Monthly Archives: February 2017

Can a Genetic Test Help Personalize Prostate Cancer Treatment for Men?

By: Joseph Longo

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Prostate cancer is the most commonly diagnosed cancer among Canadian men, with 1 in 8 men expected to develop the disease in their lifetime. Thanks to advances in early detection and screening, prostate cancer treatments have significantly improved over the years and, if caught early, the 5-year survival rate is nearly 100%. Despite these advancements, over 4000 men still die of prostate cancer each year, making it the third-leading cause of cancer-related death in men.

Treatment for prostate cancer can vary depending on the stage of the disease at diagnosis and how likely the disease is to grow and spread to other parts of the body. Men diagnosed with low-risk prostate cancer tend to go on ‘active surveillance’, where regular check-ups and testing are recommended to closely monitor disease progression. This avoids the need for invasive and aggressive therapies with unwanted side effects in patients with small, slow-growing and asymptomatic disease. Men at higher risk of disease progression are treated with a combination of surgery, radiation therapy and/or hormone therapy. While these lines of therapy are initially effective, approximately one-third of patients will have their cancer return in a more aggressive and lethal form. We currently do not understand why some patients respond to these forms of therapy, while others do not. If we can predict treatment failure, then we can spare patients from unnecessary and ineffective treatments, and potentially offer more personalized and effective treatment options at diagnosis.

A recent study led by a team of researchers from Toronto and Melbourne found that prostate cancer patients with an inherited mutation in the BRCA2 gene tend to have more aggressive and advanced forms of the disease. Mutations in the BRCA2 gene, and its relative BRCA1, are typically associated with an increased risk of breast and ovarian cancers. You may remember the news headlines from 2013 when actress Angelina Jolie underwent a preventative double mastectomy after testing positive for a BRCA1 mutation. What people are less aware of, however, is that inherited mutations in the BRCA2 gene also increase the risk of developing prostate cancer. BRCA1 and BRCA2 are important players in the cell’s ability to repair damage to its DNA. When mutations in these genes prevent them from working properly, it increases the chances of developing cancer.

Prostate tumours in men with an inherited mutation in BRCA2 tend to be more aggressive and have a higher chance of spreading to other parts of the body. These patients are also more likely not to respond to first-line prostate cancer treatments, including surgery and radiation therapy. While the chances of having an inherited BRCA2 mutation are low (less than 1% of the population), testing for this mutation at diagnosis could spare men who are mutant BRCA2-positive from going through therapies that are likely to fail. Instead, these patients may benefit from more aggressive treatment upfront, including chemo- and targeted drug therapies.

This article was written by Joseph Longo. Joseph is currently pursuing a PhD in the Department of Medical Biophysics at the University of Toronto. He studies how statins can be used to treat cancer. To learn more about Joseph and his research, check out our members page.

References

  1. Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2016. Toronto, ON: Canadian Cancer Society; 2016.
  2. Taylor et al., 2017. Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories. Nature Communications. doi: 10.1038/ncomms13671.

Drug Repurposing for Colorectal Cancer: Redesigning a House Into a Bookstore

By: Douglas Chung

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What if there was a quicker and cheaper way to bring forth more treatment options for people with cancer? Researchers are trying to do just that by repurposing drugs used for other diseases to treat cancer.

The process of drug development is a costly and lengthy process. Candidate drugs must undergo multiple stages of research and evaluation before they meet the safety and therapeutic requirements to be routinely used in the clinic.

Similar to building a new house, the drug development process requires a novel structural design, construction, and passing of safety regulations. However, once the house is built, it can often be repurposed for different uses including a bookstore, restaurant or dance studio.

Similarly, some approved drugs could be repurposed to treat other diseases than what they were originally intended for. Drug repurposing has gained a lot of interest within the cancer field. The advantage of this approach is that the initial research on how the drug works in the body and its potential side effects have already been done. Drug repurposing dramatically reduces the cost and time it takes to introduce new therapies for cancer patients.

Cimetidine: A treatment for heartburn repurposed for cancer

Cimetidine is an anti-histamine drug used to treat heartburn and peptic ulcers. In 1988, researchers reported that patients with stomach cancer, who happened to be treated with cimetidine for heartburn, demonstrated tumour shrinkage and increased survival [1]. In the past decade, an abundance of animal and clinical trials have provided evidence suggesting that this drug may be a good potential therapy for cancer. But how does a heartburn medication work against cancer?

