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Using Genetics to Target Cancer's Achilles' Heel


Next up, yet another way that genetics is giving rise to new ways to treat cancer. A few months ago I was at a conference focusing on individualized medicine; that's treating people individually, using medicines that were designed for each person's genetic makeup. It's a new frontier that we'll be talking about more.

And during one of the breaks I heard - someone came up to me with an anecdotal report that doctors were having success treating some people with late-stage cancer where no cancer drugs were used. There were none that were working on this person. But they had great success shrinking tumors with drugs used to treat other diseases. No cancer drugs.

These were off-the-shelf drugs used to treat other diseases, and the drugs worked by attacking the genetic vulnerabilities of these tumors. Now, if you could peek into the genetic makeup of cancer cells and see where their natural vulnerabilities lie, could you then stop them in their tracks? It's a tantalizing question that researchers are looking into, and perhaps it could revolutionize the future of cancer treatment.

Just imagine instead of, you know, a blanket treatment for all patients, let's say with breast cancer, doctors may be able to look at genetic information on a case-by-case basis, prescribe the medications that are tailored for the individual, a case of personalized medicine. Plus research in genetics may help pharmaceutical companies to develop new drugs to treat cancers, different kinds of cancers.

And that's what we're going to be talking about this hour. Let me introduce my guests. John DiPersio is chief of oncology at Washington University School of Medicine and Barnes-Jewish Hospital. He's also deputy director at the Siteman Cancer Center in St. Louis. He joins us from KWMU. Welcome to SCIENCE FRIDAY.


FLATOW: Thank you. I also want to bring on Gary Gilliland, is senior vice president and global head of oncology at the pharmaceutical company Merck & Co. Gary Gilliland joins us from a studio at Stanford University. Welcome to SCIENCE FRIDAY.

GARY GILLILAND: Thank you, Ira.

FLATOW: Let me begin with this case. Is this something, Dr. DiPersio, the case I described, I had heard anecdotally, is this something you're hearing more and more of these days?

DIPERSIO: Well, I think it's happening more and more, not only hearing about it, but we see it every day, and patients are - as we learn more about the genetics and genomics of cancers, we're starting to identify mutations that we didn't expect to find in these specific diseases.

And some of these mutations are actually so-called drug-able or actionable mutations so that in patients that have otherwise no other options, some physicians are actually applying therapies that were designed for other diseases to these patients with cancer.

And I can't tell you that clinical trials have been done, but obviously this is going to be the future of cancer medicine to a certain extent and that our therapy will be directed in large part to these specific mutations that define the patient's cancer even more so than that particular cancer in general.

FLATOW: Gary Gilliland, do you agree?

GILLILAND: Yes, I agree with that. I think that having a comprehensive understanding of the complexity of the genetics of tumors provides guideposts for us to use to tailor - to develop and to tailor the right medicines for the right patients. As you point out, in some cases there can be off-the-shelf opportunities for medicines based on what Dr. DiPersio described as actionable mutations. But in other cases it helps guide us and our development of new medicines to treat cancers, taking advantage of the understanding of the genetics in being able to individualize treatment according to the genetic makeup of a person's tumor.

FLATOW: We're going to take a short break and come back and talk lots more about these cancer treatments. Our number, our phone number, you're welcome to call in, our number is 1-800-989-8255. You can also tweet us @scifri, @-S-C-I-F-R-I, talking about individualized medicine and targeting cancer cells and seeing where we might develop new drugs that target the vulnerabilities on them.

Instead of just throwing a drug out for, let's say, breast cancer or other kind of cancer, we now target the cells, target the cancers, target the spots on those cancers itself. Stay with us. We'll be right back after this break.


FLATOW: This is SCIENCE FRIDAY. I'm Ira Flatow. We're talking this hour about new approaches to cancer treatment based on genetic research with Dr. John DiPersio, chief of oncology at Washington University School of Medicine; Gary Gilliland, senior vice president and global head of oncology at Merck. Our number is 1-800-989-8255.

Let's talk about what actually the targets are on the cancer cells. John, can you give us an idea why they - why these medicines attack this cancer differently than just the old style?

