Why does chemotherapy not work very well? That is, why do the cancers we treat tend to come back, and in a more difficult to treat form? The standard answer is that the drugs kill off all the cells that are susceptible, but that most tumors, being derived from genetically unstable cell lines, are a mixture of many similar (but genetically distinct) cell populations. Killing off half or more of the tumor with chemotherapy buys some time, but also leaves the field open for the resistant cells, which stage a comeback.
This seems clearly to be just what’s going on in many cases. But there are other possible answers, and over the last few years, another theory has gotten a lot of attention: cancer stem cells (CSCs). It could be that there are fast-dividing progenitor cells driving some kinds of cancer, and unless you target these, you’ll always be fighting uphill. You can see the appeal of this idea, because it has the potential to reduce things down to a more manageable target: a much smaller population of cells that are causing most (or all) of the trouble. And there’s evidence for this in some forms of leukemia, and possibly other tumor types as well.
The problem is, though, that you could be setting yourself up for a long chase. Somewhere in that mass of badly acting cells are the few that you need to stamp out, but where are they? And how do you know if you’re targeting them? No one can be sure if this idea is correct, or if it’s a reasonable therapeutic avenue, unless these questions can be answered definitively, and (so far) that’s been elusive. This article at Technology Review will serve to illustrate why. It’s about Stemcentrx, a well-funded (but rather quiet) startup founded on just this idea, and they’re finding that they’re really having to do it the hard way:
One aspect of that design was a methodical—and expensive—way of zeroing in on what cell type in a tumor is the ultimate culprit. At Stemcentrx it’s done by inserting bits of freshly obtained human cancers under the skin of a mouse with no immune system, a so-called xenograft. The cancer that grows is collected and divided into different cell types. Then each fraction is implanted into other mice. The process, called “limiting dilution,” gets repeated as long as it takes to find the one type of rare cell that never fails to regenerate a tumor just like the original. That’s the cancer stem cell.
Ay, multiple generations of xenograft dilution – what a way to make a living. The company says that they’re doing 150 xenografts a day (!) But their rationale is that trying to culture CSCs in vitro runs the risk of having them change character too much, making any assays using them unreliable. My guess is that they’re right about that, but my worry is that xenograft tumors themselves are already unreliable enough to cause trouble (and I have no idea of what happens to them after you “passage” them through multiple animals). Xenograft models are, of course, well known in oncology drug discovery, but one of the things that’s well known about them is that they’re the pure example of “necessary but nowhere near sufficient”. If your drug fails in a xenograft, it will probably fail in the clinic. But if your drug works in a xenograft, it will probably fail in the clinic, too. The odds get better, but they go from “extremely likely not to work” to “pretty likely not to work”, and you take what you can get in this business.
So how’s Stemcentrx doing in their cell hunt? They’re not going to tell Technology Review, naturally, but as the article mentions, the entire CSC hypothesis has been taking some hits recently. It’s still very much an open question. How many tumor types are driven by stem cells, whether they can be targeted (and how), how to tell when such an approach is indicated at all – there are a lot of open questions. It seems very likely that there are cell types inside a given tumor population that are more aggressive and likely to spread, but whether that narrows down to a particular stem cell group, I don’t know. What if there are 234 cell types in some particular tumor, and (say) fourteen of them are the ones to really worry about? What then? Will there be a common mechanism to target these, or not?
These are fundamental questions in clinical oncology that we just don’t quite have the answers for yet. You can hope that Stemcentrx is on to something, but we’ll see how things go in the clinic – which is, as usual, where it really matters. They’re not the only people trying to get this to work, either: Verastem, Oncomed, and others are all in there pitching, too. Even the clinical trials, though, are not going to be straightforward – as that last link has it:
. . .it may be difficult to draw definitive conclusions from these trials. Unlike traditional chemotherapy, the drugs undergoing testing are not expected to quickly shrink tumors, because they are designed to kill just the tiny subset of cells that seed and resupply the main tumor. So detecting whether the drugs are working in the intended way is not straightforward. Indeed, for solid tumors, researchers lack simple, rigorous assays for measuring the number of cancer stem cells.
The efforts also face some fundamental skepticism: Many still don’t believe cancer stem cells exist as a cell type distinct from other tumor cells, and some suggest that companies are hyping or at least oversimplifying the premise. A win in the clinic could resolve some of the controversy. . .
It could indeed, as long as we’re all working from the same meaning of “win”. The last few years have been lively ones for the CSC field, but that’s going to be nothing compared to the next few. . .