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Unit 8: Cell Biology and Cancer
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Brian Druker, MD

Brian Druker, MD
Interview with Brian Druker, MD. Druker is the director of the OHSU Cancer Institute's Leukemia Center. In collaboration with Ciba-Geigy (now Novartis Pharmaceuticals) Druker developed the drug called Gleevec, which has seen an enormous success in treating a rare form of leukemia. His groundbreaking work has garnered much media attention, because of the drug's success.



Can you describe the typical path of drug development?

A typical drug development is about four or ten years. Scientists at Novartis began working on a drug discovery program in the late 1980s. By 1992, they had synthesized Gleevec. In 1993, my lab started testing it in leukemia cells and identified as the most promising compound they had. It then took us about five years to 1998 to get to clinical trials, but then only three years from our first patient on clinical trials to have FDA approval. That three-year time span was actually record time for an anticancer agent.

Has there been a paradigm shift in developing drugs for cancer treatment?

For decades, cancer researchers have worked with the view that if we understand what's driving the growth of a specific cancer, we could target that abnormality with specific therapy and that therapy should be effective and relatively nontoxic.

Gleevec has proven or validated that paradigm. That's exactly what it's doing. It targets the specific abnormality that drives the growth of one particular leukemia. It's an extremely effective therapy with minimal side effects. So the hope now is that we can apply that paradigm to every single cancer and develop a Gleevec for every single cancer.

The problem is it is not one abnormality that drives the growth of all cancers. It could be hundreds of different abnormalities. But once we identify that abnormality there's hope that we can identify and develop a drug like Gleevec.

What is chemotherapy?

Chemotherapy is certainly a very effective therapy and in some cases it can cure advanced cancers, for example, testicular cancer or Hodgkin's Disease so chemotherapy certainly has a place.

But the problem with chemotherapy is that it is very nonspecific. It basically kills dividing cells whether they're cancerous or normal. It seems to have some sort of a therapeutic window where it kills more cancer cells than normal which is why it can even be given. But it's still nonspecific and that's why it has so many side effects. The hope is that over the next few decades we can start to replace chemotherapy with much more targeted treatments.

What was the treatment for chronic myeloid leukemia before this drug?

The standard treatments for chronic myeloid leukemia have either been a bone marrow transplant or another treatment called interferon. Now interferon can prolong patients' lives about an average of about two years, but it has horrible side effects.

Imagine the worse case of a cold or flu you've ever had. That's because your body produces interferon to fight the infection so you get fevers, chills, muscle and joint aches. Patients are treated lifelong for chronic myeloid leukemia with interferon [and] they feel like they have a cold or a flu every single day. It's no surprise that up to a quarter of patients will discontinue therapy because of the severity of the side effects. So all and all, therapy wasn't terribly effective or had lots of side effects.

How effective is Gleevec?

For patients who are diagnosed relatively early, 96%-almost all of them-have their blood counts return to normal and typically within four to six weeks. In almost three-quarters of those patients, when we look in their bone marrows we can no longer detect any leukemia cells unless we use extremely sensitive PCR techniques. The PCR techniques are the drops of blood from the O. J. Simpson trial where you can detect trace amounts of anything. We really have to look hard in most of our patients to see any signs of their leukemia.

What about side effects?

That's perhaps been the most surprising aspect of [this drug]-that there are so few side effects. Even if you have a completely specifically targeted therapy you're still going to target something that's in a normal cell.

But yet Gleevec has been extremely well tolerated. Most people have few if any side effects. If they complain about anything, they may have a bit of nausea if they take the pills on an empty stomach. Some have had some puffiness around their eyes, a few percent have had some diarrhea or skin rashes. But all in all most people are perfectly healthy leading otherwise normal lives.

How many people have been treated and what have been the results?

Within a year and a half of starting clinical trials, we've already treated over 2,000 patients with chronic myeloid leukemia and that served as the accelerated approval to the FDA. Now it's estimated that over 50,000 patients have been treated with Gleevec worldwide.

How does Gleevec work?

In chronic myeloid leukemia, we know that the leukemia cells, the growth of the white blood cells, is driven by a particular enzyme called the "tyrosine kinase." We know that this family of enzymes regulates cell growth. It's sort of like the on or off switch for a light. This is the on switch that triggers cells to grow.

In the case of chronic myeloid leukemia, there is an abnormality in the chromosomes. Two chromosomes have broken and rearranged and stuck this kinase in the "on" position so it's always signaling the white blood cells to grow and divide. A normal white count would be 5,000 or 10,000; in a chronic myeloid leukemia patient [the count is] 50,000 to 500,000, so 5 to 50 times the upper limit of normal.