Cimetidine promotes immune cells to attack tumour

One of the ways cimetidine promotes tumour regression is by promoting immune cells to attack cancer cells. The cells of the immune system are the defenders of our body from not only foreign substances like bacteria and viruses, but also from our own cells that have gone awry. They are capable of recognizing cancerous cells, and subsequently coordinating an organized attack against the tumour.

The best way to describe the epic battle between the immune system and cancer, is to compare it to famous scene in Star Wars when the Death Star (tumour) was attacked by the Rebel Alliance’s X-wing Starfighters (immune cells). Tumours have defensive mechanisms (the Empire’s TIE fighters, or in this case myeloid-derived suppressor cells and regulatory T cells) to stop immune cells from attacking it. This allows the tumour to continue to grow without surveillance.

Several studies have shown that cimetidine targets and shuts down the suppressor cells (Empire TIE fighters) [2,3]. By shutting down suppressor cells, the immune cells are free to attack the tumour with the ultimate goal of destroying that Death Star.

Cimetidine in colorectal cancer

A number of clinical trials have shown promising results using cimetidine to treat colorectal cancer. In a 2002 trial, 64 colorectal cancer patients underwent surgery and were given 5-fluorouracil, a common chemotherapy given after surgery. [4]. Of these 64 patients, 34 patients also received daily doses of cimetidine for a year starting 2 weeks after surgery. Patients were followed for 10 years and those given cimetidine had a higher survival rate.

A recent review which analyzed results from 5 clinical trials, with a total of 421 patients with colorectal cancer (CRC), further confirmed the positive survival benefits of receiving this drug post-surgery [5].

Cimetidine has also shown promise in melanoma, gastric cancer, and renal cell carcinoma [6]. More clinical trials are ongoing to investigate if cimetidine may also provide benefits in other cancer types and whether this is due to the enhancement of the immune system. Time will tell whether this repurposed drug becomes a standard treatment option for colorectal cancer and other cancer types.

This article was written by Douglas Chung. Douglas is a research assistant working in Dr. Pamela Ohashi’s Lab at the Princess Margaret Cancer Centre where he studies how to use the immune system to fight cancer. To learn more about Douglas and his research check out our members page.

References:

  1. To̸nnesen H, Bulow S, Fischerman K, Hjortrup A, Pedersen V.M, Svendsen L, et al. Effect of cimetidine on survival after gastric cancer. The Lancet. 1988;332(8618):990-992.
  2. Zheng Y, Xu M, Li X, Jia J, Fan K, Lai G. Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells. Molecular Immunology. 2013;54(1):74-83.
  3. Zhang Y, Chen Z, Luo X, Wu B, Li B, Wang B. Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells. Human Vaccines & Immunotherapeutics. 2016;12(10):2512-2518.
  4. Matsumoto S, Imaeda Y, Umemoto S, Kobayashi K, Suzuki H, Okamoto T. Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells. British Journal of Cancer. 2002;86(2):161-167.
  5. Deva S, Jameson M. Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer. [Internet]. 2012 [cited 8 February 2017]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007814.pub2/full
  6. Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme V.P. Repurposing drugs in oncology (ReDO)—Cimetidine as an anti-cancer agent. ecancermedicalscience. 2014;8.

A ‘Big Bang’ Theory of Pancreatic Cancer Development

By: Kinjal Desai, Ph.D.

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Genetic changes causing pancreatic cancer occur all at once, like a big bang, due to massive genetic instability within the cell.

Relatively rare compared to more common cancers, pancreatic cancer is the fourth leading cause of cancer death in both women and men in Canada. Survival beyond 5 years is below 10%. What makes pancreatic cancer so deadly? In part, this is due to the appearance of disease symptoms when the cancer is already at a very advanced stage, despite many efforts toward an early detection. New research out of Toronto now explains why pancreatic cancer is so hard to detect early by providing insight into how it actually develops.

