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Interview with Dr. Marianne Kortizinsky

Journalist: Amy Stewart

Image: UofT, Medical BioPhysics

AMY: Hello and welcome back to SciSection! I'm your journalist Amy Stewart, for the SciSection radio show broadcasted on CFMU 93.3 FM radio station. We are here today with Dr. Marianne Koritzinsky, a researcher at the Princess Margaret Cancer Centre, and an associate professor and director of research in the department of Radiation Oncology. Thank you so much for joining us Dr. Koritzinsky.

DR. KORITZINSKY: It's my pleasure to be with you Amy.

AMY: To get us started, give us an introduction of who you are, your education, and your career background?

DR. KORITZINSKY: Sure, I'm Norwegian, I grew up in Norway and I did my undergraduate there and most of my graduate studies there. So I actually started out doing an undergraduate degree in biophysics- physics engineering- which is something that I didn’t think would lead me to where I am today but that’s part of the fun of life I guess. And so, when I was studying medical physics really I just became very interested in radiotherapy and more and more into tumour biology. And so my PhD was more focused on radiobiology and the microenvironment of tumours and that’s really a topic that I've kept close to my heart for the rest of my research career as well. During my PhD which I did in Oslo, I also had the opportunity of visiting other labs, so I spent some time at McGill at a lab there for six months and also visited for a longer time a lab in the Netherlands in Maastricht. And that’s actually where I went for my postdoc before I came to Canada in 2008. First as a scientific associate and then later as an independent scientist at the Princess Margaret Cancer Centre.

AMY: We'll we're very happy to have you here in Ontario, that’s great. So like you said, your research which you do mostly about cancer, you guys really focus on the microenvironment of tumours. So what does that mean and why is that an important aspect of cancer research?

DR. KORITZINSKY: Well you know in cancer research I think the main challenge or what we really want to focus on is something that’s different in cancer and normal tissue. Because you know a little bit tongue in cheek we say that it's not hard to kill cancer cells; it's hard to kill cancer cells without damaging normal tissues surrounding them. So what we really need to find are some unique features or some unique vulnerabilities that we can take advantage of. And so I've been really interested in the tumour microenvironment because there's many, many unique aspects of the microenvironment of tumours that is different in chemical composition, sometimes salt pipes, than what we see in normal tissues. So this gives us some kind of opportunity to think about, you know, understanding mechanisms of that better so that we can take advantage of that for cancer therapy. And I can give you one example. So we focus a lot in previous work on the feature of hypoxia which is low oxygenation and this is a very common feature of human tumours they have areas that are poorly oxygenated through various mechanisms they often actually have a lot of vasculature but the vasculature is poorly functioning so the delivery of oxygen is poor and also cancer cells tend to use a lot of oxygen, so they use it up so that their neighbours don't get any. And this hypoxia in tumours is a problem because hypoxic cells are very resistant to treatments but it's also an opportunity. Because it means that if we could for example find a drug that was only toxic to hypoxic cells that would present a therapeutic opportunity because it would not be toxic to normal tissue cells or if we could find ways of maybe changing the tumour microenvironment so that cells could be better oxygenated they would not be as resistant. Again with a tumour specific effect. So, there are just some examples of concepts that we can think about in order to think about a very, very specific feature of the tumour. And of course a lot of people are focused on genetic differences in cancer cells and normal cells but in my lab we are more focused on the microenvironmental effects.

AMY: That’s very cool. It's nice to see that your research is really focusing on potential treatment mechanisms. And I'm interested when you guys are working in your lab are you looking more at protein pathways, metabolic pathways, what are you guys looking at specifically when you're looking to target these hypoxic microenvironments.

DR. KORITZINSKY: Yeah we have a few different angles I would say, but I'm quite interested in the deregulation of metabolism that happens in cancer cells that give rise to many of these specific features of the tumour microenvironment. And so, I don't know if you've heard of the hallmarks of cancer but this is something that we talk about in cancer research as being, you know, a specific pathway or effects that we really see very commonly changed in all human cancers. And actually the deregulation of metabolism is one of these hallmarks. And what's interesting is that leads to some vulnerabilities and that's what we're really interested in focusing on. So on the one hand we have high oxygen consumption that leads to hypoxia and on the other hand we actually have also a high production of reactive oxygen species. So this seems a little bit paradoxical but because of the way that tumours cells reprogram their metabolism they also make a lot of these reactive oxygen species and these are things like superoxide or hydrogen peroxide that the cells need to protect themselves against. So in my lab we’re interested in sort of both of these two aspects of tumour biology and so one approach we've taken to mitigate hypoxia directly in tumours is to try to reprogram metabolism again. So that we inhibit how much oxygen the cancer cells are using and so if they use less oxygen it means that oxygen becomes available to the rest of the tumour cells and so they're no longer so resistant against treatments. And so that was a concept that we demonstrated in the lab and in animal models some years ago. And we used a drug called metformin which is a very common actually anti-diabetic drug which does this job. And that has gone through some clinical trials now, we're just about to publish some of the results, so we’re quite excited about that because it really looks like this very common and non-toxic drug may actually be able to help reoxygenate human tumours and then make them more sensitive to radiotherapy. So that’s one approach and on the other side where we're talking about these reactive oxygen species that we know are highly produced in cancer cells, we’re trying to take advantage that that leaves cancer cells with some vulnerabilities so they become really dependent on antioxidant pathways to deal with all these reactive oxygen species. So, that’s really a focus on specific protein pathways as you call them and where they're certain protein that the cancer cells are really dependent on for their survival that normal cells aren't really that dependent on. So an example of that is a protein called PRDX4, Peroxiredoxin-4, which is a protein that metabolises hydrogen peroxide and so we've found that if you target this protein you get a lot of cancer cell death and even in a very nasty cancer like pancreatic cancer and so that means that that protein can be an interesting new therapeutic target and so were looking at ways to find small molecules that can actually works as drugs against this particular protein.

