Digging into the DNA of Cancer Cells

Research suggests that tweaking a certain gene found in cancer tumors might stop the cancer's growth. Ronald A. DePinho, director of the Center for Applied Cancer Science at the Dana-Farber Cancer Institute, talks about that and other new cancer treatments.

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JOE PALCA, host:

From NPR News, this is TALK OF THE NATION: SCIENCE FRIDAY. I'm Joe Palca.

For the rest of this hour, a look at what's happening on the frontlines in the war on cancer. For those of you too young to remember, the phrase war on cancer isn't mine. It's Richard Nixon's. In 1971, Nixon - then president - declared war against this enemy. Since that time, by one estimate, at least $200 billion have been spent on basic and clinical research toward the goal of ending malignancies.

My next guest says all that money and effort spent is finally beginning to pay off as we dig deeper and deeper into the DNA of cancer cells and possibly figure out how to switch tumors off for good.

Let me introduce my guest, Ronald DePinho. He's the director of the Center for Applied Cancer Science at the Dana-Farber Cancer Institute. He's also the American Cancer Society research professor, and a professor of medicine at Harvard Medical School, and the chair of the Human Cancer Genome Advisory Board. He joins us by phone. Thanks for talking with us today, Dr. DePinho.

Dr. RONALD DE PINHO (Director, Center for Applied Cancer Science, Dana-Farber Cancer Institute): A pleasure to be here, Joe.

PALCA: And if you want to join our conversation, you're welcome to call. The number is 800-989-8255, that's 800-989-TALK. And I guess the first question - and maybe it's best to start with the basics - but we all think we know what cancer is, or at least we certainly have heard of it. Now I don't think there's anybody who hasn't. But what do scientist mean when they talk about cancer?

Dr. DEPINHO: I think the context here is very important. So for a normal cell to become a cancer cell, for this aspiring cancer cell to achieve its malignant endpoint, it needs to acquire a range of biological capabilities. It needs to divide inappropriately, become resistant to death signals, acquire a state of immaturity not unlike that of stem cells, it needs to instruct the surrounding host to do things like grow new blood vessels, not attack it with its immune system and so on.

And underlying these newly acquired biological capabilities are genetic changes that occur in the cell's DNA that are required, you know, in a more or less stepwise fashion during the life history over this evolving cancer cell. And essentially these DNA changes attack two major classes of genes, genes that promote the development of cancer - those who are called oncogenes - and others that are eliminated or extinguished during the cancer process, and those are called tumor suppressor genes.

And there is a staggering amount of complexity as we peer into the cancer cell and its genetic makeup with now very high-resolution DNA scanning technologies. It is a sea of complexity where there are dozens upon dozens of changes that occur in a cancer cell. And the big challenge for us has been to identify the mission-critical changes against this sea of complexity, identifying the genes that, if we were to correct them with drugs, would lead to a collapse of the tumor. And those are called tumor maintenance genes.

You could think of them as the Achilles' heel.

PALCA: Tight. Now you just described a set of changes that have to take place in a normal cell - quite a number of them - in order for a cancer to begin and then propagate. How does it happen that we get unlucky enough for all of these things to sort of happen?

Dr. DEPINHO: Well, there are a variety of processes: inflammation, the aging process, dietary factors, environmental factors that all conspire to change, acquire a subset of changes in our DNA. And if we're unlucky enough to target some critical genes that initiate the process, what then happens over the life of that cell is that there is the opportunity for, let's say, mutate or instability mechanism to suddenly occur.

And this creates a hyper mutation situation, a cauldron of change that allows cells to acquire all of these genetic changes. And so what we see when we analyze the cancer cells at the end of the process is an enormous number of change. But we want to identify the critical lynchpins in that sea of complexity.

PALCA: So what's the evidence? I mean, you say that there have to be critical lynchpins and you have to find the Achilles' heel but, you know, people have been talking that way, oh, I'm sure for 20 years now. Why do you think we're closer, you know, to getting there today than we were 10 years ago, for example?

