The Crucial Role of Patient Samples in Cancer Research

 

kevin-patient-sample-blog

Two HeLa cells, obtained using a scanning electron microscope. Source: National Institutes of Health (NIH).

Cancer research can take on many forms, and many major discoveries have been made using organisms such as roundworms, fruit flies, mice and rats. However, patients themselves play a crucial role in research, from participation in clinical trials to providing tumour samples for researchers to study. Perhaps the most famous example is the case of Henrietta Lacks, whose cervical cancer was used to create the first human “immortal” cell line in the 1950s (HeLa). This marked the first time researchers could grow human cells indefinitely in the lab. Armed with HeLa cells, it suddenly became possible for researchers to test different drugs on cancer cells to find those that worked, and to test how different genetic mutations change the cells’ behaviour to understand why cancers arise in the first place. Not only did Henrietta’s cells have major impacts in cancer research, HeLa cells greatly improved our understanding of human biology and other fields of medicine. In 1954, Jonas Salk used mass-produced HeLa cells to develop a polio vaccine that would go on to save countless lives.

 

Unfortunately, despite the numerous advances made using HeLa cells, the story of Henrietta Lacks now serves as a cautionary tale of what not to do with patient samples. Doctors never asked Henrietta’s consent to use her cells for research, nor were they under any obligation to tell her and her family what her cells would be used for.  After Henrietta passed away from her cancer, HeLa cells were used in thousands of research studies and commercialized to generate billions of dollars of revenue, and no one had bothered to tell Henrietta’s family what was going on. When the genetic sequence of HeLa cells was published in 2013, the authors of the paper did not even ask her family before making the information publicly available. Thankfully, recent efforts have been made to commemorate Henrietta’s contributions, and her descendants were able to decide what aspect of the information would become public.

Henrietta’s story has taught a valuable lesson to researchers and doctors about the importance of research ethics. Today, informed consent is an absolute requirement before patient samples are used in research. This means that not only does permission need to be obtained, but that the donor must be made fully aware of the potential uses of the sample for research, the potential privacy risks involved, and the potential benefits the research may bring forth for society. In a time when a person’s potential identity might be inferred from genetic information, these guidelines have never been more important.

Cancer is an immensely complex disease which differs greatly from person to person. Even two people with the same type of cancer can have tumours with completely different genetic mutations, making each tumour respond a different way to treatment. In order to really understand a given cancer type, researchers need to analyze hundreds, if not thousands of tumour samples. Compared to the 1950s, we now have access to much more advanced technologies in cancer research. Genetic sequencing is almost routine in the research lab, allowing us to obtain a full picture of a person’s genome and that of a patient’s tumour.

In a recent Toronto study, scientists used cancer cells from 78 patients to learn more about acute myeloid leukemia, a type of blood cancer that is very aggressive and is often resistant to therapy. In this study, they identified a set of genes that could predict response to standard therapy [Ng]. This information allowed them to develop a tool that can help determine a patient’s prognosis, guide treatment decisions, and even identify the patients most likely to benefit from new clinical trials. This new tool is incredibly cost-efficient and reliable, outperforms previous diagnostic tools, and has a turn-around time of less than 48 hours. Development of this diagnostic tool required a large sample size of human cancers, and therefore would not have been possible without the individual contributions of cancer patients to the study.

Studies like this one illustrate why using patient samples are so important in making advances in cancer research. Thankfully, lessons have been learned from the past and patients are willing to consent to scientific research to help future generations.

This article was written by Kevin Lan, who is currently finishing his PhD at the University of Toronto. He is studying how brain cancers become resistant to current cancer therapies. To learn more about Kevin and his research you can visit our members page.

