How Can Genetic Research Improve Cancer Treatments? Scientists looking at the genetics of cancer cells say tumors -- even those of the same type of cancer -- vary remarkably from person to person, and so should their treatment. Guests discuss the latest in cancer research, from gene therapy for melanoma, to cataloging the genes associated with colon cancer and breast cancer.

How Can Genetic Research Improve Cancer Treatments?

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IRA FLATOW, host:

This is TALK OF THE NATION: SCIENCE FRIDAY. I'm Ira Flatow.

A little bit later, E.O. Wilson joins us to talk about his new book, The Creation. But first, two recent reports in the journal Science give us a look at the direction of cancer research and how all sorts of cancers might be treated one day.

Last week, a team of doctors reported that they had genetically engineered the immune cells of patients with melanoma and sort of reprogrammed the cells to attack the patient's own cancer. The experiment wasn't terribly successful, relatively speaking, because only two patients out of 17 had a response.

But the experiment was hailed by many researchers as an important proof of concept. It was the first reported successful use of gene therapy to get rid of a cancer.

And this week comes a new report about differences in cancer tumor cells. Scientists genetically analyzed tumors of colon cancers and breast cancers, all taken from different patients. And they found that even within the same cancer type, the tumor varied tremendously from one person to another. As one of the researchers put it: No two tumors behave the same way.

So if cancers are so individual, do our treatments need to be that way, too? Is genetically tailored therapy the future of cancer treatment?

That's what we'll be talking about this hour. Our number: 1-800-989-8255. If you'd like to join in the conversation.

As always when we talk about a medical topic, please do not ask our doctors to diagnose you. If you have concerns about your health, you should ask your own doctor. If you want more information, you can surf over to our Web site at Sciencefriday.com.

Steven Rosenberg is the head of the Tumor Immunology Section and the surgery branch chief at the National Cancer Institute. He joins us by phone from Bethesda.

Welcome back to SCIENCE FRIDAY, Dr. Rosenberg.

Dr. STEVEN ROSENBERG (Director, Tumor Immunology Section): Good afternoon. You're welcome.

FLATOW: Bert Vogelstein is an investigator with the Howard Hughes Medical Institute. He is also director of the Ludwig Center for Cancer Genetics and Therapeutics at the Johns Hopkins Kimmel Cancer Center. He joins us by phone from Baltimore.

Thank you for talking with us today, Dr. Vogelstein.

Dr. BERT VOGELSTEIN (Director, Ludwig Center for Cancer Genetics and Therapeutics): Thanks, Ira. I'm a big fan of your podcast, so it's exciting to be on the show.

FLATOW: Oh, great. Well you can tune in tonight and hear yourself.

Well, let me start with you then, Dr. Vogelstein. Let's talk a bit about your team completed the sequencing of the genes involved in the colorectal and the breast cancer.

First, let me ask you why you picked those two cancers to look at.

Mr. VOGELSTEIN: Well, they're two common cancers. Together, they account for about one-fifth of the total cancers in the world; over 2 million cases combined in the world. So we felt they would be representative of the most common types of tumors that affect people.

FLATOW: And you made a surprising finding comparing the two.

Mr. VOGELSTEIN: Yes. We expected to find more similarities than differences, but in fact we found the opposite. Of the 200 genes identified in the two cancers, only two of them were shared amongst colon and breast cancers, which means these two cancer types are really quite different.

In fact, not only were the genes different but the mutation signatures, the types of mutation that occur in each, were really quite distinct.

FLATOW: Wow. That really is surprising. Does that explain why certain chemotherapy used in colon cancer might work for one person, let's say, and not for another?

Dr. VOGELSTEIN: It certainly could. It could also perhaps explain the results that you mention in your introduction in the sense that it's very difficult to get uniform treatments for patients with any single disease. And perhaps part of the reason for that is because each cancer is unique.

FLATOW: Dr. Rosenberg, let's talk about your recent paper in Science where you treated patients with melanoma and got those two out of 17 to what - to be almost free of melanoma or completely free?

Dr. ROSENBERG: Well, both of the patients that responded are completely disease-free a year and a half after treatment.

The approach that we took was to try to genetically engineer the body's own immune system to recognize the cancer. The body recognizes a cancer as foreign but not foreign enough to reject it. And so we isolated normal circulating white blood cells from patients.

These are called lymphocytes. They are the warriors of the immune system that circulate through the body. These were normal lymphocytes that did not have any ability to recognize the cancer, and we genetically engineered them by putting into these cells genes that code for receptors that enable the lymphocyte to recognize and kill the cancer cell.

And when we genetically modified these normal cells to become anti-tumor cells, grew them to large numbers and gave them back, we saw cancer regression in two patients who, again, now are disease-free almost two years later.