AMY: That is very cool and it’s exciting to see how many different pathways you have that you can work with these tumours just by manipulating its microenvironment and play around with different pathways. That’s really cool. What do you predict for the future of your research? Will it be involved in diagnosis or therapeutic treatments?

DR. KORITZINSKY: Well I think that the work that we do in general I would say as a field not just my lab but as a field, I think that it will be very applicable to both predictive biomarkers as well as therapies. So, coupled biomarkers with therapies and you know this is really the direction that all of us are going now in cancer research is more individualised treatment. You know we used to make a diagnosis and also prescription for therapies that was very population based and of course to some degree they still are. Where you know a patient would present with some clinical features that would send that patient for certain treatment. And what we really want to do more and more going forward is to understand specifically in the individual patient what this particular tumour would be vulnerable to. And so use much more targeted drugs than general chemotherapy for example that are really poisons and to use something that is very targeted to the specifics of this tumour. And so I think in my field which is about hypoxia and also redox homeostasis is that you know the way we see this going is that you would for example asses whether the patient's tumour is hypoxic and you would look at maybe even start a treatment and see if that changes. And if that tumour still was hypoxic a little bit into treatment you know that you have a poor chance of curing that tumour and so that I think is when you would probably go in with some hypoxia modifying treatments. So you know one example is the drug we worked on like metformin or other drugs that other groups are working on that could be hypoxic cytotoxins. Cytotoxins are radiosensitizers or metabolic reprogrammers. So I really think that going forward we will have these pairs you could say of tests that we do to characterise the specific tumour and then matching that up to a treatment intervention like for example something. That modifies hypoxia or on the other hand something that takes advantage of a redox vulnerability.

AMY: That's very exciting that you're leaning more towards individual treatments. I think that will definitely prevent a lot of bad side effects that come with the current treatments. And it's exciting to see how you kind of funnel down from starting with one thing and then checking in with the tumour to see if the environment is still hopox or not and then adjusting as you go. I think that’s going to be a lot more effective, that’s very cool. So for my last question, what advice do you have for undergrad and graduate students who want to or are pursuing medical research?

DR. KORITZINSKY: Well first of all, I would encourage them to stay on that path. I think you know it can be a very challenging path. A lot of challenges associated with being in research but also a really, really rewarding path. And so I think one thing to think about is what we would like to learn. I think from our research experiences both in undergrad and grad. Because it's so much to learn, we learn about a specific field that we work in, we learn very specific techniques that are useful to us in that field and these are all very valuable experiences. But I think even more important is to learn about scientific approach and how to really do good research and so I would advise everyone to seek different experiences and see how this is done in different labs and really try to get experiences in environments that stimulate this kind of thinking. So for example, why is this question a really important question to ask? How does this approach or experimental design really answer an important question? How do we interpret these kinds of data? What are the limitations? All these kinds of really scientific thinking, I think is extremely important to develop as a young researcher as much as things we tend to focus on which is learning as many techniques as possible. And I would say from my own experiences I mentioned I actually visited three different labs during my PhD which is quite unusual. It was very formative because you know it could really show me how different three different research environments are and what we would strengths from all those different environments and ways to approach things. And so I would encourage trainees to seek different experiences and to think about these things and really develop their scientific skills in addition to their more sort of technical and tangible skills

AMY: Diversifying experiences seems like really good advice, you're definitely going to learn like you said how to ask those questions and I think that will lead to a lot more better science, prevent misinformation and that’s really good advice. Well thank you so much for joining us today Dr. Koritzinsky. It was fascinating to hear about the work you are doing in cancer research and I'm excited to see the impact it will have on subsequent cancer research and treatment.

DR. KORITZINSKY: Well thanks very much for having me Amy, that was my pleasure.

AMY: That’s it for this week of SciSection! I'm your journalist Amy Stewart and make sure to check out our podcast available on global platforms for our latest interviews.


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