Further reading:

The Immortal Life of Henrietta Lacks by Rebecca Skloot (Broadway Books)

Ng. et. al, A 17-gene stemness score for rapid determination of risk in acute leukaemia. http://www.nature.com/nature/journal/vaop/ncurrent/full/nature20598.html

http://www.thepmcf.ca/News-Media/Latest-News/2016/Princess-Margaret-experts-develop-new-test-for-leu

New Hope for Elderly Patients with Glioblastoma

kevin-gbm-blog-pictureGlioblastoma (GBM) is the most devastating and common form of adult brain cancer worldwide, afflicting 2-3 of every 100,000 individuals. While the pace of basic research into the disease has been fast with constant new discoveries at the bench, translation of this knowledge to the bedside has proved to be an especially great challenge. There are many difficulties when researchers try to bring a new discovery into the clinic.

A landmark GBM clinical trial by the European Organization for Research and Treatment of Cancer (EOTRC) and the Canadian Cancer Trials Group (CCTG) published in 2005 still forms the basis for how patients are treated today. The Stupp protocol (named after the first author of the 2005 study, Dr. Roger Stupp) involved a combination of radiation therapy and chemotherapy with a drug called Temozolomide (TMZ). This new treatment resulted in an improvement of patient survival from 12.1 months (radiotherapy alone) to 14.6 months (radiotherapy + TMZ). However, authors of this study noted that elderly patients tended to benefit less from the newer, more aggressive protocol.

Recently, an international clinical trial led by CCTG researchers based at Queen’s University in Ontario has tailored the Stupp protocol to elderly patients. Researchers found that patients 65 years or older benefited significantly from a regimen combining TMZ with a lower dose of radiotherapy, with an improvement of survival from 7.6 months to 9.3 months. This finding means that the same treatments being applied to lead singer of The Tragically Hip singer Gord Downie will soon be made available to many more survivors of this devastating disease. An extra 2 months can certainly mean a great deal to a cancer patient and their family.

This result serves as a great illustration of the combined potential of basic and translational research. While the aim of basic research is to understand how biological processes work (for example, how and why a tumour forms), translational researchers try to apply this knowledge to our benefit (i.e. finding new cancer therapies). Temozolomide is a successor of other drugs that were first tested in mouse models of leukemia by basic research scientists in the 1960s, and later confirmed to be able to access tumours of the brain. Oftentimes it takes years of work from many dedicated researchers before enough evidence is gathered to proceed with human clinical testing. However, findings from translational research has the greatest direct impact on patients’ lives.

 This article was written by Kevin Lan, who is currently finishing his PhD at the University of Toronto. He is studying how brain cancers become resistant to current cancer therapies. To learn more about Kevin and his research you can visit our members page.

References

Stupp, R., W. P. Mason, M. J. van den Bent, M. Weller, B. Fisher, M. J. Taphoorn, K. Belanger, A. A. Brandes, C. Marosi, U. Bogdahn, et al. (2005). “Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.” N Engl J Med 352(10): 987-996.

Venditti, J. M., I. Kline and A. Goldin (1964). “EVALUATION OF ANTILEUKEMIC AGENTS EMPLOYING ADVANCED LEUKEMIA L1210 IN MICE. 8.” Cancer Res 24: 827-879.

Green Science: The Role of Medical Marijuana in Cancer Therapy

martin-marijuana-blog-pictureCanada has announced that in 2017 it will make a monumental change to the drug policy relating to the use of marijuana.  The change to the drug policy will pursue the benefits of marijuana while emphasizing shared responsibility, compassion and human rights.  As these changes take place, it is our responsibility to examine the scientific data that support our decisions.  For many people, medical marijuana can help alleviate symptoms of pain, nausea, anxiety, and appetite loss.  Therefore, changes in legislation that ease restrictions will benefit many people living with chronic disorders.  Anecdotal and (some) scientific evidence already suggest there is much to be gained for medical conditions including epilepsy, cerebral palsy, and cancer.  In these cases, medical marijuana can be obtained in many forms including dried buds, oil extracts, and fresh leaves that can be eaten. It is important to remember that while marijuana will undoubtedly provide some benefit, smoking in any form is considered extremely carcinogenic.  That is, the tar and chemicals that our lungs are exposed to during smoking will cause cancer.  Therefore, it is critical to understand the chemicals in marijuana to control administration and eliminate the unwanted side effects of smoking or consuming raw extracts.

