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.”
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 instalment, we interviewed Dr. Connie J. Eaves is a Distinguished Scientist at Vancouver’s Terry Fox Laboratory, which she co-founded. A Professor of Medical Genetics at the University of British Columbia, she is world-renowned for her pioneering research in basic blood stem cell biology, which led to new treatments for leukemia. She also isolated breast stem cells and is a leading thinker in the field of breast cancer. Here’s what she’s excited about in 2015.
I was a co-author of a Nature paper in December that was led by Drs. Samuel Aparcio and Sohrab Shah (University of British Columbia) and described the changing genomic composition of breast cancer xenografts — that is fragments of patients’ breast tumours growing in special transplanted mice that have no immune system. In such mice, many patients’ tumours can grow as if they were still in the patient. You can thus track how the tumour evolves in relation to the original tumour.
This model has significant implications for developing new ways to treat cancer, because you can use the tumours created in the mice to determine which treatments work best and how that compares to the mutations that were present in cells that disappeared and those that may be unique to the cells that proved resistant. Groups all over the world are trying to use this approach, so we’re excited about that.
My lab has another paper in the works that has to do with making human breast tumours starting with normal human breast tissue. We have developed a protocol in which normally discarded breast tissue samples obtained from women undergoing cosmetic surgery are infected with a mutant cancer-causing gene and then produce tumours when transplanted into immunodeficient mice.
The reason this is extraordinarily exciting is because people have been trying to do this this for years with blood cells and it’s been difficult: you can count on one hand the number of different mutant genes (out of many tried) that can produce a leukemia when put into normal human blood-forming cells. Indeed, this has been very discouraging in the leukemia field.
The idea is, if you could study the early events that cause leukemia or breast cancer, then you would be able to look into the first changes that occur and get a handle on those. You could then look for those changes in a patient’s samples and try to target them specifically. Since they are the first events, they are likely going to be in every daughter tumour cell in that patient and hence better (more universal) targets.
One of the problems with treating many tumours is their genetic instability, which leads to the genesis of a tremendous diversity of subclones of cells carrying additional new mutations. Thus when you use a treatment strategy that can kill a dominant clone, there may be another 100 subclones that are not eliminated lurking at lower levels that then regrow. That is why the idea of understanding how a tumour starts to develop from its earliest stages is so captivating. Being able to do this with human breast tissue was unexpected and opens the door to all sorts of experiments. So we’re very excited about this new line of work.
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.”
We all know that unhealthy lifestyles and genetics increase the risk of developing cancer, but a new study suggests that hereditary or environmental factors are not the primary cause of two-thirds of cancer types.…
We all know that unhealthy lifestyles and genetics increase the risk of developing cancer, but a new study suggests that hereditary or environmental factors are not the primary cause of two-thirds of cancer types. Instead, misfortune plays a large part.
According to the study, published in Science and widely reported on in the media, 65% of adult cancers are mainly due to “bad luck,” or random genetic mistakes that occur during the process of cell division in the body.
“All cancers are caused by a combination of bad luck, the environment and heredity, and we’ve created a model that may help quantify how much of these three factors contribute to cancer development,” Dr. Bert Vogelstein of the Johns Hopkins University School of Medicine said in a media release.
Cell division is constantly happening in the body to replace old cells. Sometimes genetic mutations occur during the process. As might be expected, the risk of mistakes increases with the increased number of cell divisions. Drs Vogelstein and Cristian Tomasetti, analyzed the total number of stem cell divisions in 31 tissue types during an individual’s lifetime, excluding breast and prostate cancers. They estimated that 22 cancer types were a result of genetic mutations occurring during the normal cell division process and could not be avoided. These include leukemia, pancreatic, bone, ovarian and brain cancers.
“If two-thirds of cancer incidence across tissues is explained by random DNA mutations that occur when stem cells divide, then we should focus more resources on finding ways to detect such cancers at early, curable stages.” said Dr. Tomasetti in a report by The Telegraph carried in the National Post.
According to the researchers, other cancers, such as colorectal, skin and lung cancers are heavily influenced by genes and exposure to cancerous agents, such as smoking for lung cancer, UV exposure for skin cancer and poor diet for colorectal cancer.
Does the new finding mean we should abandon our efforts to prevent cancer? Not at all.
“Everything we know about altering lifestyles to prevent cancer from the environmental point of view we absolutely need to continue doing. If anything our finding puts more stress on the need to spend even more money on early detection,” Dr. Tomasetti told Time magazine.
“About half of all cancers can be prevented through healthy living and healthy public policies,” Gillian Bromfield of the Canadian Cancer Society said in a statement. “We encourage Canadians to lower their risk of cancer by not smoking, eating well, being active, sitting less, maintaining a healthy body weight, limiting alcohol, being safe in the sun and avoiding indoor tanning.”