FLATOW: Can you speculate or do you know why only - you had such great success with two and not the other 15?

Dr. ROSENBERG: We began these studies that we reported last week two years ago. In fact, the patients were treated a year and a half to two years ago. And at that point, we were utilizing genes that coded for receptors that were actually quite weak.

We now have isolated receptors that can recognize melanoma as well as many common cancers that are anywhere from 10 to 100 times more potent in their ability to recognize cancer antigens than ones we used in the Science paper.

And so I think we were teetering on the brink of getting it to work. The fact that two patients could respond when they received normal genetically engineered cells is a proof of the principle that it can work. And we're about to institute trials now with these more potent receptors. I'm hoping it will work more effectively. But of course it needs to be studied, and these clinical trials will begin soon.

FLATOW: Dr. Vogelstein, will your work be of use at all to someone like Dr. Rosenberg?

Dr. VOGELSTEIN: Well, there was an interesting finding which could be relevant to Dr. Rosenberg's work. In each cancer, we found that there are approximately 100 changes that affect the amino acid sequence and therefore the structure of the proteins. That means there are 100 different proteins in every cancer cell that are found nowhere else in the person's body. And finding such distinct proteins which could potentially be antigens is one of the holy grails of immunology.

So I would hope that those kinds of proteins could prove useful targets for Dr. Rosenberg to develop immuno-therapeutic approaches against.

FLATOW: Dr. Rosenberg? Sound like…

Dr. ROSENBERG: You know, I think that's an important point. Any change that occurs, any mutation that occurs - and Dr. Vogelstein has so elegantly described the important ones - can potentially be a target of the immune system.

Now if that were to be the case, we would actually have to target the genetic manipulation individually for each patient.

What we're searching for are shared receptors that will recognize more common determinants. So what we're doing now in melanoma patients is targeting a gene, a receptor, an antigen called MART-1 which is expressed in about 95 percent of melanomas.

The clinical trial we hope to start in a few months targets a gene called p53, which, when over-expressed, puts molecules on the cell surface that can be recognized by lymphocytes and are expressed in about half of all common cancers, including breast cancer, colon cancer, and other types of common epithelial cancers. So this work is all intertwined.

I want to emphasize how critical it is for the development of these translational studies to understand the more basic scientific studies that have been so elegantly done by Dr. Vogelstein and his group over the past several decades. The support of that kind of basic science is what is required to take these kind of findings to effective patient treatments.

FLATOW: Mm-hmm. 1-800-989-8255 was the number. Dr. Vogelstein, were we very naïve in our thinking when it comes to cancers to think that all colon cancers are the same and they can be treated the same way? Is that what this work really show, that cancer is much complex than we thought it was?

Dr. VOGELSTEIN: Well, I think there has probably been a discrepancy among physicians who've long noted and realized that every cancer patient seems to be different both in the way their tumors appear and behave clinically and respond to agents.

And they certainly understood this heterogeneity, these differences. On the other hand, basic scientists, molecular biologist like me, perhaps were somewhat naïve. We had discovered a variety of common mutations that affected a significant fraction of tumors, but really hadn't realized the depth to which those differences actually occur.

It's kind of like we were looking under the street lamp for our lost keys, and we were only finding the keys that were under the street lamp. Now we have the capacity to shine a giant spotlight on that street and see keys that we never thought existed, and now perhaps we realized just how complex this beast is.

FLATOW: Dr. (unintelligible) is melanoma so much different, Dr. Rosenberg, that you can create these that attack all the melanomas as opposed to the colon cancer, which might be more specific?

Dr. ROSENBERG: No, we've studied melanomas as a model system. But one can identify receptors that can recognize antigens on all common tumors. It doesn't appear that when tumors are targets of the immune attack there is very much difference between them.

But to further enlarge on what Bert has said, I think what we're beginning to realize more and more is that we are going to need to tailor treatments to the individual characteristics of patients' tumors. And so in the genetic manipulations that we use, basically every patient gets treated with an individual drug, their own cells that are genetically modified to recognize an antigen on their tumor.

FLATOW: Mm-hmm. And so we will be going to a new kind of medicine then?

Dr. ROSENBERG: I think the kind of personalized medicine that involves a treatment - the decision that's based on the genetic basis of a patients tumors the mutations that are identified may well be the future of cancer treatments. And the kinds of mutations that Dr. Vogelstein is identifying are going to be crucial to the development of that treatment approach.

FLATOW: Is your approach using the immune cells applicable to other cancers beside the melanoma?

Dr. ROSENBERG: Well, we have identified now receptors that we actually generate in a mouse that is not subject to all of the normal tolerance mechanisms that exist in the human. The body recognizes it owns self-antigens and tends to raise only very weak receptors against it.