One such family of chemicals in marijuana is the cannabinoid family.   These chemicals act on the central nervous system by connecting to receptors found mainly on our neurons.  One cannabinoid, delta-9-tetrahydrocannabinol (THC), is the chemical that causes the major psychoactive effect, or ‘high’, associated with marijuana use.  Many studies show promising health benefits associated with purified THC.  However, while THC is arguably the most famous active chemical in marijuana, clinicians would ultimately prefer to yield a cannabinoid that does not alter a patient’s cognition.  The answer will likely be found in one of the approximate one hundred other cannabinoids that have yet to reveal how they affect the cells of our body.  One type of cannabinoid showing promising results are the cannabidiols (CBD). Because they connect to receptors that are slightly different than THC, CBDs do not elicit the psychoactive effects that are unwanted in everyday life.  Several studies have shown benefits to those living with epilepsy, cerebral palsy, and cancer.  If studies are able to prove the benefits of CBD, it will undoubtedly become a major treatment option for managing daily symptoms.

For cancer, the benefits of CBD may extend far beyond managing symptoms.  Large studies are currently being conducted that hope to harness direct anti-tumor properties.  Several pathways have already been identified that indicate CBD may inhibit the growth and spread of some cancers, including solid and blood-borne cancers.  One study seeks to combine CBD with traditional brain cancer treatments in the hopes of seeing benefits on killing cancer cells (Nabissi et al., Carcinogenesis (2013) 34(1), pp. 48-57).  Other studies are looking at close comparisons between anti-tumor effects on brain cells between THC and CBD in the test tube and mice (McAlister et al., Molecular Cancer Therapeutics (2007) 6(11), 2921-2927). As we uncover more about CBD it could provide the benefits of marijuana while eliminating the unwanted mind altering side effects and heavy stigma associated with smoking marijuana.

Throughout any discussion of the medical and scientific benefits, it is important to remember that marijuana use is currently illegal in Canada.  Anyone that needs marijuana for medical purposes must obtain a letter from their medical practitioner and purchase all products from licensed dispensaries.  On the other hand, our friends to the south, the United States of America, have already implemented some policy changes.  Marijuana has been legalized in several states providing both social and economic benefits.  Perhaps an even more powerful statement illustrating that the US government has recognized the potential of marijuana is the fact that CBD extracts from hemp are legal in all states. This makes it easier for  families pursuing this line of symptom management and provides scientists a far easier path to understanding how CBD works.  As Canada moves forward with marijuana legislation, we will certainly learn more about this provocative substance.

This article was written by Dr. Martin Smith. Dr. Smith completed his PhD at the University of Waterloo studying how proteins can cause cancer. He currently works for the Ontario Brain Institute where he studies brain disease. To learn more about Dr. Smith and his research check out our members page.

The Easiest Place to Hide is in Plain Sight

martin-melanoma-articleIn recent years one type of skin cancer has received particular attention due to one person in particular.  Jimmy Carter, the 39th President of the United States of America, brought melanoma into the public eye when he announced that doctors were treating him for several metastasized “spots on his brain”.  Thankfully, soon after treatment Mr. Carter announced to the world that his cancer was in remission.

What is melanoma? Melanoma is a skin cancer that affects the cells that produce color, also known as melanocytes.  Scientists are showing that overexposure to the sun causes changes in the DNA of melanocytes leading to tumors on the skin.  Some may think that because melanoma is on our skin it would be the easiest of cancers to spot.  However, a melanoma is often hidden amongst the healthy moles on our body,  allowing this menacing mole to go undiagnosed until it spreads to other parts of the body.  Once melanoma has metastasized, treatment options can become limited.