This recent study demonstrates that pancreatic cancer appears to develop spontaneously and rapidly following an event that causes the genome to become highly unstable, leading to thousands of genetic changes happening all at once. This is in stark contrast to the previous views on how cancer forms.

The previous theory is that cancer follows the principles of evolution much like what was identified by the great naturalist Charles Darwin. He proposed a theory of natural selection, that can be described in the following example: a bird has randomly acquired a DNA mutation that causes it to have a very long beak compared to other birds in its flock. Supposing there is a drought in the region and the only seeds available were buried deep in the ground, the once abnormal long-beaked bird now has the most advantage and survives, whereas the shorter-beaked birds in its flock are more vulnerable to starvation. When the long-beaked bird reproduces, it passes on its mutation and the long beak becomes more common or “selected” in the population. However, once the drought passes and long beaks are no longer beneficial to birds for survival, the mutation, offering no particular advantage, may start to once again become a minority in the population.

Darwin’s evolutionary model is frequently seen in cancers too. Cancer cells, which arise from normal cells, randomly acquire mutations in key genes that offer them a growth advantage. Every time a cell acquires a “cancerous” mutation, it gains greater power to grow faster and survive. These mutations, occurring randomly and in a stepwise fashion, eventually create a full-blown cancer.

But this new study from Toronto makes us rethink this theory when it comes to pancreatic cancer. It had previously been observed that pancreatic cancer becomes aggressive almost as soon as it begins forming. This new research suggests that the reason for this is that the disease-causing mutations may be occurring simultaneously with a “big bang” event, rather than in a gradual and stepwise fashion. The authors, led by a team based at the Ontario Institute of Cancer Research (OICR), used a computational method to track the genetic changes in over 100 pancreatic tumour samples to reach their conclusion.

They proposed that pancreatic cancer follows a model of evolution known as “punctuated equilibrium.” The theory was first proposed by Stephen Jay Gould and a colleague, Niles Eldredge, to refer to significant evolutionary changes that occur rapidly in spurts, and which are preceded and followed by long periods of slow and gradual changes described by Darwin’s natural selection. A similar process was also reported in colon cancer, and was referred to as a “big bang” model of cancer growth. This striking analogy is a powerful description of the rapidly changing state from normal to cancerous in certain cases.

This study offers an important new perspective to understanding cancer evolution. By more carefully identifying the different ways in which cancer can evolve in our bodies, researchers and clinicians can better design specific therapies to target them.

This article was written by Dr. Kinjal Desai. She is a postdoctoral research fellow at the Hospital for Sick Children in Toronto, where she works on medulloblastoma, the most commonly occurring malignant brain tumour in children. To learn more about Kinjal and her research check out our members page.

References:

Notta F., Chan-Seng-Yue M., Lemire M., Li Y., Wilson G.W., Connor A.A., Denroche R.E., Liang S-B., Brown A.M.K., Kim J.C., et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature 538, 378–382 (20 October 2016) | doi:10.1038/nature19823

Sottoriva A., Kang H., Ma Z., Graham T.A., Salomon M.P., Zhao J., Marjoram P., Siegmund K., Press M.F., Shibata D. & Curtis C. A Big Bang model of human colorectal tumor growth. Nature Genetics 47, 209–216 (2015) | doi:10.1038/ng.3214

Darwin, C. On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life. Nature (1859). London: John Murray, 5 (121): 502.

Eldredge, N., Gould, S.J. Punctuated equilibria: an alternative to phyletic gradualism. Models in Paleobiology (1972) pp 82-115.

 

Tackling the Fear of Cancer Recurrence: An Interview With Survivorship Researcher Dr. Christine Maheu

 

By: Sangeetha Paramathas

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Dr. Christine Maheu is an associate professor in the Ingram School of Nursing at McGill University as well as a FROS Junior 2 Research Scholar and a clinical scientist at the Princess Margaret Cancer Center. Her research is focused on cancer survivorship with particular interest in developing clinical interventions for fear of recurrence and a difficulty with going back to work.

How long have you been in the research field?

I started my PhD in 1998 and began conducting research in 1996 by being a research assistant at the master’s level.

What does your research focus on?

