stem Cell Foundation’s Science Advisory Council, Dr. Weiss discovered adult neural stem cells.
“Brain tumours in children and adults contain a small number of cells called stem cells that resist treatment and continually regenerate, driving tumour growth and recurrence after initial responses to treatment,” Dr. Dirks said in a news release. “Our team will conduct multiple analyses of brain cancer stem cells, profiling their biological makeup to identify drugs that are likely to block the uncontrolled growth of the tumours, and carry out clinical trials across Canada to find the safest and most effective drugs to treat these cancers.”
Team members include:
- Dr. Cheryl H. Arrowsmith, the University Health Network (UHN) in Toronto (structural and chemical biology);
- Dr. Gary D. Bader, University of Toronto;
- Dr. Amy A. Caudy, University of Toronto;
- Dr. Nada Jabado, McGill University;
- Dr. Mathieu Lupien, UHN;
- Dr. Marco A. Marra, British Columbia Cancer Agency Branch in Vancouver;
- Dr. Trevor Pugh, UHN;
- Dr. Michael Salter, The Hospital for Sick Children Research Institute; and
- Dr. Michael D. Tyers, University of Montreal.
“Brain tumours are not as common as many other forms of cancer, but they are devastating, especially when they strike the very young,” said Dr. Phillip A. Sharp, a Nobel laureate and professor at the Massachusetts Institute of Technology. Dr Sharp, who co-chairs the SU2C Scientific Advisory Committee, said the Dream Team “will bring new insights to brain cancer research, which has been an underfunded area.”
Co-chair Dr. Alan Bernstein, President & CEO of CIFAR (Canadian Institute for Advanced Research), said the Dream Team builds on Canada’s research strengths. “Stem cells and cancer stem cells were discovered in Canada,” said Dr. Bernstein, who also chairs the Canadian Stem Cell Foundation’s Board of Directors. “By bringing together a top-flight team of scientists and clinicians from across Canada and applying what we have learned about brain cancer and cancer stem cells, our hope is that novel treatments will be developed.”
Science Minister Dr. Kirsty Duncan welcomed the new Dream Team: “In supporting the Dream Team, the Government of Canada is investing in promising discoveries that could improve the outcome of patients who live with brain cancer.”
Her sentiments were shared by Health Minister Dr. Jane Philpott: “Canada is a leader in stem cell research, and the Dream Team is carrying on this proud tradition,” said Dr. Jane Philpott, Minister of Health.
Canadian researchers have identified a new stem cell population in the colon linked to tumor growth. Their findings, published in Cell Stem Cell, could lead to new treatment approaches.…
Canadian researchers have identified a new stem cell population in the colon linked to tumor growth. Their findings, published in Cell Stem Cell, could lead to new treatment approaches.
Colorectal cancer is the third most common cancer and the second most common cause of death in Canada. On average, 423 Canadians are diagnosed with this type of cancer every week.
There are two kinds of stem cells in the intestine: a rapidly recycling one called Lgr5+ and a second slower one. Researchers at the Lawson Health Research Institute in London, Ontario have identified the second stem cell in the colon, one that is long-lived and radiation resistant. They also found that this new stem cell population not only gives rise to tumors in the colon, but also helps sustain and support the growth of the cancer.
According to Dr. Samuel Asfaha, a clinician-scientist at Lawson Institute and an assistant professor of medicine at the Schulich School of Medicine & Dentistry at Western University, the identification of the cellular origin of colorectal cancer is critical to understanding how cancer arises and identifying new targets for treatments.
“These findings are exciting as we have identified an important new target for cancer therapy. It is also proof that more than one stem cell can give rise to and sustain tumors, telling us that our cancer therapy needs to target more than one stem cell pool.” said Dr. Asfaha in a press release.
Until now, physicians believed that radiation therapy was effective. “With this new information, we now know this is not always true and we must find new forms of therapy to target the disease,” said Dr. Asfaha.