But, let’s return to the successful case of Jimmy Carter.  As described in the media, his treatment was a combination of the three pillars of cancer treatment: radiation, surgery and chemotherapy.  One part of the chemotherapy is the drug called Keytruda, also known as pembrolizumab.  The drug is an example of new immunotherapies, called antibodies, which recognize specific targets in your body.  When they find their target, they turn on immune cells to identify and destroy cancer cells.  It is one example of a growing number of treatments that are based on helping our immune systems recognize cancer.  As the number of antibody treatments increase, successful cases like this one are on the rise.   Mr. Carter’s personal triumph over cancer emphasizes the need for effective diagnosis and aggressive treatment.

In addition to diagnosis and treatment, there are several important things that we can do every day to help prevent melanoma.  We know that melanoma and other skin cancers are caused by exposure to the sun.  The Canadian Cancer Society has recently released guidelines for good sun practice.  In order they are: check UV (stay out of the sun between 11-3 when UV is 3 or higher), seek shade, cover up (clothes, hat, sunglasses), and wear sunscreen (broad spectrum, SPF of 30).  For more information check out this page from the Canadian Cancer Society.  In general, cancer prevention should also include quitting smoking, limiting alcohol intake, moderate exercise and a healthy diet.  Just remember: in the the hot days of summer when we play sports and picnic outdoors, it’s incredibly important to stay safe while enjoying the sun.

This article was written by Dr. Martin Smith. Dr. Smith completed his PhD at the University of Waterloo studying how proteins can cause cancer. He currently works for the Ontario Brain Institute where he studies brain disease. To learn more about Dr. Smith and his research check out our members page.

Chasing Down Metastatic Cancer

Mike Mets Blog PostWhat is metastatic cancer?

Cancer has many nasty features that make it one of the most difficult and complicated diseases to treat and cure.  It doesn’t sit still- it is constantly growing, changing and moving.  In simple terms, metastatic disease is cancer that has spread from the original tumour to another location in the body and set up shop.  Metastases (commonly called “mets”) may not go very far and just form another tumour within the initial affected tissue, or they can travel great distances to different organs.  Mets can be discovered at the same time as original diagnosis, or can remain undetected for months, or even years.  If cancer reoccurs in a patient previously treated, it is most likely a met.

How do metastases spread?

Although most cells are normally immobile, cancer cells can “turn on” a set of genes that exist in all cells, which allows them to move around and travel to new locations in the body.  This set of genes exists because some normal cells have to be able to migrate when needed. For example, if you were to cut yourself, skin cells must replicate and travel to the cut site to heal the wound.  Immune cells also move freely around the body looking to respond to danger, such as bacteria and viruses.  Metastases are an example of a type of cell, specifically cancer cells, hijacking normal cellular processes for their own benefit.

When these migrating cells move away from the initial tumour they may not travel too far to form a second tumour near the original. By definition, though, this is enough to be called a metastatic tumor.  However, what this really indicates is that these cancer cells have acquired the ability to spread, and it is this behaviour that signals the possibility that they have spread to more distant locations in the body.  Metastasizing cells travel in the blood stream or lymphatic system (a series of vessels that immune cells use to travel across the body), and use these systems as highways to access any location in the body.  Some types of cancer prefer to travel to particular locations: breast cancer often relies on calcium for its growth, so it often spreads to the bones, which are full of calcium ions.  Also, it is common for skin cancers to metastasize to the brain since skin and brain cells have a common origin during development.  We can think of cancer cells as the “seed”, but they also need to be in the right “soil” for a met to take root. This highlights an important point- since mets are so dependent on particular signals found in their new location, this is weakness that can be exploited.

So as you can see, it is no small feat for cancer cells to metastasize!  Cancer cells must break away from the original tumour, find their way to either the blood or lymph vessels, travel to another site in the body and survive well enough to start growing in an entirely new environment.  All this while evading the body’s immune system.  Some of these properties are reminiscent of cancer stem cells, as metastasizing cells do not proliferate, can lie dormant for long periods of time, and are capable of creating a new tumour. Scientists want to study and understand exactly how these cells are capable of these tasks to prevent, help detect and treat cancer cells that have metastasized.

How is metastatic cancer treated? How do we study it?