Dr. DEPINHO: Well, I think there's been truly a revolution in our understanding of cancer thanks to the investment that you mentioned at the very beginning of the talk. But about 10 years ago, we asked a very similar question that was published recently in a series of papers that we'll be talking about shortly; where asked the question: If we were to engineer mice with a switchable ankA gene, a gene that initiates the cancer process, once that cancer acquires many other genetic alterations, is that inciting genetic alteration still important in maintaining the tumor? And what we found in this mouse model of a skin cancer called melanoma is that if we extinguished that particular gene, which was the RAS ankA gene, it led to a complete collapse in the tumor and the mice were essentially cured.

And so if we can identify such critical genetic elements against the backdrop of all of these other changes, then they would be worthy therapeutic points of attack. And in fact this concept has now been translated into clinical reality, so there are certain drugs that I'm sure you talked about in the past on your program called Gleevec that target emission-critical change in a blood cancer that, upon treatment, these patients - and this was essentially an incurable disease of the blood, a blood cancer - led to the elimination of those cancer cells from these patients and essentially elimination of the gene product and its aberrant activities, leading to substantial cures and prolongation and survival in many of the patients.

PALCA: We're talking with Ron DePinho of Harvard University Medical School about some of the latest advances in cancer, particularly cancer genetics, and we're happy to take your calls at 800-989-8255. And let's take a call now from Matt(ph) in - is it Kennewick, Washington. Matt, welcome to the program.

MATT (Caller): Yeah, thank you. I'm not in any way a scientist. I'm an avid reader of scientific information, though, and this subject fascinates me. So I have kind of a - something that I've gleaned from my research that maybe might be somewhat of a controversial view.

I totally like how you're, you know, talking about it being a foreign entity, invasion, you know, the tumor in the body. Of course, I don't know all the scientific terms for it. But I think a lot of times through our lifestyle that we've brought it upon ourselves, allowed our bodies to have that invasion. And you know, I think everyone always speaks of looking for a magic cure, a drug or something, which might be possible.

I think a lot of times, though, just our health, just changing our diet or the way we live can also remove a tumor. I've seen it firsthand in my mom, for example. I just wanted to point that out. I think there's a lot of things that could be done to counteract that organism that has, you know, come into the body.

PALCA: Matt, thanks for that call. Go ahead, Ron DePinho.

Dr. DEPINHO: That's a very insightful question. So cancer is really the culmination of all of these genetic alterations, and those genetic alterations come from a variety of sources. One is we're born perhaps with a few of those from our genetic makeup. That's called family history and risk.

Others are accumulated during the normal aging process. And in fact advancing age is the most important cancer-causing agent, so to speak. And the other thing, which we have a tremendous amount of control over, is our behavior and the kinds of insults that are brought about as a result of extensive ingestion of certain compounds or - such as tobacco smoke or excessive drinking and things of that nature.

And a great deal of what we can do in our lives is try to alter our exposure to those kinds of activities that can have a dramatic impact on the risk of developing cancer as we age.

In fact, there has been recent news over the past couple of years - the deaths due to cancer are declining. This is quite remarkable because with advancing age, cancer incidents should increase, and yet we're seeing a reversal in the trend. So this is remarkably good news, and a great deal of that has to do with prevention and change in lifestyle, such as reduced smoking and a variety of other things.

So I think it's critical to make sure that you adopt a healthy lifestyle, exercise, don't smoke, don't excessively drink, and listen to your mom and eat your vegetables.

(Soundbite of laughter)

PALCA: Yeah, that sounds like good advice always. Let's take another call now and go to Minnie(ph) in South Carolina. Minnie, welcome to SCIENCE FRIDAY.

MINNIE (Caller): Yes, sir. My question is - I'd like to hear him speak about the research that's been done on women who breast-fed their babies, how that effects a woman's rate of cancer or if there's any effect on the child.

PALCA: OK, Minnie, thanks for that question. Ron DePinho?

Dr. DEPINHO: I can answer that question, sure. Actually, there have been excellent studies that have shown that there are dramatic reductions in the risk of developing breast cancer for those women who do breast feed. And in fact if you breast feed for a collective time of two years, you get the most dramatic reductions, and they're quite remarkable.

