Michael Weller Discusses the Role of TGF-beta in Glioblastoma
Special Topic of Glioblastoma Interview, November 2011
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Although the latter has attracted more research in the last five years, most of the important contributions of our lab have been looking at the soluble factors that a tumor cell produces to inhibit any aggressive action by the immune system.
Is there a particular soluble factor that you think plays a critical role and takes up a lot of your research time?
The one that pops up in several of these publications is called transforming growth factor beta (TGF-beta)—that's my master molecule. That was discovered in the 1980s. I just picked up that story and ran with it, but the story was out there. Our laboratory has contributed to understanding how this works but the ideas were all out there.
The simple story is that the tumor cells make this molecule and the molecule then moves through the body, hits immune cells, and interferes with biochemical pathways that are required for an immune cell to be active. Then there are obviously basic biological questions that may be difficult to explain for a broader audience. The questions that interest us are: how does the tumor cell find out that it's good to produce this factor? What is the biochemical pathway? And how can we shut it down in terms of a therapeutic approach?
There are a series of small biological steps that are necessary for cancer cells to make such molecules, and there are certain pressures of selection that cancer cells survive if they're able to produce such molecules. That is quite complex and it is really going down to a single-cell level, looking at single biochemical steps, but it's clearly a major pathway by which tumor cells make sure that they can hide from the immune system.
What's the role of TGF-beta in a healthy state?
It is required to control the immune system in a negative way. That means if our immune system over-responds to a situation, we have problems. There are very prominent diseases where this happens and we have too much inflammation, too much immune response—rheumatoid arthritis or multiple sclerosis are two examples. These are diseases in which there's too much immune activation, and TGF-beta is very helpful because it controls over-shooting immune responses.
What factors stimulate TGF-beta release or regulate it naturally?
That is essentially unknown. It's something we're working on. The primary question is how does the tumor learn that it's good to produce TGF-beta? It could be simply Darwinistic, in the way that cancer cells that produce these molecules will survive and the others are killed by the immune system. That's what some people believe. I'm not sure that can be proven. What is clear is that most types of cancer, in one way or the other, produce immunosuppressive molecules. That is very clear, because it's absolutely vital for a cancer not to be recognized and attacked by the immune system.
"…with glioblastoma there was and still is an obvious medical need to improve treatment options…"
Do you have an idea how to shut down the production of TGF-beta by tumors without affecting its role elsewhere in body?
This turns out to be quite tricky, because TGF-beta does have more important roles than previously assumed. The simple solution would be to knock down TGF-beta only in the brain. That's been done by infusing therapeutic agents directly into the cavity from which the tumor has been removed. You can implant a catheter after surgery, and then you can infuse therapeutic molecules into that cavity and try to knock down TGF-beta, without actually affecting the levels of that protein in the body.
That, of course, is ideal, but there are a lot of technical challenges. Infusing large bodies of fluid into the human brain requires getting there in the first place. And when TGF-beta inhibitors have been given systemically, the way we would any other drug, a lot of side effects do become apparent in experimental animals. Most people think TGF-beta is a good target for cancer treatments, but side effects are definitely a problem, even in the animal research.
Are there other tumors that upregulate TGF-beta production or is this unique to glioblastomas?
It's not unique. TGF-beta plays a big role in prostate and in lung cancers also. So we need something like a pill, right, because these other cancers, which tend to metastasize, cannot be treated locally anyway.
What are you working on at the moment or hoping to start soon that you think holds a lot of promise?
In the laboratory it is still TGF-beta, but we're also asking the question, "What's driving the cancer cells decision to make a lot of TGF-beta, and can we go one step back and inhibit that process, and might that be better tolerated?" We are looking at the chemical pathways that control the enhanced production of TGF-beta. We are trying to identify the signals that regulate this and by inhibiting the signals in the tumor cells we can inhibit the production of that molecule.
On the more clinical side, we are trying to develop something beyond the classical type of cancer therapy—these are immunological treatments. You must have come across the idea of cancer stem cells. 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. That might take only 20 words to say, but it will take maybe ten years or more to do. That's the overall idea, though—shooting the cancer stem cells with immunological means.
If you had unlimited funds—in other words, if you lived in an ideal research environment—what one study or project would you do that you can't afford to do now?
I would take 10 or 20 patients with big tumors, get their tumors out, separate the cancer stem cells from the other tumor cells, and then sequence the whole genome of these two populations—stem cell vs. non-stem cell. Then I'd look at every single protein these stem cells make and try to develop a vaccine against the proteins sitting on the surface of the stem cells. That's all doable. It just costs a few million dollars, that's all.
Prof. Dr. Michael Weller
Chairman
Department of Neurology
University Hospital Zurich
Zurich, Switzerland
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MICHAEL WELLER'S MOST CURRENT MOST-CITED PAPER IN ESSENTIAL SCIENCE INDICATORS:
Stupp, R, et al., “Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma,” N. Engl. J. Med. 352(10): 987-96, 10 March 2005 with 2,076 cites. Source: Essential Science Indicators from Clarivate.
KEYWORDS: GLIOBLASTOMA, BRAIN TUMORS, TREATMENT OPTIONS, CLINICAL TRIALS, LABORATORY RESEARCH, TUMOR CELL LONGEVITY, TEMOZOLOMIDE, RADIATION THERAPY, SURGERY, SURVIVAL, MOLECULAR PROFILE, MGMT ENZYME, DNA DAMAGE, MOLECULAR MARKER, STRATIFIED MEDICINE, ANGIOGENESIS INHIBITION, IMMUNE FUNCTION, SOLUBLE SIGNAL, HORMONE, CELL-CELL MECHANISM, TGF-BETA, SIDE EFFECTS, CHEMICAL PATHWAYS, SIGNALS, IMMUNOLOGICAL TREATMENTS.
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