Skip to Content

Cancer

The Cancer Stem Cell Saga

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?

20 comments on “The Cancer Stem Cell Saga”

  1. Imaging guy says:

    Today Harvard announced that they are retracting 31 cardiac stem cells papers from the lab of former professor Piero Anversa. One researcher was thus quoted, “There are no stem cells in the heart. Quit trying to publish those results”.
    https://www.statnews.com/2018/10/14/harvard-brigham-retractions-stem-cell/

  2. Paul says:

    Rather than look for a specific ‘cancer stem cell’, I think the more relevant and targetable biology is the quiescent / dormancy / latent properties of a subset of cancer cells that appear to drive a lot of resistance (which are likely more plastic vs. fixed, thereby eluding the CSC definition). This idea still has merit, and should not be lost in the disillusionment over cancer stem cells.

    Some recent examples:
    https://www.nature.com/articles/s41586-018-0603-3
    http://science.sciencemag.org/content/early/2018/05/16/science.aao4908

    Pro-differentiating agents are interesting in this respect, particularly in leukemia:
    https://www.cell.com/cell/fulltext/S0092-8674(16)31154-0?code=cell-site

  3. cynical1 says:

    Paul – Based on that last reference, it would appear that they need not test the hypothesis using brequinar in mice given that leflunomide (a DHODH inhibitor) is a marketed drug for RA. Given the report you cite is from 2016, has there been clinical efforts with using leflunomide in AML (or any other cancer)? Based on my quick Google Scholar search, the active metabolite of leflunomide also inhibits BTK which is the mechanism for Ibrutinib, approved for CLL.

    1. Paul says:

      That’s interesting that the active metabolite of leflunomide also inhibits BTK, did not know that. Though ibrutinib failed in clinical development for AML (https://www.clinicaltrials.gov/ct2/show/results/NCT02351037?term=ibrutinib+aml&rank=1)

      In terms of DHODH inhibition, there is this phase 2 ongoing, so we will see in the not too distant future (I would argue this is fairly rapid translation from proof of principle):
      https://clinicaltrials.gov/ct2/show/NCT03451084

      This program received an orphan designation this summer (per the press release stronger binding affinity than leflunomide): https://www.mdedge.com/hematologynews/article/173068/aml/fda-grants-orphan-designation-dhodh-inhibitor-aml

      There is also evidence suggesting that approved IDH inhibitors in AML function by promoting differentiation

      1. cynical1 says:

        Thanks, Paul. I looked up ASLAN003 and it’s about ten times more potent than Teriflunomide against DHODH so, assuming decent PK and tolerability (and it’s a Phase IIB study you linked so I’m guessing the PK is decent), it would seem like an appropriate compound to address the mechanism you reference. (That compound was originally disclosed by Almirall with a priority date back in 2006. They are not exactly progressing at lightening speed.)

        Though no expert in the area, I might argue that it would potentially work better as a combination therapy versus a mono therapy which is what they are doing. We’ll see.

  4. loupgarous says:

    Cancer cell lines, as you’ve observed before of the SK-BR-3 cell line implicated in HER2-positive breast cancer in “A Close Look at a Cancer Genome” are often genomically unstable.

    I guess one might predict that even were there targetable stem cells responsible for repopulating tumors, they’d also be genomically unstable, with some variants responsive to drug or other therapies, some not. You’re not really any better off if your recurrence and metastatic spread are owing to proliferation of “regular” cancer cells or “stem cancer cells”, are you?

    My particular paragangliomas don’t correspond neatly to either of two previously-recognized types (some take up MIBG, some don’t, but my tumors are a mixed bag that way, a problem that cost me eight years in which my liver was gradually colonized by tumors that didn’t take up MIBG, “the gold standard” in diagnosing paraganglioma. Insurance wouldn’t cover In-111 octreoscans, which would have shown what was happening). Genomic instability seems to explain what the idea of “cancer stem cells” does, to me at least. You get a range of cell lines, some of which behave in one way, some in others.