DIPERSIO: Well, some of the cancers actually are - have genes that are mutated to produce products, which constitutively are always active. And so these are genes that are normally expressed at relatively low levels and are minimally active, but then when they get mutated, they become hyperactive.

And in that situation, drugs which temper down the activity of those genes or those mutated genes actually have an impact on the growth rate and spreading of some of these tumors. So that's an obvious situation where a gene is activated and a drug is used to inhibit that activity.

FLATOW: So you can turn off the gene, you can turn off the cancer cell by turning off the gene.

DIPERSIO: Yeah, and the cancer cell sometimes is dependent upon that gene or we call it addicted to that gene. But there are other mutations which look good on paper and look like a drug would work well, but the cancer cell is actually not addicted to that pathway, and those genes may not have a significant effect on the growth of those tumor cells.

FLATOW: Gary, if genome sequencing becomes available to more people in the future, how does that change the type of research done at companies like Merck and other pharmaceutical companies?

GILLILAND: Well, it is changing, and it will change. I think there's a time in the near future when every individual will have a complete understanding of the genetic content of their tumors, and that will help guide us not only to develop new medicines but to specifically identify those patients that are most likely to respond.

We're already bringing that into play with a number of our programs. For example, we're looking at a protein called p53; it was discovered back in the late 1970s, that serves as a guardian of our DNA. And its job is to sense mutational damage to DNA, and when it senses that, it activates a series of programs in a cell that result in suicide of that cell.

This is one of the ways that the body prevents us from developing cancer. We know from the work of many investigators that cancer cells have not just dozens of mutations but in many cases thousands of mutations. And in those cells, p53, the guardian is handcuffed to a molecule, a protein called Hdm2, and we and others have been working for years to identify the molecular key that unlocks that handcuff and allows p53 to sense DNA damage in cancer cells and to engender the suicide programs in those cells.

So the genetic sequencing actually gives us the opportunity to do something that for John and I, as hematologists and oncologists, is an emerging paradigm of not treating with chemotherapies in all patients, that have both salutary effects in treating cancer but also their toxic side effects, but rather using these exquisitely targeted laser-directed treatments to a specific genetic alteration that we think will help that particular patient.

FLATOW: I have a question here from - a tweet that came in from Julie Sudameir. It says: Can this genetic research be used to test for presence of cancer before it spreads, like we use blood-specific antigens?

GILLILAND: Well, that's a very good question, and I think your previous story speaks a little bit to that, that we can look for mutations that we know are associated with specific kinds of cancers, in that case in a cervical Pap smear. But there's an emerging literature that suggests that a very small number of cancer cells circulate in the peripheral blood and may be the harbingers of the development of cancer or may provide opportunities to measure treatments of cancer where you're assessing the presence of the mutation in the peripheral blood.

FLATOW: Dr. DiPersio, tell us about benefits that you have seen. Any specific cases you can tell us about?

DIPERSIO: Well, I think that probably the most obvious example of how targeted therapies work in a specific disease is chronic myelogenous leukemia. And that did not require any next-generation sequencing approaches to figure this out. Many investigators have been looking at the role of an enzyme called tyrosine kinase in that disease.

And this is again another example of how a tyrosine kinase, which is normally expressed in the nucleus of cells and expressed in a very low level, is somehow corrupted to exit the nucleus and go into the cytoplasm because it's inappropriately fused to another gene.

And this fusion product then essentially corrupts the biologic behavior of these cells and allows them to grow and proliferate faster, and you develop a kind of chronic leukemia, which over time can develop into an acute leukemia. That's a very specific example of a single mutated gene, in this case a fusion of two genes which results in a mutated gene product, which drives the proliferation of these cells.

And that is the primary mutation in CML. We don't know for sure, but we think it's one of the primary mutations, and therefore a single gene, if it could be inhibited, might actually work to control the disease. And this is exactly what's happened. A number of small molecule inhibitors have been developed that inhibit this enzyme and actually make this disease, which was previously a lethal disease, into a chronic disease like diabetes or hypertension, and people can live with it for decades just taking this pill. There are many other examples.

FLATOW: Yeah, I've heard of an example of Lukas Wartman. Can you tell us that story?