What Gleevec does is bind to this specific enzyme and turn it off. It just completely shuts it down, and in fact because of the way that this enzyme works, the cells stop growing and then ultimately die.

How does this represent a new way of treating cancer?

Up until now the way we've treated cancer has been with relatively nonspecific therapies, things like chemotherapy which takes advantage of the fact that cancer cells are growing and dividing, but so are normal cells.

What Gleevec has done is it takes an understanding of what specifically drives the growth of one particular cancer, targets a drug against that specific abnormality-and just that abnormality-and thereby has been a very effective and relatively nontoxic therapy.

That's an important paradigm shift. It's like introducing antibiotics for infections whereas before you treated them pretty nonspecifically. Now you can actually target the abnormality and just attack the cancer cells without harming the normal cells.

What is your next stage in research?

We have several things that we're doing in our lab. The first is to try to optimize therapy with Gleevec. I mentioned that three-quarters of the patients have no detectable leukemia.

There are a number of things we're doing in our laboratory. One of them is just to optimize therapy with Gleevec. Even though the majority of patients don't have detectable leukemia, if we use very, very sensitive monitoring techniques we can still see traces of that leukemia. In other words, we haven't completely eradicated this leukemia and so one of our goals is to try and get to a stage where we can actually completely cure this leukemia and use Gleevec as one of the major building blocks toward that goal.

The other thing we're doing is we're using our experience with Gleevec in trying to apply that same paradigm to other cancers or leukemia. So, for example, there's another leukemia, acute myeloid leukemia, where there's a different enzyme that we know drives the growth of that particular leukemia. We're working with another drug company that's developing an inhibitor of that enzyme and has begun clinical trials in acute myeloid leukemia.

So we're just building on the paradigm: understand what's broken, develop a drug that targets that abnormality, and bring that into clinical trials and hopefully improve the lives of our patients.

What does the development of this drug represent in cancer research?

To me what this represents is enormous hope for the future. What it tells us is that we're on the right track that if we can identify what's broken we can fix it.

What Gleevec has done is validate this important paradigm in cancer research which has been predicated on the notion that if we understand cancer at the molecular level we'll be able to develop better therapies. But we also have to fit this into a much broader picture so, for example, if you think about how we treat infections. We have preventative measures. Public health measures like chlorination of water, pasteurization of milk [to] make our food and water supply safe. We have vaccinations and we also have antibiotics.

In the big scheme of cancer therapies we also need to think about prevention, early diagnosis, plus specific therapies like Gleevec. And if we can combine all [of] those, my view is in this century cancer will become much like infectious diseases where in the last century-they'll become much more easy to treat and perhaps even much more trivial than we think about today.

Will cancer be trivial one day?

If we were sitting here a century ago and you were thinking about how are we ever going to get rid of infections and we've got tuberculosis and typhoid and cholera and these were menaces in the year 1900. You couldn't even begin to imagine how to attack them and a century later you think about pneumonia and whooping cough, or polio and these are diseases you just don't hear about anymore. If you get them you treat it with an antibiotic and they're gone. So a century from now, why couldn't the same be true for cancer?

When did our understanding of cancer change?

We've undergone a revolution in our knowledge of cancer. When Nixon declared war on cancer in the 1970s many thought that viruses were the major cause of cancer. Now we understand that it actually is something in our own genes, something that's broken inside of our own cell that triggers the growth of a cancer cell. This so-called gene theory of cancer has completely revolutionized our understanding of this disease and it's begun to demystify it. We've begun to identify what the parts are broken inside of a cell. What that means is once we've identified a part that's broken we have the ability to target that abnormality. That's what's been such a huge paradigm shift in the 1970s where we had no clear understanding of cancer.

How is Gleevec administered and how does it compare to chemotherapy?

One of the amazing things about Gleevec is that it is a pill, so most patients take four pills once a day. That's very different than coming into a clinic, getting hooked up to an IV and sitting for hours hooked up to an intravenous infusion. To me that sort of captured everybody's imagination that you have something that's so simple--you take an anticancer pill and the cancer melts away. It's very simple, it's very easy, and it has minimal side effects.

The success of Gleevec has certainly been extremely important for patients with CML. It's provided them with an extremely effective and nontoxic treatment option. But beyond that what Gleevec has done is it's validated this approach to cancer, which is to target the cancer cells specifically to have an effective, nontoxic therapy that just attacks the cancer cells. That's what's so important about Gleevec in the grander scheme of things.

Has Gleevec cured cancer?

We've been very cautious about using the word cure with Gleevec. It's still very early. We need longer follow-up on our patients. What I've been saying is that my hope is that this will be an important building block toward a cure for this particular leukemia.

