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Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on the Scope.

Host: Only 15% of patients with squamous cell lung cancer survive to five years past their diagnosis. It is a difficult cancer to treat. My guest, Dr. Trudy Oliver has developed a new tool for understanding the disease and developing targeted therapies.

Dr. Oliver, you've developed a mouse model for lung squamous cell carcinoma. Why is this important?

Dr. Trudy Oliver: This is really important because, up until now, we've known very little about this disease. Most patients with squamous cell carcinoma are treated with chemotherapy and when that doesn't work, patients really don't have any second line treatments. Whereas for other lung tumor types, over the past 10 or 20 years, there've been tremendous advancements in developing targeted therapies and we really lack these targeted therapies for squamous cell carcinoma of the lung and one of the reasons why our understanding of this disease has lagged behind is because we don't have good model systems.

Host: And in the process of making this model for lung squamous cell carcinoma you've made some important discoveries about what triggers formations of these tumors.

Dr. Trudy Oliver: That's right. So in 2011 a group called the Cancer Genome Atlas sequenced about 200 human squamous tumors and in that process they discovered the genes that are most frequently altered in the disease, one of which is called SOX2 . So SOX2 is frequently overexpressed or highly expressed in the human squamous tumors and so we took a unique approach to use viruses to deliver genes to the mouse lung that we think are important drivers of the disease. And so we put SOX2 in viruses and delivered them to the mouse lung by having the mice inhale the viruses and the viruses then allow the expression of SOX2 in the mouse lung. This in combination with other - specific other hits in the lung that we engineered - led to the exclusive development of squamous lung tumors.

Host: When you tested these in mice, I mean, did you think it would work or did you think it would work as well as it did? I mean I don't know. It seems kind of amazing to me actually.

Dr. Trudy Oliver: It definitely felt like... and that's probably why it was so exciting is it definitely felt like this is a longshot and part of the reason why it was a longshot was our approach. So we knew that these genes were important and we knew that if we made genetically engineered mice, that costs thousands and thousands of dollars and take years to develop, we believed we'd ultimately have a model but we didn't know what combination to use.

Host: Oh, I see.

Dr. Trudy Oliver: So realistically, to test every important combination would take millions of dollars and five, ten years and I knew that I couldn't afford to do that. So the longshot was we said, let's take advantage of these viruses that will allow us to develop - to deliver many genes in a short amount of time with a lot less money but, technically, to deliver these genes is not an easy thing. So we infected a lot of mice with a lot of genes in different combinations and then we monitored the mice by micro-CT imaging.
So we actually have a device where you put a mouse on a little bed that rotates in a machine and then we get 3-D images of what's going on in the lung. They're tiny. If you kind of look at your thumb, the mouse lung is really no bigger than the end of your thumb and the first time we saw a big mass in the lung was thrilling.

Host: Yeah.

Dr. Trudy Oliver: The whole lab was excited and screaming and running around high-fiving each other. Just to see this blob in the lung. And once we started seeing the second tumor and the third tumor, we knew we were on to something.

Host: So how similar are these tumors in the mice to what humans get?

Dr. Trudy Oliver: They are remarkably similar. In fact, I would say that a pathologist, looking under the microscope at our tumors, would not know it's from the mouse. They would think they're looking at the human disease. So they visually look like human tumors and then when we stain them for biomarkers of the human disease, which are used to diagnose that this is a human squamous tumor, our mouse tumors light up for those markers.

Host: In your model you actually combined two changes to gene expression, right? So there was the SOX2 change and then one of another gene...

Dr. Trudy Oliver: That's right.

Host: Lkb1.

Dr. Trudy Oliver: So SOX2 expression alone in the mouse lung doesn't really do anything in terms of cancer. But what we found is that when we combine that with loss of this gene called Lkb1, which is also called a tumor suppressor, what we found is that that led to squamous cell lung tumors.

Host: So help me understand how, like, if someone were to develop this kind of cancer, how it might happen. Would they inherit one of those mutations first or you just don't know, sort of, the sequence of events that would lead to those changes and tumor formation?

Dr. Trudy Oliver: So we know that in many cases in cancer, having just one genetic change is not sufficient to make a tumor. It usually requires two or three or seven hits, as we call it, to - for cancer to develop. We know a lot of things in our environment that predispose to cancer. Smoking is definitely one of the biggest risk factors for lung cancer but there're other things, like, asbestos exposure, radon exposure, which is common in Utah. Poor diet, lack of exercise, any of these things can lead to cell stress in the body and when we undergo any kind of cell stress, which could be from our environment but could be just the internal workings of our cells, this can lead to mutations.

Host: What do you intend to do with this model now?

Dr. Trudy Oliver: Well, this model is really the first step now to begin to understand the disease like we've wanted to do and so there are so many exciting things that we can use this model for. One of which is to really understand what is the cell of origin of this tumor. What lung cell type do these hits, SOX2 and Lkb loss, arise in that lead to the development of this specific tumor type?
The second thing that we can ask, that I'm really excited about, is what therapies work. We can use the mice to test novel therapies, novel combinations of therapies and we can do this in a way that would be impossible to do in humans. This is the most exciting thing we've done. Now that we have a model it just unleashes so many questions that we can ask to gain a better understanding of the disease.

Announcer: Interesting. Informative. And all in the name of better health. This is the Scope ÈËÆÞÖгöÊÓƵ Sciences Radio.