DIPERSIO: Well, that's - Lukas is a junior faculty member in our group, and it was an amazing story. We had been sequencing cancer genomes for about a decade and were some of the first in the world to do that. And many thought that we were crazy trying to dissect or decipher the sequence of three billion base pairs of human genomes associated with cancer cells.

But I think, in retrospect, the visionary behind this, Tim Ley and Rick Wilson here, were right in that this has become and will become part of medicine. And we have been doing - we had been doing this for some time. Lukas was actually a medical student and a fellow in training and then a young faculty member, and he had developed acute lymphoblastic leukemia.

It had relapsed several times, and he went through a transplant and multiple therapies, and he finally was left with relapse disease after a transplant with essentially no therapies that were working. So we sequenced his genome in record pace, probably we finished the whole sequence in about seven to 14 days, and ironically did not - identified a number of mutations, but none of these mutations we thought we could intervene with to arrest the disease or control the disease.

We did one last genetic manipulation, which is called RNA sequencing, which is to take the RNA of those cells and to see if any normal genes, not mutated genes but normal genes, were inappropriately over-expressed, in other words expressed at some enormously high level or low level so that we could intervene with the activity of those normal genes.

And in fact one of the genes we found was over-expressed 800-fold in his tumor cells, and that was a kinase, and that was associated actually with a completely different disease, for which there was a biologic small molecule, several small molecules, actually, that targeted this enzyme.

So we used it in his situation and induced a complete remission. He was then able to go on and get a second (unintelligible) transplant two and a half years ago, and he's been well since, and he's a fulltime faculty member doing well with us right now.

FLATOW: So if I were to boil that down, it would be to say that you found a drug that was used for another kind of disease and treated his cancer with it successfully.

DIPERSIO: Right. And we actually targeted a normal gene and not a mutated gene in this particular situation. But it was altered in that it was over-expressed almost 1,000 times.

FLATOW: There must be other kinds of cancers that could work this way, no?

DIPERSIO: Many, yeah. I mean every cancer has its own Achilles' heel, I'm sure. We just have to figure out what that Achilles' heel is and intervene.

FLATOW: And Gary, it would be your contention that you might find new drugs instead of just looking for off-the-shelf drugs that would be targeting these.

GILLILAND: Yes, I think a complete understanding of the genetics will provide an opportunity for the development of new drugs based on these insights. So that's certainly an active area of investigation. One other area that I would point out that's extremely exciting focuses not so much on the genetics of the cancer cell, but on this interesting observation that tumors have a soporific effect on our host immune system. In effect, they can put the immune system to sleep so that they can escape the normal immune surveillance mechanisms.

We've identified a molecule called anti-PD1 that can reawaken the immune system, awaken this slumbering giant so that it can seek out and destroy cancer cells. So we're using the host's immune system - no chemotherapy, no small molecules, no radiation therapy, but truly harnessing the power of the host immune system to attack tumor cells within the body. And we think these are likely to be very effective, not only for single-agent treatments, but to combine with some of the mechanisms that John's been describing where you take small molecule inhibitors and work together to target the cancer cell both from the immune system perspective, as well as targeting defects from the cancer cell itself.

DIPERSIO: So I'd like to jump in here, Ira...


DIPERSIO: ...and agree with Gary. I mean, this is - what Gary's mentioned is really an incredibly amazing aspect. You know, we, you know, an example would be melanoma, which has a gene that's - we and others have found that is - has mutated frequently. And this mutation, again, represents an activated kinase in some patients. And so you're...

FLATOW: What is a kinase? What is it?

DIPERSIO: It's an enzyme that actually puts a phosphate group on a target amino acid, and that event results in some change in the biologic behavior. It could be growth. It could be survival, et cetera. So in this particular example, melanoma, the gene is called B-Raf, and there are small molecules that work quite well that target that enzyme. But they actually work for a relatively short period of time. So here's a targeted therapy directed to a mutation in melanoma, which works only for a short period of time.

And then the broad-based immune approaches, such as what Dr. Gilliland was mentioning, have had - actually, you wouldn't think, but they've actually had incredible effects, not only in inducing responses, but the responses have been much longer lived. And so it's pretty exciting that broad-based immune activation effects like this can have a long-term benefit in patients. And I'd like to say one other thing...