Recently, we asked several of Canada’s leading stem cell scientists to tell us about what they think will be the next big thing in regenerative medicine.…
Recently, we asked several of Canada’s leading stem cell scientists to tell us about what they think will be the next big thing in regenerative medicine. Where do they see things going? What are they excited about? For today’s final instalment, we interviewed Dr. Samuel Weiss is a Professor in the Cumming School of Medicine’s Departments of Cell Biology and Anatomy and Physiology and Pharmacology at the University of Calgary and Director of the Hotchkiss Brain Institute. In 1992, he discovered adult neural stem cells. He shared his thoughts on cancer stem cells (cells that can initiate tumours and that cause cancer to return) and advances being made in brain cancer research.
There is a significant move afoot to apply the knowledge we have gained to understand the stem cell biology of brain tumours. We learned a lot about normal neural stem cells and then there was a big flurry after brain tumour stem cells were identified (in 2004) by Peter Dirks (University of Toronto) and others. Now we’re entering an era of greater sophistication in terms of understanding of the various cell types that make up a brain tumour, because there is still a need to fundamentally understand how a very small number of cells, even a single cell, can end up producing a massive tumour.
That’s part of where I’m going. My lab, working with many others, has also been involved in the development and testing of new compounds. And we have the first compound that we identified in the lab as being very powerful in terms of its ability to block brain tumour initiating cells in cell culture — as well as prolonging survival of xenografted animals – is moving into a clinical trial.
Regardless of the outcome of the trial, what’s exciting is that we published the paper in Clinical Cancer Research in October and simultaneously announced that AstraZeneca had agreed to test it in the clinic — and in Canada first. It will be led out of the Princess Margaret Cancer Centre by Dr. Warren Mason. We are able to collapse the timeframe from publishing our results to testing them in the clinic to less than a year. It shows that we are developing a strategy, based on the science and based on cancer stem cells, to help accelerate testing of new compounds for cancer.
We all know that many compounds need to be tested before a new one is likely to have a big impact, especially in a heterogeneous disease like brain cancer, but at the very least, the approach, which was championed initially by Dr. David Kaplan (The Hospital for Sick Children) through a Stem Cell Network grant and then by the Terry Fox Research Institute, has allowed us to begin bringing compounds to the clinic in a timely fashion.
That’s a predictor of some of the things to come. In fact, we have another (compound) that is very close. We’re working with a biotech company in the States and finalizing the last series of experiments. We will be meeting with them in Chicago in June at the American Society of Clinical Oncology meetings and there may be a second compound in the clinic before the end of the year.
Five to 10 years ago, you would never have suggested that laboratory-based results would be moving from the lab to clinical testing in months rather than years.
Today is World Cancer Day. Under the tagline “Not beyond us,” the campaign’s goal is to raise awareness about the leading cause of death in Canada.…
Today is World Cancer Day. Under the tagline “Not beyond us,” the campaign’s goal is to raise awareness about the leading cause of death in Canada. Cancer is responsible for 30% of all deaths.
This year’s global campaign encourages prevention, early detection, treatment and care. Its message is a simple one: solutions to fight cancer are within our reach.
Canadian scientists are at the forefront of cancer research. One of the major contributions to the field comes from Dr. John Dick, senior scientist at Princess Margaret Cancer Centre and the McEwen Centre for Regenerative Medicine in Toronto. He was the first to isolate cancer stem cells — in leukemia in 1994 and in colon cancer in 2007. Recently, he and his team found a way to disarm a gene called BMI-1 that regulates colorectal cancer stem cells.
But there is potential to do more. The Canadian Stem Cell Strategy & Action Plan, could lead to novel treatments for cancer. In fact, the goal of the Strategy is for Canada to lead the way in delivering five to 10 safe and effective treatments for chronic diseases within 10 years.
By making stem cell research a national priority Canada has the potential to show that cancer is “not beyond us.”
The best and the brightest are teaming up against cancer.
In October, Stand Up To Cancer Canada (SU2C Canada), with support from the Cancer Stem Cell Consortium (CSCC), Genome Canada and the Canadian Institutes of Health Research (CIHR), announced a $10.6 million SU2C Canada Cancer Stem Cell Dream Team Research funding opportunity.…
The best and the brightest are teaming up against cancer.
