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June 19, 2005
What Makes A Target, Anyway?
I had a question a while back about how often researchers are fooling themselves when they think they've found a new signaling pathway or a new disease target. That one's pretty easy to answer, to a rough approximation: the less work you do, the better the chance that you're fooling yourself.
But it can take years before you know if you were right, so there's really not enough data to give a more quantitative answer. Take a notorious example, beta-amyloid in Alzheimer's disease. That's been noted as a sign of the disease every since Alois Alzheimer described it nearly one hundred years ago. Huge mountains of data have piled up since then about the disease and what might be causing it, but we're still not one hundred per cent sure if amyloid plaques in your brain give you Alzheimer's or if Alzheimer's gives you amyloid plaques in your brain. Most of the money is on the former, but it's not quite a sealed case yet.
The same uncertainty hovers around everywhere. Let's say you study a particular form of cancer, and you find that there's a particular kinase that's always found in greater than normal amounts in the tumor cells as compared to normal ones. Is that a new target for therapy? The answer is a firm, resounding, "maybe!"
Perhaps it's the real deal, but there are other enzymes that will step right in to do your kinase's job if you inhibit it - in that case, you'd better be prepared to take those on, too, or get ready to pack it in. Perhaps it's part of the real problem, but it's just a sideshow. If it's not the key or limiting step in any given pathway, inhibiting it won't do anyone much good. Or maybe it's there to phosphorylate the realculprit, in which case you should put some resources on tracking that thing down, too - it could be a better handle on the disease. But on the other hand, maybe your kinse is only acting downstream of that real culprit, phosphorylating something else entirely, which is an extreme example of the sideshow possibility mentioned above. Or it may be that this kinase is upregulated because it's part of a mechanism that's trying (unsuccessfully) to get the cancer cell to shut down. You probably wouldn't want to inhibit that!
Unraveling all this is not a job for the impatient, or for the light of wallet either, for that matter. So many of these pathways have turned out to be more complicated than anyone had ever imagined, that it's gotten to the point that people are questioning the whole reductionist-molecular-biology approach to drug targets. Eight or ten years ago, I would have considered that a radical or even crazy position. These days, I kind of want to sign up. . .
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