    1. aairfccha says:

      Research is going to be better off when researchers stop chasing something that doesn’t exist.

    2. Da Vinci says:

      I’m sorry, but why is anyone doing or reading anything based on cell lines? They are worse than useless.

  5. Scott says:

    Hello Derek,

    The Rova-T analogy is inaccurate. Napoleon’s invasion of Russia failed. Rova-T did not fail it’s 3rd line (3L) trial and if one understands 3L+ SCLC, the data is actually very impressive (https://meetinglibrary.asco.org/record/160032/abstract). The data was so impressive it was selected for an oral presentation at ASCO, while also selected for subsequent presentation as part of the “Best of ASCO” series. ABBV simply chose not to file for accelerated approval and has several large pivotal trials currently enrolling world wide. I encourage you to read and digest the emerging data vs. piling onto other news reports that also don’t appear to be paying attention to the finer emerging data points.

    1. johnnyboy says:

      Don’t stop believin’
      Hold on to that fee-lay-ee-yay-in’…

    2. Jenasis says:

      Poor AbbVie, no one will listen to their side of the story.

      Oh, wait. NRDD tried. “The company declined to respond to written questions about its Stemcentrx programmes.”

    3. Old Time says:

      Obviously, Scott isn’t up on the history of the Napoleonic wars. The analogy is perfectly reasonable. They invaded! Success! Moreover, they even made it back to France with some 27k soldiers after killing >400,000 Russians. That doesn’t sound like failure to me! Even if they did invade with almost 700k troops. (Although, I wasn’t there, so I had to rely on the fake-Wikipedia news for those numbers 🙂

    4. Generalist says:

      Hmmm Scott
      Wasn’t’t one of the founders of StemCentryx named Scott? Probably a different guy…

  6. hector says:

    It hasn’t been a great few months for pseudo-stem cells. In August the AHA published an editorial titled “Undeniable Evidence That the Adult Mammalian Heart Lacks an Endogenous Regenerative Stem Cell.” [1] Then Nature published a comment calling for scientists to abandon the idea of a “mesenchymal stem cell.” [2] Now this on the weak support for the cancer stem cell hypothesis (at least for most kinds of tumors). Looks like it’s time for the field to cut its losses and regroup.

    1) https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.035186
    2) https://www.nature.com/articles/d41586-018-06756-9

  7. Passerby says:

    Stemcentryx was funded by Peter Thiel. Enough said.

  8. Ireallywanttobefamous...ihaveanobel says:

    Sweet analysis bro……here is some advice…go back to calling lawyers for major research institutes on their own students….. this MAYBE will get your name in the big lights.

    1. Muster Mark says:

      What does this mean?

  9. Jim Hartley says:

    Do purified (by FACS) stem cells remain pure, and does the non-stem cell fraction (from the FACS) also remain pure? I’m thinking of Eric Lander’s 2011 paper (open),

    https://www.ncbi.nlm.nih.gov/pubmed/21854987

  10. Barry says:

    Cancer researchers have accepted “multifactorial etiology” since the ’80. It takes several events to get from wt to full-blown cancer, and there will be cells at all intermediate stages present in a tumor mass. Some will have defeated the Hayflick limit (expressed telomerase) but will not have defeated cell-cycle checks, some will be expressing extracellular proteases but won’t have learned to stimulate neo-vascularization, etc. etc.
    “Cancer Stem Cells” is and always was a fallacy

  11. Ernesto says:

    I always thought that one key paper raising eyebrows on the CSC hypothesis was the highly cited Cell paper by Bob Weinberg’s Lab (Mani et al) where they found that cells can dynamically enter and come out of the ‘stem cell’ state. A stem cell that can change its mind is unlikely to be a stem cell.
    https://www.sciencedirect.com/science/article/pii/S0092867408004443.

Leave a Reply

Your email address will not be published. Required fields are marked *

Time limit is exhausted. Please reload CAPTCHA.