In October, Stand Up To Cancer Canada (SU2C Canada), with support from the Cancer Stem Cell Consortium (CSCC), Genome Canada and the Canadian Institutes of Health Research (CIHR), announced a $10.6 million SU2C Canada Cancer Stem Cell Dream Team Research funding opportunity.
SU2C Canada is an innovative funding initiative created in July 2014 to accelerate advances in cancer research. Sharing a common mission with the U.S.- based Stand Up to Cancer, active since 2008, SU2C Canada provides grants to multidisciplinary groups of scientists, called Dream Teams, who work collaboratively to develop treatments for cancer patients.
The American Association for Cancer Research International – Canada (AACR International – Canada), the Scientific Partner of SU2C Canada, issued a Call for Ideas inviting the Canadian research community to assemble into a Cancer Stem Cell Dream Team. Scientists from across the country are invited to submit a Letter of Intent by December 8th.. Complete proposals must be sent by April 27th, 2015. Please click here for information on eligibility and submission requirements.
The qualifying Dream Team will receive approximately $10.6 million over a four-year term from CSCC, through Genome Canada and CIHR. Additional funds up to $3 million over four years from Ontario Institute for Cancer Research (OICR) will be available for clinical trials conducted in Ontario.
The research proposals will be reviewed oby the SU2C Canada Scientific Advisory Committee (CSAC), co-chaired by Nobel Laureate Dr. Phillip A. Sharp, Institute Professor at the Massachusetts Institute of Technology (MIT), and Dr. Alan Bernstein, President & CEO of the Canadian Institute for Advanced Research, and Chair of the Board of Directors for the Canadian Stem Cell Foundation.
“Dr. Sharp and I are very pleased to launch this collaborative approach to cancer research with an emphasis on working across disciplines and institutional lines to deliver new treatments in an accelerated timeframe,” says Dr. Bernstein in the SU2C Canada press release. “We look forward to reviewing extraordinary approaches to cancer research assembled by the best and brightest minds, and to selecting the best possible science that Canada has to offer.”
Back in June, we announced the release of another StemCellShorts video: “What is a cancer stem cell?” narrated by Dr.…
Back in June, we announced the release of another StemCellShorts video: “What is a cancer stem cell?” narrated by Dr. John Dick. Stem Cell Shorts is a series of about-a-minute-long informative videos produced by Ben Paylor, a PhD candidate at the University of British Columbia, and Dr. Mike Long, a post-doctoral fellow at the University of Toronto.
Dr. Dick, senior scientist at Princess Margaret Cancer Centre and the McEwen Centre for Regenerative Medicine, was the first to isolate cancer stem cells — in leukemia in 1994 and in colon cancer in 2007. Recently, he and his team found a way to disarm a gene called BMI-1 that regulates colorectal cancer stem cells.
The new video is co-sponsored by the Canadian Stem Cell Foundation and the Stem Cell Network.
All the videos — including “What is a stem cell?” narrated by Dr. Jim Till, “What are embryonic stem cells?” voiced by Dr. Janet Rossant, “What are induced pluripotent stem cells?” narrated by Dr. Mick Bhatia, and “What is a cancer stem cell?” — are now available on the Foundation’s You Tube channel. Click here to view them.
Another instalment, “What is a retinal stem cell?” narrated by Dr. Derek van der Kooy, will be released soon.
While patience is a virtue for most of us, it is an absolute prerequisite for stem cell researchers.
The recent news that scientists have identified a gene called BRG1 that appears to regulate leukemia stem cells marks an important advance in understanding the dread disease.…
While patience is a virtue for most of us, it is an absolute prerequisite for stem cell researchers.
The recent news that scientists have identified a gene called BRG1 that appears to regulate leukemia stem cells marks an important advance in understanding the dread disease. It also signifies years of work by the team led by Dr. Julie Lessard at the Institute for Research in Immunology and Cancer (IRIC) of Université de Montréal.
“About four years,” says Dr. Lessard, pictured left, one of Canada’s leading researchers in the field of hematopoiesis — the art of blood production.