DIPERSIO: ...that Gary was mentioning combining small molecules with this kind of immune stimulatory intervention. And so I think that that's one of the other great potential future aspects of sequencing cancer genomes. And I think it's been underappreciated up to this point, and that is that not only are we going to identify mutations, but we're also going to identify genes that are mutated that could be antigens, that could be specific, and the molecules that the immune system can recognize.

And so for every cancer cell, there may be many mutations, and that represents potential for many, many new antigens that are specific to that tumor. And if we can generate specific immune responses to those tumors associated in specific antigens, coupled with what Gary was mentioning, it could have a really dramatic, long-term effect on survival in some on these patients.

FLATOW: This is SCIENCE FRIDAY, from NPR. I'm Ira Flatow, talking with John DiPersio and Gary Gilliland. Give me some follow-up on that. Is it possible to get the immune system to specifically attack that kind? Can you make - can you, you know, put a little beacon out there that says go to that cancer cell? Is that how that might work?

GILLILAND: Well, yes, in fact, you can. And tumors, as John alluded to, elaborate those signals. They do have beacons that the immune system is capable of seeing, and destroying cells based on the expression of these abnormal beacons on the surface of the cell. But tumor cells have what amounts to a cloaking device that they can engage that hides them from the immune system so that the immune system, although it's competent, is not able to see the tumor and destroy it.

And we now have a better understanding of the molecular switches that allow us to turn off the cloaking device and allow the immune system to do its job, which is to destroy foreign entities. That includes infectious agents, but also cancer cells. And I think you sense the excitement both from John and I around the potential for this type of therapy, both alone and in combination, based on an evolution of the understanding of the genetics of tumors, as well as our immunobiology.

FLATOW: When does the excitement get translated into product?

GILLILAND: Well, we have a clinical trial that's ongoing that's very exciting. We reported the results of this recently at the melanoma conferences. John mentioned metastatic melanoma, where in patients that have widely metastatic melanoma, refractory to all of our conventional therapies, a very difficult disease to treat, we're seeing so far in the study, at an interim assessment, about a 50 percent response rate in patients. And in some cases, about 14 percent, we're seeing complete responses, meaning that after treatment with this single agent that does nothing more than activate the immune system - no chemotherapy, no radiation therapy - we can't detect any evidence of disease on imaging analysis with tools like CT scans. It's very exciting.

FLATOW: That is, because melanoma is so hard to treat once it gets out of control. Well - but can you get - can you understand why the other 50 percent don't work?

GILLILAND: That's a great question. We're working very hard on that. This is one switch. The anti-PD1 switch, in essence, is a switch that takes the brakes off of the immune system, and we know that there are at least five different switches that do the same thing. We don't understand how they interrelate or how they work with each other, but our working hypothesis is that these other switches may themselves be targets for the 50 percent of melanoma patients that don't respond.

It's a very complex system, and there are, of course, many other hypotheses, but we're actively investigating all of those so that we can understand - on an individualized basis - who it is that's most likely to respond to these treatments.

FLATOW: So this is past the laboratory - past the lab animal stage. This is testing on real people.

GILLILAND: Yes, Ira. We're in phase two randomized studies - phase one studies, looking at different indications. We think there's extraordinary opportunity here, so we're actively pursuing it with a rapid pace, because for John and I as hematologists and oncologists, there's an urgent need. There are patients out there that need these treatments yesterday for their cancers, so we're moving as quickly as we possibly can to move these towards a registration pass, an FDA approval.

FLATOW: All right. We're going to take a short break, come back and see if we can get - it's been so interesting, I haven't gotten to the phone calls yet. We'll see if we have a couple that we can get in there before we have to go, with John DiPersio, chief of oncology at Washington University School of Medicine. Gary Gilliland is senior vice president and global head of oncology at Merck. Our number: 1-800-989-8255. You can tweet us @scifri. We'll be back right after this break.


FLATOW: I'm Ira Flatow. This is SCIENCE FRIDAY, from NPR.


FLATOW: You're listening to SCIENCE FRIDAY. I'm Ira Flatow. We're talking this hour about the genetics and the future of cancer treatment with John DiPersio, chief of oncology at Washington University School of Medicine, Gary Gilliland, senior vice president and global head of oncology at Merck.