Breast cancer also brings up some opportunities to talk about how great the advances have been in cancer science and cancer care, because it's there that we've had dramatic effects on the deaths due to breast cancer. There's another magical drug that has been developed called Herceptin that targets one of these mission-critical genes that we talked about in the development of cancer.

It's called the - it's a receptor that's important for regulating the growth of breast-cancer cells, and this has had a dramatic impact on the survival of patients with cancer.

PALCA: We're talking with Harvard University Medical School's Professor Ron DePinho about cancer and about the war on cancer. I'm Joe Palca, and this is TALK OF THE NATION from NPR News.

So you mentioned just a minute ago that cancer rates are - cancer deaths are going down; and surprisingly so because the population in general is aging, and you'd expect to see more deaths, more cancers because of that. So the question I'm wondering is, you know, does it make sense to load your research dollars into prevention and realize that maybe, you know, basic research is just going to take a long time and it's not going to really find the answers in the same kind of time scale as prevention research is in terms of at least helping save the population lines?

Dr. DEPINHO: I think that - you need a balanced portfolio. You need Normandy invasion on this beast that we call cancer. I think prevention will shift the dial so that you diminish the risk, but there are certain individuals that are going to develop cancer as a result of exposures, as a result of advancing age, that are due to intrinsic processes that push people towards this increased risk for developing a malignancy.

So we need to have increasingly sophisticated strategies to do a number of things. One is to prevent. There are now vaccines that can be directed that will lead to dramatic reductions in the development of cervical cancer, for example.

We need increased ability to scan into a patient's body to identify early-stage cancers so that they can be surgically removed. And for patients that present with established fully formed disease, for cancers that grow enormously fast, we need to really understand what makes those cancers tick.

And what's really different, what feels differently now than it did even just five years ago is that we were truly on the threshold of understanding in a very complete way the genetic basis for cancer. We now have in hand model systems that can help us understand which changes are critically important, and we now have increasingly sophisticated technologies to develop drugs that can, like smart bombs as opposed to carpet-bombing, really target those activities that are conferred by those specific tumor-maintenance genes.

So this is a really an inflection point in the history of the field, where I think, you know, I'm a collector of medical textbooks, and I have textbooks that range back from the 1930s. And there are whole textbooks that are devoted to infectious diseases that are now mere footnotes in today's textbooks because of all of the treatments.

And it's safe to say that with the remarkable advances that we're seeing in science now, our children will look back on this period as a very similar period where there was an inflection point. We'll have the equivalent of antibiotics that will allow us to quell these rogue cells in our body and really have an impact on the quality of life.

PALCA: Let's take one more quick question. Robin(ph) from Reno, Nevada. Welcome to the program. Quick question. Robin, are you there?

ROBIN (Caller): Yes, thanks for taking my call. I would like to have your guest talk about and explain the recent finding of cancer stem cells and specifically how those cells differ from the rest of the cells of a cancer. I'll take my call offline.

PALCA: Great, thanks. So Ron DePinho, the 30-second answer on that one, please.

Dr. DEPINHO: So essentially, cancer is an organ system and there small - a subset of cells in the cancer, within the tumor, that are responsible for giving rise to the tumor mass. And those are equivalent to, let's say, our normal blood cells, our stem cells, that give rise to the many blood-cell types that we have in our body.

And the notion is that if we can specifically target those cells, we would be able to generate durable cures against cancer. And so this is just another example of an exciting breakthrough that cancer science has illuminated as a result of the investment, and it's now positioning us to develop therapies that are going to attack this particular compartment that is responsible for maintaining the tumor at large.

PALCA: OK, Dr. DePinho, we have to leave it there. Thank you very much for coming in to talk to us.

Dr. DEPINHO: My pleasure. It's been delightful.

PALCA: Dr. Ronald DePinho is the director of the Center for Applied Cancer Science at the Dana-Farber Cancer Institute.

For NPR News in Washington, I'm Joe Palca.

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