Monthly Archives: January 2017

Autophagy: a Fundamental Cellular Process That Goes Haywire in Cancer

By: Mike Pryszlak

mike-autophagy

Image: tumour cells exploit the autophagic process

The Nobel Prize, established by Alfred Nobel in 1895, is the highest award an individual can receive for their academic, cultural or scientific contributions.  Alfred was himself a chemist and inventor who amassed a fortune by inventing Nobel’s Blasting Powder, or dynamite, and subsequently became a major armaments manufacturer.  His invention changed the world- and although it revolutionized the mining, quarrying and construction industries, Nobel struggled with feelings of guilt as he realized the death and destruction he had brought upon society.  In his will, he established the Nobel Foundation with the mandate to use his wealth for the greater good by awarding a prize to individuals who “confer the greatest benefit on [human]kind” in physics, chemistry, physiology or medicine, literature and peace.

This year, the Nobel Prize for physiology or medicine was awarded to Dr. Yoshinori Ohsumi for his discoveries of the mechanisms for autophagy.  What is autophagy you may ask?  Turns out you are not alone- on the Nobel website, which typically attracts a highly scientific audience, 44% of people randomly polled had never heard of it before.  So what is so special about autophagy when hardly any one knows what it is? Let me explain why this research is so important and what it means for cancer.

Autophagy, also known as “self-eating”, is the controlled break down and recycling of cellular components, which is an essential part of a cell’s normal housekeeping duties.  Similar to an aquarium, a cell can be thought of as a closed ecosystem where only a limited amount of resources exist; they need to be preserved and reused.  Over time, cellular structures, both large and small, break down, get old or are damaged by normal wear and tear.  The cell recognizes they need to be replaced and sends a signal to begin the autophagic process by “fencing off” the target in a structure called an autophagosome, marking it for recycling.  The autophagosome then fuses with a lysosome, which is full of enzymes that can break down any biomolecule into its raw components.  These pieces can then be used as building blocks for new, or other cellular components.   Dr. Ohsumi was the first to identify the genes necessary for autophagy.  When they fail or go haywire, cells cannot functional normally and this is the root cause behind many diseases including cancer.

Cancer cells use autophagy in very unusual, abnormal ways.  The reasons behind “why?” or “how?” are very poorly understood, and are active areas of research.  What is really interesting, is that scientists have seen autophagy involved in both promoting and preventing cancer, depending on the stage of tumour development or the type of cancer.  In early stages, it can inhibit cancer growth by preventing the accumulation of any damaged proteins or structures, keeping cells healthy and happy.  In more advanced tumours, on the other hand, when faced with chemotherapy or radiotherapy, cancer cells deliberately use autophagy to cope with these stresses and to repair or replace any damaged structures.  Autophagy also allows cancer cells to keep producing energy to survive and grow in conditions where a normal cell wouldn’t stand a chance.  For example, in environments where cells have no access to nutrients to grow, cancer cells can recycle and re-direct their existing nutrients into pathways that allow them to survive and continue to grow. Fortunately, this process can be exploited to restore sensitivity to chemotherapy, increasing response to treatment, which makes it a highly promising and exciting area of research.  Just earlier this year, here in Toronto, the research group of Dr. Peter Dirks at SickKids Hospital showed that when dopamine (a signaling molecule in the brain) receptors are “turned off”, autophagosomes accumulate and contribute to the death of brain cancer stem cells.  This opens the door for new therapeutic strategies as this is typically a notoriously difficult population to target.

Despite that fact that most people haven’t heard of autophagy, the pioneering work of Dr. Yoshinori Ohsumi has massively advanced our understanding of both normal and cancer cell biology, opening up countless avenues of research.  As with all Nobel laureates, their legacy will impact generations to come.  Congratulations on winning the Nobel Prize, Dr. Ohsumi, and thank you.

This article was written by Mike Pryszlak. Mike is currently completing the fourth 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.

References and further reading:

Dolma, S., Selvadurai, H.J., Lan, X., Lee, L., Kushida, M., Voisin, V., Whetstone, H., So, M., Aviv, T., Park, N., et al. (2016). Inhibition of Dopamine Receptor D4 Impedes Autophagic Flux, Proliferation, and Survival of Glioblastoma Stem Cells. Cancer Cell 29, 859–873.