Metastatic cancer is still named after the original, or primary cancer. For example, breast cancer cells that have spread to the lung are called metastatic breast cancer, not lung cancer.  This means that these cancer cells share common features with the original tumour, such as how they look (morphology) as well as genetic and molecular features allowing chemotherapeutics that a patient is taking for the original tumour to also have some effect on the metastasizing cells and slow their growth.  Similar to treating the original tumour, mets are targeted by surgery and radiation to slow their growth and spread, but also present their own challenges.

One major hurdle in studying metastases, is that, by definition, they are only found and diagnosed after they have metastasized, which is often at later stages of the disease.  This makes it difficult to study the processes of how they form; mets start from very small numbers of cells- and in theory even a single cell can give rise to a metastatic tumor.  Finding one cell within trillions of normal cells is nearly impossible.  To get around this problem, some research groups label cancer cells with fluorescent markers before injecting them into mice.  Over time, mice develop cancer, or a tumor, in an initial tissue.  The researchers then wait and watch for some cells to metastasize to different locations in the body.  Since these mets now “glow in the dark”, they literally shine like beacons to researchers, allowing them to be found and studied at a genetic level.  One of the most powerful aspects of these sorts of studies is that it is very tightly controlled. The exact properties of the starting cells are known, allowing researchers to more easily pinpoint the precise genetic changes that took place for metastasis to occur!

What is interesting, is that when you compare a patient’s mets at a genetic level, it doesn’t matter if they started in the breast, prostate or lung: they are actually more similar to each other, than to the cancer cells found at their tissue of origin.  Although this can complicate therapy since these metastatic cells have evolved or adapted, having this  core similarity is encouraging from a therapeutic perspective based on the idea that drugs can be developed to target all of a patient’s mets, no matter if they’re in bone or lung.

Some of the latest therapies designed to target metastasizing cells are a branch of immunotherapy.  These strategies “rewire” or enhance a patient’s own immune system to target and destroy cancer cells.  One advantage unique to immunotherapy is that immune cells can move around the entire body and chase down metastasizing cells, no matter where they are located

Finally, let’s remember that cancer metastasis is a complicated process with many steps.  This is good news!  Researchers can devise therapies targeting any one of these steps.  It is likely that treatments will one day include destroying the “seed” or cancer cells, and tainting the “soil” or environment in order to contain and prevent mets.  Although metastatic cancer poses a significant challenge to the research community and patients alike, it is just another roadblock, or hurdle, to overcome.  Each and every day, we get one step closer.

This article was written by Mike Pryszlak. Mike is currently completing the third year of his PhD at the University of Toronto. He studies how normal stem cell genes are changed in cancer stem cells. To learn more about Mike and his research check out our members page.

How is obesity linked to colon cancers? The answer lies in stem cells.

Kevin Blog PictureAccording to The World Health Organization, 13% of adults worldwide (600 million people) currently suffer from obesity. In addition to causing/increasing the risk of heart diseases, arthritis, and diabetes, obesity is also a well-established risk factor for certain cancers of the colon, breast, esophagus, pancreas and liver. But it’s not clear how obesity can cause cancer, and this remains a very active area of cancer research today.

Recently, researchers at The Massachusetts Institute of Technology (MIT) unexpectedly discovered a link between high-fat diets and intestinal cancers (Beyaz et al. 2016). When mice were fed with high-fat diets, normal cells in the intestine were suddenly converted into stem cells. Generally speaking, stem cells are unspecialized cells with the ability to either make more specialized cell types, or generate more stem cells. For example, intestinal stem cells can divide to create cell types that are responsible for absorbing nutrients (enterocytes), and other cell types that secrete mucus into the gut (goblet cells). Interestingly, when the researchers took out these new stem cells and grew them on a petri dish, they were even capable of forming “mini-guts” in the lab (see image above)! But what does having more stem cells have to do with intestinal cancer? How could having more stem cells cause cancer?