Gentlemen, as you can imagine, people want to know all about different kinds of cancers and what the possibilities of using these kinds of treatments are, and one in particular.

I'll start - I'll just take one off a tweet from Tom, who wants to know about foods that are found to attack tumors. Do they work on lung cancer? Would they help for stage four? I'm going to expand, and out of foods, because I think I know what the answer is. But how - lung cancer is also a very tough - like melanoma - a very tough cancer to treat, especially in late stages. How close could something like this come to treating lung cancer using these types of techniques?

GILLILAND: I can take the question about the role of these immune therapies for lung cancer and say that we're also exploring metastatic lung cancer in clinical trials that are ongoing. And we have seen activity with this anti-PD1 mechanism in some patients that have metastatic lung cancer. This has been refractory to prior treatments. I would say that I personally don't know of specific foods that have potent effects for most metastatic cancers, but I'll also defer to my colleague, Dr. DiPersio, for his perspectives on that.

DIPERSIO: Well, the - I have to agree with Gary. I don't know any specific good examples that have been proven in clinical trials. But, you know, there's a number of oral agents that are antioxidants that enhance the survival of T cells, the cells that are involved in immune activation, and also a number of agents that are in food ingredients - echinacea is one of them - that activates a type of cell called a natural killer cell. And there are all sorts of examples where people have taken food stuffs and ingredients in foods and tested them in these - in the laboratory on the bench-type in-vitro systems and showed that they actually have immune stimulatory effects. So in theory, I think it probably - there probably are some that do this. We just haven't proven that's the case in clinical trials.

FLATOW: Let's get a quick call in from Derek in Tucson. Hi, Derek. Welcome to SCIENCE FRIDAY.

DEREK: Hi. Hi. Thanks for taking my call. I just want to say I really appreciate you guys doing the research you're doing. A couple of years ago, my dad passed away from lung cancer. Part of the problem was he had a liver transplant a couple, like, months before he was diagnosed, and ever since that, he wasn't able to get any of the treatments for his cancer. And so we basically weren't able to do anything about it because of the anti-rejection drugs. And I was just curious if this new look into the mutations will allow for treatments for people who are on anti-rejection drugs and are dealing with other health issues like that looking to treatment for the cancer.

DIPERSIO: So I think I can try to field this question. The answer is yes because many of the treatments that are being developed by Gary and others in the field - in the pharmaceutical industry and also the research that's being done - are not the traditional chemotherapies, not the traditional therapies that actually knock down your immune system or knock down your blood counts. And in that case, patients that are on immunosuppressive drugs really just don't tolerate those kinds of treatments at all. So those are the traditional kinds of ways that we used to treat patients with cancer.

And now these new therapies are actually - we give them all the time in the context of people who have had transplants for all sorts of different things. I do bone marrow transplantation, and in that situation, we give treatment for all sorts of kinds of cancers with impunity, but we have to be careful not to use chemotherapy drugs that are too difficult for the patients to tolerate. And all these new drugs are very well-tolerated.

FLATOW: Are there cancers for which these new kinds of treatments will not work?

DIPERSIO: I'm sure - you know, we haven't - to be quite honest, we haven't found treatments for - that are really effective for most cancers yet. But it - I think it's - I'm the ultimate optimist here, and I think it's a matter of time and it's a matter of understanding the biologic systems. And it's a matter of not only knowing what the dictionary of cancer mutations are, but also, as Gary mentioned, how you actually alter the immune system. Because in some situations, it may be really a primary defect in the immune system that lets the normal cancerous events which occur in every one of our cells every second of the day.

It's sort of depressing to think that, but we know that that happens, and we know that we accumulate mutations as we live longer and longer. And so to figure out how to combat the specific genes that are mutated, but also how to enhance the immune system and make us younger, immunologically, that's going to have a major impact, as well.

FLATOW: All right. We're going to end on that hopeful note. Thank you, gentlemen, for joining us this hour. John DiPersio, chief of oncology at Washington University School of Medicine. Gary Gilliland is a senior vice president and global head of oncology at Merck. Thanks again, gentlemen, for joining us this hour.

DIPERSIO: Thank you, Ira.

GILLILAND: Thanks, Ira. Transcript provided by NPR, Copyright NPR.