An Ingenious Approach to Combatting Drug Resistance in CancerJul 18, 2014
Cancer is difficult enough to treat as it is, but when it become drug resistant, it becomes nearly impossible to stop. Trudy Oliver, Ph.D., an assistant professor of oncological sciences at the University of Utah, has devised an exciting approach to understanding and combatting drug resistance. She describes her work, progress, and hopes for the future.
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Host: Cancer is difficult enough to treat as it is but, when cancers become drug-resistant, they become nearly impossible to stop. My guest Dr. Trudy Oliver, a professor of oncological sciences at the University of Utah and a Huntsman Cancer Institute investigator, has come up with an exciting approach to understanding and combating drug resistance.
So, Dr. Oliver, I was at a talk of yours where you said that you have some crazy ideas for studying drug resistance in cancer. Why do you think they're crazy? What is crazy about your ideas?
Dr. Trudy Oliver: Well, I think I should say that they're ambitious. So we're at a time now where technology has come to the point that we can ask, in a very comprehensive way, what are all of the genes that are altered in a given cancer cell? And so we want to, for the first time, address resistance, address drug resistance, not from having a specific hypothesis that we test but to say globally what is everything, what are all the changes that have occurred in a drug-resistant cancer cell and to integrate that knowledge with high through-put drug screening that temps to identify drugs that resistant cells are now sensitive to.
So our approach is extremely comprehensive, quite expensive and will generate a lot of data that we are going to have to sift through to sort of find the needle in the haystack.
Host: How did you hatch this idea?
Dr. Trudy Oliver: Well, like I said, the timing is right that sequencing, comprehensive deep sequencing, is now really affordable for the first time in history. We can really, for about $1000 instead of $10,000 or $20,000 or even $100,000 ten years ago, we can pretty quickly and relatively affordably understand all of the genetic changes in a drug-resistant cell compared to a non-drug-resistant cell and that just wasn't possible before.
Host: Can you explain how it is that drug resistance happens? I mean, what's happening within the tumor to give it that ability?
Dr. Trudy Oliver: Well, if you think about a tumor, tumors are composed of many cells, thousands, millions of cells, and those cells are not all the same. They all have different properties and some of those cells are going to be sensitive to therapy and some of those cells are going to inherently have the capacity to avoid the drug. And so what happens is that the sensitive cells die and the resistant, the inherently resistant, cells live and go on to make daughter cells that are also resistant.
And so you can imagine that, because cancer has this ability to evolve and change, that the qualities that allow a tumor to resist therapy are selected for and the qualities that make them sensitive to therapy eventually go away. This is actually survival of the fittest. It's Darwinian evolution...
Dr. Trudy Oliver: In a very rapid scale...
Host: In your body.
Dr. Trudy Oliver: ...in which we can actually follow it.
Dr. Trudy Oliver: Exactly. And that's what makes cancer so difficult to treat.
Host: So let's talk about the cancer that you're applying this technology towards. What cancer are you investigating?
Dr. Trudy Oliver: Small-cell lung cancers. So small-cell lung cancer is the second to third most common type of lung cancer but it's really the most aggressive type of lung cancer. Ninety-five percent of patients with this disease do not survive five years and most of them really do not survive one year. It's a highly metastatic disease so it spreads very easily and it's just extremely deadly.
Host: But you're saying that - you were telling me earlier that it actually does respond to treatment, at least initially. Right?
Dr. Trudy Oliver: Right. Back in the 1970s doctors thought that this was going to be one of the next curable cancers because small-cell lung cancer responds exquisitely well to chemotherapy. Tumors really can sometimes just melt away and patients may think that they have a cure but the tumor cells are never completely gone. There may be only a few of them that are very difficult to see but they're there and they grow and divide and tumors come back and when they come back, they are completely resistant to the drugs that they were once sensitive to. And we really have no therapeutic options for patients with chemo-resistant small-cell lung cancer.
Host: Seems like this is kind of the next frontier for cancer research. I mean, attacking drug resistance which is a terrible problem.
Dr. Trudy Oliver: Absolutely. We're getting better and better at treating diseases with frontline therapies but the problem is cancers can evolve and that's what makes them so deadly and so they almost always find a way to evolve around that first treatment. And then we really need to understand what do we do next and what can we do to delay that resistance process?