Welcome to the first instalment of the Stem Cell NewsDesk, the Foundation’s attempt to help Canadians better understand where a “breakthrough” fits on the research lab-to-clinic continuum.…
Welcome to the first instalment of the Stem Cell NewsDesk, the Foundation’s attempt to help Canadians better understand where a “breakthrough” fits on the research lab-to-clinic continuum.
Essentially, the aim of NewsDesk is to try to answer one question: how does [insert news-making development/discovery/breakthrough here] contribute to finding a treatment or a cure for a currently untreatable or incurable disease? The idea is not to hype stem cell science but to provide realistic reports on developments as they occur.
It won’t be easy. Stem cell science is complicated and it can be hard to decipher whether a discovery represents a monumental leap forward or is just an incremental improvement in understanding how stem cells function. Sometimes it is obvious, as with Dr. Shinya Yamanaka’s 2006 Nobel-winning discovery of how to make embryonic-like stem cells from almost any cell in the body – cells we now call induced pluripotent stem cells. Sometimes it’s not. Remember that the first demonstration of the unique properties of stem cells 50 years ago flew in under the radar.
In email correspondence, Dr. Connie Eaves, a Vancouver-based researcher whose team was the first to isolate breast stem cells, shared her thoughts on why this is such a challenge:
- Every ‘new’ piece of information about how cells work and how their behaviour can be predictably manipulated is potentially a breakthrough – but it may take years to understand whether/when/where/or for what that will be true. So, making a fast judgment is rarely possible.
- Current efforts use unknowns (new molecules with an experimental rationale) to treat unknowns (human tumours we don’t understand).
- Clinically, an improvement of long-term survival from 5% to 15% would be considered a big advance. But if you were an affected patient, you might not see it that way, as overall your survival chances would still be pretty bad.
- What is useful clinically requires a controlled trial and this usually takes a long time (10 years) and the result may appear sort of boring by the time the answers are all in.
Case in point: the ‘sharpshooter’ story
Dr. Eaves is part of the 100-person team led by Princess Margaret Cancer Centre’s Dr. Tak Mak and Dr. Denis Slamon, (pictured at right) of the University of California, Los Angeles that made headlines in mid-June by announcing they had developed a new kind of “sharpshooter” anti-cancer drug. Given the excellent track record of the two scientists – Dr. Mak revolutionized how scientists think about the human immune system by cloning the T-Cell receptor and Dr. Slamon developed the breast cancer drug Herceptin – it’s not surprising the announcement garnered major media attention.
As the Toronto Star explained, the new drug, which has been tested on mice for ovarian, breast, pancreas, lung and colon cancer is called a sharpshooter because it goes after a specific enzyme to shut down cancer. Unlike chemotherapy, which can kill healthy, quick-replicating cells, the drug, called CFI-400945, takes aim only at the cancer cells.
On CTV’s Canada AM, host Bev Thompson described it as “being hailed as a major breakthrough in cancer research” and said while “we’ve talked about breakthroughs before … this seems like a cut above.”
In the Globe and Mail, however, Canada’s leading health writer André Picard, pointed out that CFI-400945, has “not been tested on a single person” and that “even in a best-case scenario” a new cancer drug “is at least a decade away.”
As excited as they were, the Princess Margaret researchers also urged patience. On that Canada AM segment, Dr. Philippe Bedard explained that the three-phase clinical trial process is a marathon, not a sprint, stressing that there is a long road ahead and it “can take many years.”
So where does that leave cancer patients?
Officials at Princess Margaret say there has been lots of interest from people who want the new drug. That will take some time: Health Canada approved CFI-400945 for use in human trials in mid-July. Next, it goes before the University Health Network’s Research Ethics Board for approval. A trial involving a small number of patients to see if CFI-400945 is safe – likely will begin in November.
So why did Princess Margaret bang the drum so loudly at such an early stage? The sharpshooter announcement actually came from The Princess Margaret Cancer Foundation to make donors aware of the potential advances that are critically dependent on the funding support that their donations provide. Makes sense: Canadians support medical research through their charitable donations as well as through their taxes and want to know how their investments are doing.
No quick fixes
But the reaction shows that there is a real and growing need for a resource to help people understand how a treatment may have an impact on them. As stem cell research moves closer to providing new treatments, people will want to know more.
NewsDesk hopes to help in this. Again, not an easy task. And there will be lots of cautions and caveats attached to our discussions of breakthroughs. Because the reality is: there are no quick fixes or magic bullets. But progress is being made – almost every day.
So let’s go back to Dr. Eaves, who is a member of the Foundation’s Science Leadership Council, and her thoughts on the sharpshooter announcement:
“The Tak Mak result looks very exciting in the experimental models studied to date. But there is not much history yet to know how these will correlate with patient outcomes. I can’t say much more than that and don’t think anyone can at this early stage.”