Using mice as subjects, Dr. Lessard’s team found that removing the BRG1 gene left the leukemia stem cells and progenitors unable to survive, divide and make new tumors, permanently shutting down the cancer. But while they are delighted with their findings, the researchers know they are in for many more years of work.
“We need to identify BRG1 inhibitors that will work in vitro (in test tubes and Petri dishes) and in vivo (with animals and humans),” says Dr. Lessard. “We believe that it is the ATPase activity that is the essential function we need to target for potential drug development, so that’s what we’re going after.”
In essence, that means finding small molecules that can stifle BRG1, the research equivalent to finding a needle in a haystack. Fortunately, IRIC is equipped with computer-driven high throughput screening to search their library of about 120,000 molecules for one that will do the trick. “We are hoping we can get there in the coming years,” she says.
Dr. Lessard’s findings further strengthen Canadian leadership in the field of stem cells and hematopoiesis. It was two Ontario Cancer Institute researchers — Drs. James Till and Ernest McCulloch — who first proved the existence of stem cells in the early 1960s while trying to find new treatments for leukemia. Dr. John Dick, of Toronto’s University Health Network, first identified tumour-initiating cancer stem cells in 1997.
What’s particularly intriguing about Dr. Lessard’s findings is that shutting down the BRG1 gene only appears to affect leukemia-generating stem cells. “Its function in the normal stem cell is rather modest. So you can take the gene out of leukemic cells and it will shut them down without shutting down the other stem cells you need to continue growth.”
While Dr. Lessard is excited about this project, she’s realistic about the amount of time and work involved.
“First of all, we have to have a very solid preclinical product to test in animals. We think that a therapeutic window must exist. And this is what makes this study more interesting. It will be very exciting to explore in the coming years.”
When Dr. John Dick unveiled his latest cancer discovery last week, he also issued a challenge.
“I think this work will hopefully stimulate (drug) companies to get into the game,” he told the Toronto Star.…
When Dr. John Dick unveiled his latest cancer discovery last week, he also issued a challenge.
“I think this work will hopefully stimulate (drug) companies to get into the game,” he told the Toronto Star.
Dr. Dick, senior scientist at Princess Margaret Cancer Centre and the McEwen Centre for Regenerative Medicine, led a team of scientists and surgeons that found a way to disarm a gene called BMI-1 that regulates colorectal cancer stem cells.
In his own words: “When we blocked the BMI-1 pathway, the (cancer) stem cells were unable to self-renew, which resulted in long-term and irreversible impairment of tumour growth. In other words, the cancer was permanently shut down.”
Some context: Dr. Dick was the first person in the world to identify cancer stem cells, the evil twin of the stem cell. Just as stem cells spark the creation of millions of specialized cells to repair and regenerate tissues and organs (while also renewing themselves) throughout a lifetime, cancer stem cells drive the production of millions of tumour cells (while also replicating themselves).
Current cancer therapies — essentially, surgery, chemotherapy and radiation — go after the tumour cells but leave the cancer stem cells unscathed. Which is why, researchers believe, cancer often comes back.
When Dr. Dick discovered the cancer stem cell — first in leukemia in 1994 and then in colon cancer in 2007 — he opened up a new front in the war on the dread disease. With his latest finding, published in Nature Medicine, he has provided a schematic diagram for building a major new weapon in that war. One that can be aimed at colorectal cancer, the third leading cause of cancer-related deaths in the Western world.
The discovery, which made news across Canada, is based on research conducted with mice. The team replicated human colon cancer in the rodents and identified BMI-1, a gene implicated in other cancers, as the pivotal regulator of the cancer stem cells, driving the cycle of self-renewal, proliferation and cell survival. Then they put an existing small-molecule inhibitor to work blocking BMI-1.
While the implications are enormous, there is a huge chasm to be bridged between working with mice and testing a drug with people. It could take years and many millions of dollars. But an important start has been made.
What happens now?
“So the next step … is to find the best possible drug to target this gene,” says Dr. Dick in a University Health Network video. “We’re actually testing a number of drugs that are able to target this gene. We’re trying to determine which is the best one and working with other investigators and other companies to try to develop and optimize the drugs so they can be delivered to patients in the best possible way.”