Host: So explain your approach.
Dr. Trudy Oliver: So our approach is very integrative. We want to understand all of the genes and pathways that are altered in the course of drug resistance and then to identify the genes and pathways that are really responsible for driving that resistance so that we can stop them or prevent them from happening. And to do that we're taking advantage of deep sequencing. So we're sequencing both DNA and RNA of resistant cancer cells, compared to the non-resistant controls.
And so this sequencing information will tell us all of the genes and pathways that are altered in the course of resistance. We're then integrating that knowledge with high-through-put drug screening where we subject the resistant and sensitive cells to large panels of drugs to ask, well, we know that these resistant cells are resistant to a lot of things. A lot of things don't work but what drugs now do work? Because we think the changes that occur, in the course of resistance, also make the cells sensitive to other things and we want to find those things. And so we overlay what we know about the genetic changes that are happening with the drugs that are working to gain a better understanding of resistance and how to target it.
Host: How far have you gone in this process?
Dr. Trudy Oliver: We've been able to see in cell-lines that there are correlations with certain pathways being activated in the cancer cells and that we have drugs that are available for those pathways that are sensitizing the resistant cells to therapy. So now we want to know how common is this? Does this happen uniquely in every different cancer cell line we look at or is this a common trend?
And then the next step will be to take this into a more physiological system like a mouse model. So we do have mouse models of small-cell lung cancer and we're going to ask whether the particular drugs that we found in vitro, in a dish, also work in the mouse model. And at the same time, we are collaborating to obtain human tissue to see whether in human tissue there's a correlation with activation of these pathways during drug resistance and, if there is, we think that ultimately this will lead to taking some of these drugs forward into clinical trials.
Host: So this is really a step towards personalized medicine, right?
Dr. Trudy Oliver: That's right. We're really going to need to, in the future, when a patient comes in with drug-resistant disease, look for evidence of particular pathways being altered. And if they are activated, then we know that particular patient needs to receive this particular drug.
Host: Sounds like a really big undertaking. I mean, are you doing this just in your lab alone or are you working with other groups as well?
Dr. Trudy Oliver: So we are collaborating to obtain human tissue with Intermountain Healthcare and then we're also collaborating with other groups across the country to better understand the drug-resistant state. For example, we have a collaborator in Texas who is helping us understand how the metabolism of cancer cells change in the course of resistance.
Host: And you were telling me that there was sort of a timeline you thought.
Dr. Trudy Oliver: I expect that, within a year, given that we already have some pathways identified that we think are involved, I think, within a year, we should know whether or not this is translating to human tissue and whether or not these drugs are affective in mouse models and at that point we'd be able to submit a story for publication.
Host: Sounds good. And you've been working on cancer for quite awhile, right? What spurred your interest in cancer?
Dr. Trudy Oliver: That's right. So when I was in college, I had two family members, one on each side of my family, develop cancer and they both had very polar opposite outcomes. One was my uncle on one side of my family who had a brain tumor and he was diagnosed around Thanksgiving and had passed away by Christmas.
Host: Oh, gee.
Dr. Trudy Oliver: So very rapid disease. On the other side of my family, my great-grandmother was 91 when my grandmother found a little mass on her neck and she discovered that she had lymphoma and began receiving chemotherapy and I went with her to her chemotherapy sessions and sat on the floor next to her. And that really made a tremendous impact on me just seeing, in this room, a lot of people were receiving chemotherapy, from teenagers to middle-aged people to my great-grandmother.
Dr. Trudy Oliver: And she actually went on to survive and she lived to be 105 years old.
Dr. Trudy Oliver: So she's really a success story. That peaked my interest in college to learn more about cancer. I had experience doing summer research programs and I particularly sought to do a summer research program in cancer in Colorado in the lab of Dr. Paul Bunn. And it turns out that he's a world leader in lung cancer. So that was really my first exposure to cancer, which then led me to pursue my PhD.
Host: Well, very good. Well, thank you so much for speaking with us.
Dr. Trudy Oliver: Thank you.
Announcer: Interesting. Informative. And all in the name of better health. This is the Scope Health Sciences Radio.