Baba, M., Takeshige, K., Baba, N., and Ohsumi, Y. (1994). Ultrastructural analysis of the autophagic process in yeast: detection of autophagosomes and their characterization. J. Cell Biol. 124, 903–913.

Takeshige, K., Baba, M., Tsuboi, S., Noda, T., and Ohsumi, Y. (1992). Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J. Cell Biol. 119, 301–311.

Statins: From Cholesterol Control to Cancer Care

By: Joseph Longo

statinsFaced with increasing costs for the development of new drugs, researchers are now looking to repurpose older drugs as a relatively quick and inexpensive way of improving treatment options for cancer patients. One promising class of drugs that is receiving increased attention is the statin family of cholesterol-lowering medication. Statins have been used for decades to manage high cholesterol, and chances are that either you or someone you know is taking statins for this purpose. More recently, many studies have reported a link between statin use and reduced cancer risk and/or cancer-related death [1-4]. These observations have generated much excitement, as statins are already used in the clinic, are relatively cheap and are fairly safe, and therefore can be immediately repurposed to improve cancer patient care.

Repurposing statins to exploit a cancer cell addiction

Statins block a key pathway in cells that is important for the production of cholesterol and other lipid molecules. By blocking this pathway, statins lower the amount of these products inside the cell. In cancer, the products of this specific pathway are in high demand, as cancer cells rely on them for growth and survival. It is still unknown exactly how statins kill cancer cells, but many studies have shown that statin effectively “starve” cancer cells of these crucial products that are necessary for them to thrive [5]. Ongoing research is focused on identifying the specific products within this pathway that cancer cells are addicted to that make them sensitive to statin treatment.

Transitioning statins to the cancer clinic

Rarely are cancer drugs prescribed as a single therapy; rather, a combination of therapies is often prescribed to increase the effectiveness of the treatment and reduce the risk of relapse. Similarly, if statins are going to be repurposed to treat cancer, they will likely be co-prescribed with other treatments. Hence, an important focus of many current studies is to identify new and effective statin-drug combinations. For example, a recent phase II clinical trial evaluated the combination of high-dose pravastatin (a type of statin) and standard chemotherapy for the treatment of relapsed acute myeloid leukemia (AML). The authors of the study reported a 75% response rate, with 74% of the responders experiencing complete remission when given the statin drug alongside chemotherapy [6].

Despite evidence like this that supports the use of statins in the cancer clinic, other clinical trials have reported that statins offer no additional benefit when combined with standard therapy [7]. We need to better understand why some patients respond to this therapy while others do not, and use this information to better identify the patients who will benefit from treatment with statins. Moreover, if we can better understand why some patients do not respond, then we can identify more effective drug combinations that will work in these patients. Along this line, a recent study screened 100 clinically approved compounds and identified that dipyridamole, a drug approved for stroke prevention, increased statin-induced cell death in AML and multiple myeloma cell lines [8]. The statin-dipyridamole combination was also effective at delaying tumour growth in an animal model and killing primary AML cells collected from patients. Future clinical trials will be needed to assess the safety and effectiveness of this drug combination in actual cancer patients.

To date, over 100 clinical trials have tested or are actively testing if statins, either alone or in combination with other therapies, are effective at treating cancer. As the results of these studies become available in the coming years, they will inform us how best to use these clinically approved drugs in the fight against cancer. If the results are positive, then we will be in a strong position to immediately improve cancer patient care.

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] Poynter et al. (2005). Statins and the risk of colorectal cancer. New England Journal of Medicine 352:2184-2192.

[2] Platz et al. (2006). Statin drugs and risk of advanced prostate cancer. Journal of the National Cancer Institute 98:1819-1825.

[3] Ahern et al. (2011). Statin prescriptions and breast cancer recurrence risk: a Danish nation-wide prospective cohort study. Journal of the National Cancer Institute 103:1461-1468.

[4] Nielsen et al. (2012). Statin use and reduced cancer-related mortality. New England Journal of Medicine 367:1792-1802.

[5] Mullen et al. (2016). Interplay between cell signalling and the mevalonate pathway in cancer. Nature Reviews Cancer 16:718-731.

[6] Advani et al. (2014). SWOG0919: a phase II study of idarubicin and cytarabine in combination with pravastatin for relapsed acute myeloid leukaemia. British Journal of Haematology 167:233-237.

