In this 2015 post I looked at the cancer stem cell field – the idea that some tumor types are kept going by a stem cell population, and that unless these are dealt with, no durable response to treatment can be expected. A number of pharma companies have looked into this idea, most famously (and so far, most expensively) AbbVie, with their purchase of Stemcentrx to get their lead compound Rova-T. That hasn’t gone smoothly, one could say, in much the same way that Napoleon’s invasion of Russia didn’t go smoothly. Verastem was another company that went public in 2012 on this idea, sort of, and that hasn’t worked out, either. So how’s the rest of the field holding up in the clinic?
Like this. It’s not pretty: Nature Review Drug Discovery has a look at the area, and it’s seemingly in the process of being abandoned. OncoMed was another big player in the area, and their CEO is quoted in the article as saying that they gave the hypothesis “a pretty good test”, which is why they’re not working in the area any more (!) Why did things go this way? Some of it is just the way science works – ideas get proposed, tested, and accepted or discarded. But this one had some extra juice, because of the possibility that there was an avenue to cancer treatment that no one had really explored. A lot of people jumped into the area, and the whole cancer-stem-cell idea took on more reality than it may have ever deserved:
While there is broad agreement that cancer stem cells exist, at least in some tumour types, “a lot of the work done on cancer stem cells wasn’t done carefully enough,” says Morrison, now at the University of Texas–Southwestern in Dallas. Ten years ago his lab found that previous work vastly underestimated the number of cells that could repopulate a tumour. Earlier studies claimed that only one in a million melanoma cells could repopulate a human tumour when transplanted into mice. Morrison’s group reported in Nature that with different assay conditions they could bring that number up to one in four, essentially invalidating the stem cell model for melanoma.
That paper was from 2008, which appears to be the same year that Stemcentrx was founded. Now, types of cancer are quite different from each other, and the stem-cell hypothesis has a lot more weight when applied (for example) to some types of leukemia. But is that a special case? Blood cells are constantly being renewed from stem cell populations to start with, so extrapolating the idea to other kinds of tumors, especially solid ones, was always a bit of a leap. Another big problem has been that no one has actually been able to reproducibly isolate any defined population of cancer stem cells, no matter what the tumor type. That sounds a bit hard to believe, given the amount of money and time that went into this idea, but there it is. If you look at that last link, you can see that Stemcentrx, for one, thought that they were isolating such cells, but were they kidding themselves?
The inability to precisely identify and isolate cancer stem cells also makes it impossible to specifically target them. “There is no strategy at this time, no tool available or no drug available that would only target the [cancer] stem cells,” says Fred de Sauvage, vice president of Molecular Oncology at Genentech. “[Out of] all the drugs that companies have put in the clinic and claimed that they were stem cell or cancer stem cell-specific, none of them are.”
Perhaps those remarks are on the way to making a case that if you just do it right, this approach can still work? While many companies have pulled out of the field, AbbVie has apparently taken five other Stemcentrx agents into the clinic (they’re on this list with “SC” codes). Back when they acquired the company, most of the focus was on Rova-T, but the press release did mention four other compounds. The company did not comment to NRDD when asked about these, so we’ll have to wait to see if any of them progress or (as is sometimes the case in this business) they end up sitting in the pipeline slide as placeholders until quietly disappearing.
None of this has worked out as hoped. In 2010, the New York Times brought the idea of cancer stem cells to people outside of biomedicine, in an article by Siddhartha Mukherjee that gave an honest assessment of the field, describing it as “overheated” even by 2005. The years since then have at least cooled things down, and for those hunting for a new way to treat cancer, that’s not good news. Will there be another sadder-but-wiser chapter in the next few years?