Special Episode - SMACing Cancer (uOttawa SciComm 2023)

Armita Kalani from the Translational and Molecular Medicine (TMM) program at the University of Ottawa interviews Dr. Shawn Beug on behalf of her team for the TMM4950 Science Communication course. Dr. Shawn Beug is a Scientist at the CHEO Research Institute and an Assistant Professor at the University of Ottawa. Dr. Beug’s research group focuses on understanding the factors involved in apoptosis (programmed cell death) and aims to develop new immune-based therapies for the treatment of cancer. In his quest to defeat cancer, Dr. Beug shares with us his research on a new class of drugs known as 'SMAC mimetics' as well as major findings from his 2017 Nature paper on the use of SMAC mimetics for glioblastoma treatment, and the results from ongoing clinical trials.

To learn more, please visit: https://med.uottawa.ca/bmi/en/people/beug-shawn 


Episode credits: Ana Spasojevic (Producer), Armita Kalani (Host), Nicole Chu (Content Writer), Kirsten Chua (Video Editor)

Transcript

0:05

Hi everyone, and thanks for tuning in to BEaTS Research Radio, a podcast and YouTube channel dedicated to disseminating research in science and engineering to the community. My name is Armita Kalani, a student in the Translational and Molecular Medicine program at the University of Ottawa and I'll be your host on today's special episode for the TMM4950 Science Communication course. Cancer remains the leading cause of death in Canada, affecting 2 in 5 Canadians during their lifetime. One of the major challenges in managing this disease is the ability of cancer cells to evade programmed cell death or apoptosis. As a result, cancer cells become immortal, allowing them to grow in the body unchecked. In his quest to defeat cancer, today’s guest has been investigating a new class of drugs known as 'SMAC mimetics', equipping the body's defense mechanisms to combat these indestructible cells. Dr. Shawn Beug is a Scientist at the CHEO Reseach Institute and an Assistant Professor at the University of Ottawa. Dr. Beug’s research group focuses on understanding the factors involved in apoptosis, and aims to develop new immune-based therapies for the treatment of cancer. Welcome, and thank you so much for joining us today, Dr. Beug! Happy to be here. Awesome, it's an honour to have you. So for those of us who may not know, what exactly are SMAC mimetics? That’s a fabulous question. This is something we’ve been working on for the past decade or so. So SMAC mimetics is a form of drugs that are developed to inhibit a group of proteins called“inhibitors of apoptosis”. And this group of proteins, they’re very very critical for regulating cell death. And we have later learned that these proteins are actually critical for immune function. So SMAC mimetics are actually tools that can be used to investigate biological questions concerning the role of IAPs in cancer and immunity. But, it is now actually being used for treatment against cancer - clinical trial studies - and also against infectious diseases. Great! It’s fascinating how these SMAC mimetics work to kill cancer cells by stopping the IAPS or inhibitors of apoptosis as you mentioned. So in class usually we learn about cancer, and what are the hallmarks of cancer. And so one of the hallmarks of cancer is failure for cancer cells to actually undergo genetically programmed cell death. How can SMAC mimetics be used to overcome this challenge? So this goes back to the inhibitors of apoptosis proteins. So the - I call them IAPs for short - what they do is they block caspase activation. For a cell to die by apoptosis, programmed cell death, you need to have activated caspases. And cancer cells have a very strong propensity to stay alive and so they have mechanisms to stay alive. And that is through IAPs blocking caspases. So what we use the SMAC mimetics for is to actually inhibit the IAPs. When you inhibit the IAPs, the caspases are free to cleave its target proteins and then programmed cell death occurs. Oh nice! We did actually learn about caspases in our courses so we have a bit of a background knowledge on how caspases allow programmed cell death by cleaving vital cellular proteins. It’s cool to see how SMAC mimetic drugs use these caspase-mediated pathways to stop cancer cells, and this actually brings me to your recent work on this topic. So your research team has published a Nature paper in 2017 on the use of SMAC mimetics and immune checkpoint inhibitors to promote tumour immunity against glioblastoma specifically. So can you share with us some of the major findings from your study? Oh fantastic. I actually really like this study because it really showcases the potential of SMAC mimetics to enhance immune-based therapies against cancer. And, so as I was saying earlier, SMAC mimetics actually antagonizes the function of IAPs. The IAPs have two main roles. One, allowing cancer cells to survive and two, to enhance immune cell function. So, actually, actually, other way around, the IAPs actually dampen immune cell function. So by using SMAC mimetics, we remove a barrier for cancer cells to survive. And by using SMAC mimetics we allow immune cells to...be, be more effective in mounting an immune response against its target. So in this paper, we found that we can use SMAC mimetics to kill glioblastoma cells and at the same time, we discovered that SMAC mimetics can actually enhance the immune attack against the dying glioblastoma cells and the healthy glioblastoma cells. So one of the things that we discovered is that while we’re mounting this beautiful and potent immune response against cancer cells - this is limited by a negative regulator of immune cell function called PD-1. So if you block PD-1, then the immune cells, typically T cells, can actually now recognize cancer cells and kill them. So we can actually “superactivate” these T cells with the SMAC mimetic and antibodies that block the PD1(PD-L1 is still going to be active) to allow for stronger immune attack against cancer cells. So those were the major findings in that one. We went into more detail, discovering how does it work, or also more critically, why does it not work? Great! So for the audience who may not be familiar with the T cell activation and apoptosis, PD1 proteins on T cells prevent them from causing cell death under normal conditions. So, it’s awesome to see that Dr. Beug’s recent discoveries showcase that SMAC mimetics inhibition of IAPs ultimately superactivate T cells through PD1’s negative regulation. Therefore, cancer cells in the brain, such as in glioblastoma, are actually able to undergo apoptosis. So, in your paper it was also highlighted that clinical trials for SMAC mimetics are actually ongoing. Can you tell us about the future of therapeutic directions for this novel therapy? Yes... so… Our group and other groups around the world used SMAC mimetics as the tools to kill cancer cells and so we actually rely on the power of SMAC mimetics to be used in combination with immunotherapy.[For instance] we have partnered with clinicians at The Ottawa Hospital to launch a clinical trial for lung cancer where they combined SMAC mimetics with anti-PD1 antibodies. And so the trial was actually centered in Ottawa but has additional sites in Canada and has expanded in Europe. So that trial finished and they are evaluating the results. But that’s not the only one, there’s about a dozen other SMAC mimetic based combination immunotherapy trials, mainly with immune checkpoint inhibitors. And so, some of them are actually working very well and progressing very nicely. So... that’s going along, but that’s not the only trial that we want to initiate. Me and others are now looking into using SMAC mimetics as a tool to enhance different forms of immunotherapies. And... because it's not just improving the ability of innate immune response or host immune response, but you can now enhance adaptive cell therapies, for example CAR-T. And…SMAC mimetics can actually “super activate” those cells and lead to enhanced attack against cancer cells. Thank you so much for the explanation, it’s incredible to see that SMAC mimetic drugs application is not only limited to to therapies for brain tumors but they also have implications in other types of cancers such as lung cancers. So that brings us to the end of our podcast. Once again, thank you so much Dr. Beug for joining us today! We hope to see the research on SMAC mimetics pave the way for the design of more effective cancer drugs. On behalf of the whole BEaTS research radio team and our radio director, Dr. Emilio Alarcón, we thank you all for tuning in. Don’t forget to follow our Twitter, Instagram and Youtube platforms to stay in the loop of our latest uploads! Wishing everyone good health, and see you next time!