[7] Kim et al. (2014). Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. European Journal of Cancer 50:2822-2830.

[8] Pandyra et al. (2014). Immediate utility of two approved agents to target both the metabolic mevalonate pathway and its restorative feedback loop. Cancer Research 74:4772-4782.

Ready-or-not here we come: opening our eyes to the fight on cancer

By: Martin Smith, PhD

martin-open-eyes-blogCancer cells are locked into an epic game of hide-and-seek with our body.  Naturally, our body is tuned to recognize and eliminate foreign matter with the help of our immune system.  Cancer is no exception.  Routine inspection shows the presence of tumour infiltrating lymphocytes (TILs) deep inside of tumours removed during surgery.  These TILs are immune cells that have the natural ability to recognize and attack cancer cells in our body.  However, cancer cells can send out signals that shut down the ability of our immune system to recognize them.  In other words, they are effectively hiding from the immune system.  Recognizing this dangerous game of hide-and seek, scientists have learned how to isolate and expand the small number of TILs trapped in tumours in the lab so they can be reintroduced back into the patient.   The process of reintroducing the TILs into patients has become known as adoptive cell therapy (ACT) and shows promising results towards treating many types of cancer, such as metastatic melanoma, methothelioma, ovarian, breast and pancreatic cancers.

During surgery, complete removal of cancer with a rim of normal tissue around it called a clear margin. It is crucial for helping to prevent cancer from returning (1). Current efforts to assess whether the entire tumour has been removed rely on pre-operative imaging, post-operative reports, and the good judgment of physicians during the heat of surgery.  However, failure to fully remove the tumour can result in additional surgeries, delays in subsequent therapy, not to mention to the higher emotional distress of the patient and increases in health care costs. It is also possible that microscopic traces of tumour can remain to re-emerge at a later date.  A recent breakthrough comes from the lab of Réjean Lapointe at the Université de Montreal (2). He and his research team developed an “immuno-super gel” to help overcome some of the hurdles of current cancer therapies.   His 3D matrix gel, containing large numbers of cultivated TILs, may be poised and ready to destroy any cancer left behind during surgeries.  Imagine for a moment the potential for this technology.  The gel, charged with power of our own immune system, is injected into a surgical site.  Once there, the TILs multiply and migrate out of the gel into the surrounding tissue where they seek out and destroy the left over cancer cells not removed.   By destroying the left over cancer cells the new technology reduces the chances that any cancer will re-emerge.  This research has the potential to solve a pitfall in current cancer treatment by combining surgery with immunotherapy!

Scientists are continuing to push the boundaries of innovation by combining new technologies with ACT.  The technology behind the 3D gel matrix is a modified version of naturally occurring substances found in shellfish.  The chemical modifications provide additional matrix stability.  The leap forward comes from scientists discovering conditions that facilitate the physical support of the TILs, maintain them in a healthy state, and enable their slow release out of the gel.  Studies carried out in the lab have shown that these specialized immune cells released from the gel can kill cancer cells in a petri dish.  In a second part of the study, they also showed preliminary evidence that the gel is safe when injected into mice.  The safety and stability of a therapeutic is critical in the success of early-stage clinical trials.

If reading about exciting new therapies like this fosters a deep sense of hope and excitement; you are not alone.  The Canadian Cancer Society has recently released their top ten Canadian cancer discoveries of 2016 (3).  It’s no surprise that the immuno-super gel described here ranks among the discoveries which provide new insights into cancer biology and treamtment, turning the lights back on in the efforts to seek out ever last cancer cell in our body.

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.

References:

1) Using 3D to fine-tune breast cancer surgery and save lives. Link:

http://www.cancer.ca/en/about-us/for-media/media-releases/ontario/2014/0929-using-3d/?region=on

2) Monette A, Ceccaldi C, Assaad E, Lerouge S, Lapointe R. Chitosan thermogels for local expansion and delivery of tumor-specific T lymphocytes towards enhanced cancer immunotherapies. Biomaterials. 2016 Jan (75): pp. 237-49.

3) Our top ten research stories of 2016, Canadian Cancer Society. Link: http://www.cancer.ca/en/about-us/our-research/research-impact/?region=on

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