Are we going to find the cure for cancer?

It would be about like taking your car into a mechanic and them saying to you, "Oh, yes, every single car that's broken we always replace this one part." There are 30,000 genes in a cell-there are thousands of parts in a car-and lots of them can break and cause a cancer.

If you're going to fix your car, what you want to do is figure out what part's broken so you can just replace the broken part rather than having to replace the whole engine. And the same is true with cancer. If you can figure out what part is broken, then you can just attack that one particular part. But it could be very different parts in each and every cancer, and in fact every cancer might have several different parts that could be broken and we may start to subdivide each and every cancer depending on the part that's broken.

With the knowledge that we have, does it inform us about different cancers?

Where we are with cancer has really built on the past 30 years. So, for example, you look at the Genome Project being completed: that's given us a parts list. Now we've got to figure out how these parts fit together and what part is broken in each and every disease. Once you do that then you can begin just target those abnormalities. That's like developing the replacement parts. So first you figure out how the parts fit together, what part is broken, and then you develop the replacement parts.

How does Gleevec work in relation to oncogenes?

Well, much like Dr. Weinberg identified the ras oncogene as being something that drives the growth of one particular type of cancer, another group of investigators identified a different oncogene that drives the growth of chronic myeloid leukemia cells. What Gleevec does is stop this oncogene in its tracks so it can no longer drive the growth of the cancer cells. [There are] other groups of investigators looking at ways to stop the ras oncogene in tumors that are driven by the ras oncogene and you can expand that paradigm to each and every oncogene that drives the growth of cancer cells.

What is the oncogene that Gleevec addresses?

The oncogene is called "BCR Able" and it actually came out of a very similar style of experiment to what the ras oncogene came from. There was this animal virus that caused tumors called "V-Able" and ultimately that led to that identification of this "Able" oncogene.

In chronic myeloid leukemia, researchers were able to identify an oncogene that drives the growth of that particular leukemia. What Gleevec does is bind to that oncogene which normally is sitting in the cell to grow continuously and completely shuts it down.

What is the future of cancer in relation to Gleevec?

The hope for Gleevec is that it really represents a new way of treating cancer and that way of treating cancer is based on specific knowledge of what's broken in the cancer, in targeted cancer cells specifically. In a broader sense, it really ties into the paradigm of can we diagnose cancer earlier, can we treat it earlier, can we treat it more specifically, and to me that's what I see for the future is the more we understand about cancer the more we're gonna be able to target it.

Gleevec has come out of decades of cancer research. In many respects it comes right out of the discovery of DNA 50 years ago because what that really led us to was to the inner workings of what drives the growth of cells. From that came the discovery of oncogenes, which we now drive the growth of many cancers, and by understanding oncogenes we can identify the specific oncogenes that drives the growth of chronic myeloid leukemia cells. With that understanding we can develop a drug that shuts down that abnormality and that was Gleevec.

It's a direct descendant of almost 50 years of research from DNA to understanding of what drives the growth of a cell, oncogenes, to Gleevec. And that really is the paradigm for the future, understanding what's broken, develop something to fix it.

What has been the paradigm of the past?

The paradigm of the past was cancer is this mysterious disease, we will throw anything possible at it, and if it stops in its tracks we'll see if it works. And that's been chemotherapy that basically kills dividing cells nonspecifically. We don't really understand how chemotherapy works. We just know that it does. You couldn't take a chemotherapy drug and predict where it's going to work.

For the future, if we understand what drives the growth of a cancer and have a drug that shuts it down, you'll be able to predict. This drug should work for this disease but it won't work in another disease because that abnormality's not broken. In other words, you match the right patient to the right drug with the right disease and it works perfectly. That's the future of all of medicine including cancer therapy.

Do you feel hopeful about cancer research today?

I'm extremely hopeful and Gleevec has really validated decades of cancer research and to me it's no longer a matter of can we target cancer cells. We know we can. It's just a matter of when will we get the job done. We still have a lot of work to do. There's still a lot we don't know about in most of the common cancers but to me it's just a matter of time for us to get there. It's no longer a matter of "if." It's just a matter of "when."

What is the next step?

The next steps are to continue to expand our knowledge of what drives the growth of each and every cancer and with that knowledge we can then begin to diagnose patients earlier, intervene earlier and more effectively. That to me is the real future.

And ultimately if you could figure out how to prevent cancer, what our risk factors are to develop cancer, we might have much like a vitamin pill or cocktail that you could take that could even prevent cancer from developing in the first place, and do that in an individualized fashion. To me that's the real future and that may be decades from now but I could certainly see that happening.


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