Certain properties of stem cells, such as their ability to continuously divide to replace lost tissue without exhaustion, can be taken advantage of by cancers to drive their own growth. This is not a new idea; in fact, the link between stem cell function and cancer itself has been quite well established from scientists in our own neighbourhood! In the 1990s, researchers in Toronto were first to discover that leukemias contain rare “cancer stem cells” which maintain the cancer much like normal tissue stem cells (Lapidot et al. 1994). This relationship between stem cell frequency and cancer risk was also the subject of another recent controversial study, which demonstrated a correlation between the number of stem cell divisions and the risk of developing cancer over a life time, for different human tissue types (Tomasetti and Vogelstein 2015). Here, the authors explained that each time stem cells divide, they carry an inherent risk of acquiring a cancer-causing DNA change, suggesting that stem cells are really at the root of many cancer types.

The answer for this current study lies in the change of a single gene. When researchers changed a gene called Apc in intestinal stem cells, they found that only those which are subjected to conditions that mimic high-fat diets are able to form tumours in mice. Therefore, rather than acting as a direct source of cancer, high-fat diets seem to increase the number of cells that are capable of being “transformed” into cancer cells by changes in their DNA.

So what does this potentially causal link between obesity and cancer mean in practical terms? First, we know that obesity is only one of many different risk factors linked to cancer. Some (such as smoking) are well-established, while others (such as cell phone use) are still debated. Having a better understanding of how these factors contribute to cancer will hopefully allow us to make better lifestyle decisions on an individual basis, and prevent cancer from ever arising in the first place. As well, the knowledge of how high-fat diets activate intestinal stem cells might also allow researchers to identify new drugs that halt intestinal tumour growth.

This article was written by Kevin Lan, who is currently finishing his PhD at the University of Toronto. He is studying how brain cancers become resistant to current cancer therapies. To learn more about Kevin and his research you can visit our members page.

References:

http://www.who.int/mediacentre/factsheets/fs311/en/

Beyaz, S., M. D. Mana, J. Roper, D. Kedrin, A. Saadatpour, S. J. Hong, K. E. Bauer-Rowe, M. E. Xifaras, A. Akkad, E. Arias, et al. (2016). “High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.” Nature 531(7592): 53-58.

Lapidot, T., C. Sirard, J. Vormoor, B. Murdoch, T. Hoang, J. Caceres-Cortes, M. Minden, B. Paterson, M. A. Caligiuri and J. E. Dick (1994). “A cell initiating human acute myeloid leukaemia after transplantation into SCID mice.” Nature 367(6464): 645-648.

Tomasetti, C. and B. Vogelstein (2015). “Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions.” Science 347(6217): 78-81.

 

Taking Medicine Personally

Taking Medicine Personally PictureWould you prefer to buy a suit from the rack or instead a suit tailored to every inch of your body?  That’s not a strange question.  Across, we have begun to adopt a personalized approach to medicine. We are starting to recognize that everybody affected by an illness is different and identifying these individualities can help clinicians provide a personalized treatment.  Clinicians now know the importance of their patient’s individual biology in developing the right treatment.

It’s time we adopted this thinking in cancer medicine. One example of this personalized approach is using mice avatars.  Using this technique, a sample from a patient’s tumour is removed, separated into individual cancer stem cells, and grown individually.  Each tumour is then implanted into a mouse where individual cancer therapies can be tested to determine which one works best.

However, much like a tailored suit, the added benefit of personalized medicine comes at an added cost.  In any cancer treatment, timing is critical.  Significant time commitments are needed to grow, culture and test individual tumors against a already developed therapies options. This approach will also increase the initial cost of cancer therapy that are associated with developing the new materials needed to carry out the personalized approach

Despite these drawbacks, personalized medicine promises to offer the most impactful treatment to the person affected by cancer.  As we continue to improve this personalized approach to medicine, clinicians will reduce both the time and financial investments involved.  Techniques like these recognize that every cancer is different, and ensure that clinicians are choosing the right treatment for the right person at the right time.

This post was written by Dr. Martin Smith, PhD. He currently works at The Ontario Brain Institute studying brain diseases. To learn more about Martin and his research check out our Members page.