And so one can immunize mice, raise T-Cell receptors that you could put into patients cells that can recognize tumor antigens on lung cancer, breast cancer. The antigens we've targeted are P53, and then another kind of antigen called ESO1(ph) which is only present on tumor cells. And the only normal cell it's present on is the testis, which is a immunologically protected site.

And so, I believe we do have receptor molecules now, obtained from the mouse, from the human, that we can put into human cells that can recognize a variety of cancers.

FLATOW: Were going to take a short break and come back and talk lots more with Steven Rosenberg and Burt Vogelstein. See if we can take some of your questions on these cancer treatments, so stay with us will be right back.

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FLATOW: I'm Ira Flatow, this is TALK OF THE NATION: SCIENCE FRIDAY from NPR News.

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FLATOW: You're listening to TALK OF THE NATION: SCIENCE FRIDAY. I'm Ira Flatow. We're talking this hour about new research in cancer with Steven Rosenberg and Bert Vogelstein. Our number 1-800-989-8255.

Let me ask you whether we can use any of these techniques now for earlier detection of cancers and maybe earlier treatments?

Dr. ROSENBERG: Well, when one is developing new treatments of unknown effectiveness but possibly toxicities, one always begins those clinic studies in patients with advanced disease that have no other known effective treatments available to them. And that's what we've done. All the patients that we've treated thus far with these genetic engineering approaches are patients with metastatic cancer that have proven refractory that is not responsive to other standard treatments.

When in medicine and medical research you find treatments that can work, then the natural tendency is to move it earlier in the course of the disease. But this is very much a gene therapy in the infancy of its development, and hopefully, if we can continue to successfully develop it, then it would be moved to patients that have earlier stages of the disease. Right now every patient we treat has life expectancies of just a few months.

FLATOW: Mm-hmm. Let - go ahead, sure.

Dr. VOGELSTEIN: The - I think perhaps one of the things you were trying to get at with that question is early diagnosis or prevention. And the kinds of innovative studies that Dr. Rosenberg has long pioneered are going to be crucial in the fight against cancer.

But there is another strategy entirely that, in the long run, may be at least as effective for minimizing suffering and deaths from the disease. And that is detecting them when there at a stage very early, early enough that they can cured by straightforward conventional surgery without really the need for new types of therapies.

And one of the basis - reasons for trying to discover the genes better involved in these cancer is to try to get new markers, mutant genes that are only found in the cancers, not normal cells, and then to look for evidence of those mutations, say, in the blood.

So one can imagine in the future, a patient comes in for his or her yearly checkup, takes a sample of blood, and the physician would be able to tell them with great definitiveness that they have a cancer in some organ. And then in the best of worlds that could be removed and they would be cured.

FLATOW: Mmm-hmm. 1-800-989-8255 I think we will have time for a call or two. Let's go to Susan(ph) in Lakewood, Colorado. Hi, Susan.

SUSAN (Caller): Hi. My question is do any of these new findings shed light on the cause of cancer? I mean can you reverse engineer to, say, it's a natural deterioration or it's viral or environmental?

FLATOW: Mmm-hmm.

SUSAN: Thank you, and I'll take my answer off the air.

FLATOW: All right. Dr. Vogelstein, you found all these mutations. Were they there at the beginning or did they happen over time? Or what was the cause of the cancer.

Dr. VOGELSTEIN: Yes, that's an interesting question. None of the mutations, the hundred mutations that occur in a cancer, were present at birth. They all developed after birth and it - the reason that they developed is still a bit mysterious, but there are some clues provided by the new study.

For example, we thought that the mutations in breast and colon - the kinds of mutations would be the same. But they really were remarkably different. That is, in breast cancers the mutations would often be say a G to an A, whereas in colon cancers, they were often a G to a T. And that really strongly hints that there is some isogonics agents, perhaps mutagens or carcinogens, that are responsible for some of those mutations, if not most of them.

And if we could identify those agents epidemiologically, that could provide a good start on preventing cancer.

FLATOW: Mm-hmm. Gentlemen, I want to thank you for taking time to be with us today, and have a good weekend. And good luck to you. We'll have you back when you're publishing your next papers.

Dr. VOGELSTEIN: Thank you.

Dr. ROSENBERG: Thanks.

FLATOW: You're welcome. Steven Rosenberg is the head of the Tumor Immunology Section and a surgery branch chief at the National Cancer Institute.

And Bert Vogelstein is an investigator with the Howard Hughes Medical Institution. He's also director of the Ludwig Center for Cancer, Genetics and Therapeutics at Johns Hopkins Kimmel Cancer Center.

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