Michael Weller Discusses the Role of TGF-beta in Glioblastoma

Special Topic of Glioblastoma Interview, November 2011

Michael Weller

According to our Special Topics analysis of Glioblastoma research over the past decade, the work of Prof. Dr. Michael Weller ranks at #1 by total papers and #2 by total cites, based on 128 papers cited a total of 7,149 times. Four of these papers appear among the top 20 papers over the past decade and over the past two years.

In Essential Science IndicatorsSM from Thomson Reuters, Weller's work appears in the top 1% in the field of Clinical Medicine and Neuroscience & Behavior. He is the Chairman of the Department of Neurology at the University Hospital Zurich in Switzerland.

Below, ScienceWatch.com correspondent Gary Taubes talks with Weller about his highly cited work as it relates to glioblastoma


SW: What prompted you to take up glioblastoma research as a career?

One of the first things you do in medical school is find a really challenging disease on which to do research, and glioblastoma is certainly challenging. That's the simple answer. I always wanted to do something related to the neurosciences, something between neurosurgery, neurology, and psychiatry. But I also wanted something challenging and practical, which means something that really causes problems to patients and problems that need to be addressed. So with glioblastoma there was and still is an obvious medical need to improve treatment options, and I found that interesting even from a science political view—how do you introduce new treatments into medical practice?

As you'll see, most of the highly cited papers in this field are clinical trials; they're not derived from ingenious work done in the laboratory, but from large cooperative studies where a lot of people have to contribute and only a very few get the credit at the end. That's what we get cited for, but then there's the laboratory research, where we're actually looking at single cells, sometimes animals.

"If I were to summarize what I do, it is effectively asking, 'What is the mechanism that immune cells don't recognize cancer as something foreign? What are the active mechanisms of a cancer cell to prevent detection?'"

In that work, what we want to know is what drives the fate of these cells? Why don't they die? What makes them different from other cells in that they seem to have an unlimited lifespan? Those are the critical questions and that's what I do in the laboratory—ask questions about the longevity of tumor cells. How does that come about? Why don't they ever die?

SW: Are you suggesting that your two most-cited papers on temozolomide in 2005 are not what you consider your most important contributions to the field?

I do think that the number of citations does not always necessarily reflect what will be important in the long run. If you look at the temozolomide trial and that highly cited paper (Stupp R, et al., "Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma," New. Engl. J. Med. 352[10]: 987-96, 10 March 2005), there was no real intellectual contribution on our part. At some point in time, a network of investigators decided that this was a good drug to study. It had not been developed by either myself or any of the other authors on that paper. We were just lucky to select right the drug at that point in time. So the 2005 New England Medical Journal articles on temozolomide are certainly the most-cited papers in my career and probably in the career of everybody else who's on those papers.

What you have to remember is that at that point in time, the only therapeutic modality available was radiation. The patients always get surgery because you have to know what kind of disease you're dealing with, and for that you need tissue. So surgery is always first, because otherwise you cannot make the diagnosis. And certainly if you take out more of the tumor, it's better for your brain than if you leave a lot in. But whether the extent of surgery prolongs survival or not has always been an open question. It's very clear that surgery doesn't solve the problem.

Since the 1980s, new drugs have been tested against glioblastoma and no drug ever worked. Temozolomide was the first one to work in a well-designed clinical trial with a real control group of patients treated with radiation alone.

SW: How long was the benefit?

The benefit, if you take the whole population, was only 2.5 months. That seems to be a very, very minor benefit, but that's not the whole story. The other way of looking at it, for instance, is to ask, "What about surviving two years?" And then the answer is one in four patients survive two years with the drug, versus one in ten without the drug. That sounds better, right?

And then you find another paper, which is probably number two in citations in my scientific life, with Monika Hegi as the lead author (Hegi M, et al., "MGMT gene silencing and benefit from temozolomide in glioblastoma," New Engl. J. Med. 352[10]: 997-1003, 10 March 2005). That's the back-to-back paper in the same journal. We described the molecular profile of patients deriving most of the benefits, and that's the story of the MGMT enzyme, the protein that is responsible for repairing DNA damage.

If a cell is hit by temozolomide, that cell suffers DNA damage. But if a cell has a lot of the MGMT protein it can repair most of the damage and be quite resistant to chemotherapy. On the other hand, if the cancer cell does not have a lot of MGMT protein then that cell would be predicted to be sensitive to the treatment. Again, the ideas were all out there, but we did it. We were lucky. The status of that enzyme in the cancer cells predicts whether patients derive a lot of benefit or not, and if you looked specifically at that subgroup of patients with the right MGMT status—meaning the cancer cell did not have a lot of that protein—the benefit was really very remarkable.

"In a nutshell, what we're trying to do is to identify the few stem cells in these tumors and try to find out what makes them different from all the other cells, and then try to develop an immunological treatment directed specifically against that cancer stem cell population."

And that's the content of the second paper. The molecular marker predicted the extent of benefit. In that subpopulation we even had patients surviving four or five years. Clearly that is a major step ahead. If you can possibly do a molecular test that will identify who is going to show benefit from a particular type of cancer treatment that is both expensive and not without side effects, you can do what we call personalized medicine today—although I would call it stratified medicine. You have at least two groups of patients, you run a test, and then you can tell patient A is going to derive a lot of benefit and patient B may not do so well with that treatment.

SW: Are there other promising drugs that have been approved for glioblastoma or are in the pipeline?

Temozolomide is still quite unique in that it's the only drug considered standard of care at the moment. But there is the expanding field of inhibitors of angiogenesis, and there are two drugs at the moment that have completed clinical trials for use in glioblastoma but the data are not there yet. We are waiting anxiously to see what the results are, but the trials have not been concluded with regard of the endpoint of overall survival. In the more clinical science world, going away from the lab into the clinic, these novel compounds that inhibit angiogenesis are probably the most important ones in 2011. Two of these drugs, as I said, have completed the clinical trials in terms of putting the patients on the trial, but the results are not in yet.

SW: What do you consider your most important contribution to cancer research not including these large collaborative studies on temozolomide?

I would say it's a series of contributions looking at the way that tumor cells interfere with immune function. That's my topic. If I were to summarize what I do, it is effectively asking, "What is the mechanism that immune cells don't recognize cancer as something foreign? What are the active mechanisms of a cancer cell to prevent detection?"

SW: How do you approach the problem and what have you learned?

There are essentially two ways cancer can inhibit the immune system. It can be a signal sent by a cancer cell, a soluble factor—effectively like a hormone—that you release into the bloodstream, and it's hitting every immune cell in the body. The other way would be two cells meet and one is knocking on the head of the other cell. It's a cell-cell mechanism. That's more like warfare—a certain number of cancer cells meeting a certain number of immune cells and the question is who at the end is going to win the battle.

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