For my PhD at UBC, I interviewed 22 families who were testing inconclusive for the genes BRCA1 and BRCA2. They had a very strong family history of breast and ovarian cancer but they couldn’t find a mutation. I studied what the psychological impact is of knowing that you are at risk of developing cancer. For my post-doc at U of T, I developed an intervention to deal with the anxiety and the uncertainty that arises from living with an unknown inherited mutation for cancer. Afterwards, that study led me to the fear of cancer recurrence study for patients finishing cancer treatment. Fear of cancer recurrence is often the number one concern and is also often unscreened and untested. With a colleague from the University of Ottawa, Dr. Sophie Lebel, we put together an intervention – it is a 6-week therapy group, that was built from evidence and is theory based. It is a cognitive existential group therapy that is currently offered for breast and gynaecologic cancer survivors and is available in Montreal, Ottawa, and Toronto.

What is cognitive existential therapy?

It focuses on how to reframe your thoughts in such a way that the patients do not automatically feel that every pain, ache or bodily sensation is a sign of recurrence. We help them look at how to unfreeze themselves from their anxiety and what the impacts of living in constant worry are. We’re teaching them coping skills such as: reading, going out for a walk, doing relaxation exercises and calming self-talks. We teach them how to self assess so that they know when to use their coping skills and what method is more effective for them to lower their anxiety and fear of recurrence.

What does a typical workday, like today, look like for you?

I am involved in many studies. Right now, we are in the recruitment phase for three studies. I ensure that we have pamphlets and ads up for recruitment and I talk to physicians to see if they have patients to refer. I like to keep up-to-date on where we are with data collection and oversee data entry from questionnaires. I coordinate follow-ups with patients, prepare for presentations and talks and work on my own scientific papers. I also supervise graduate students!

What are the best and hardest parts of the therapeutic interventions that you run?

The last session of the 6-week intervention is what I look forward to the most. Realizing that we’ve made a difference in these women and that it has helped them. Rarely do I see that the work we do hasn’t made any change, and it is nice to see that.

The hardest part is helping patients go through difficult sessions (such as sessions 4 and 5) where they talk about their worst-case scenarios and having to discuss it. Often their fears are about “What happens if I pass away” and “What would happen to my family”.  These are difficult moments that we need to prepare for ourselves as group leaders to make sure that we are well grounded.

Why is survivorship research important?

All the late and long-term effects of cancer and its treatments are important. Often patients who have finished their treatment will tell you that they feel they are forgotten, that they still have questions, and wonder who will be following up with them. Cancer survivorship is a stage of the disease and cancer is a chronic illness that you have to live with; it’s not like catching a cold. We have to develop a program of care for these patients who will be feeling different (long-term) symptoms that require professional care.

Is integrating survivorship care into primary care important?

Once patients finish treatment, the transition to their primary care (family) physician is difficult; there is no streamlined approach. Some patients will get good follow-up care whereas others may not. Ideally, we would like for the family physicians to be involved with the patients cancer care from the start with the oncology team. Patients would gain from being informed early on of the possible late and long-term effects that may result from their cancer and cancer treatment, and these include the psychological impact. Survivorship care needs to be discussed at the start of treatment using a standardized approach, and perhaps one that is universal across all provinces. The issues with cancer and its treatment remains the same no matter what province you are from.

How has research in survivorship research changed since you started in research?

The psychological aspects of cancer care weren’t considered an issue 15-20 years ago. Now it is becoming more known and accepted that there is a psychological aspect to cancer care. Now, there are many organizations and conferences (such as the Canadian Association of Psychosocial Oncology (CAPO) for nurses, social workers, doctors, psychologists and psychiatrists to come together and discuss the psychosocial aspects of cancer. Distress and anxiety are becoming additional vital signs that are screened for as part of follow-up cancer care. Today, most provinces have in place a survivorship program or a wellness centre available to patients right from the beginning.

Thank you so much for your time Dr. Maheu. Your work sounds very important and it addresses key aspects of cancer care and illustrates cancer research in a new light. You are doing some amazing work, good luck!

This article was written by Sangeetha Paramathas. Sangeetha is currently a PhD candidate in the Department of Medical Biophysics at the University of Toronto. She studies how liquid biopsies can be used for cancer surveillance and diagnosis. To learn more about Sangeetha and her research, check out our members page.