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Animal Testing

A New Chemotherapy Idea

This is a study whose immediate applications are in the clinic, but it could have follow-on effects in drug discovery and development as well. Writing in Science Translational Medicine, a team from the Moffitt Cancer Center and USF (with analytical help from Bruker) have been trying a new approach in mouse models of cancer. The standard way to treat most forms of cancer, when it comes to chemotherapy, is to hit it as hard as possible. That makes sense, and it’s a natural human impulse, too: here’s something that is in the process of killing the patient, so why wouldn’t go you all out? But in recent years, data on what’s going on inside tumor cell populations has called this approach into some doubt.

Some tumors are obviously heterogeneous, but cell-by-cell sequencing has shown that they’re even more varied than people had thought. This has a lot of functional consequences – metastatic tumors, for example, tend to be formed from cell line mutations of the original tumor that have ended up with weaker cellular adhesion proteins and the like. Along these same lines, a recent study showed that targeting the metabolic anomalies in cancer cells, a popular area of research the last few years, will also be affected by this variability. Inside a given tumor, it turns out, some of the cells are showing Warburg-effect metabolism, but some of them aren’t.

This all means that if you charge in and try to blast the cancer out of a patient, you’re going to end up only blasting some of it out – probably the easier part, in many cases. Oncologists have realized this for a long time, naturally, but there hasn’t been much that could be done about it. This style of therapy still leads to increased survival (well, most of the time), even if the cancer does generally come back in a much less treatable form. But what else is there to do? That’s what this latest study addresses: the authors are deliberately taking an evolutionary approach, trying to fight the tumor population to a long-term draw rather than wipe it off the board. To that end, they start with high doses of chemotherapy, but back off, titrating down so that there’s still a population of treatable cells left, one that will possibly compete with the untreatable ones and keep them from taking over. (The resistant cells are presumably paying a metabolic penalty for being so hard-core).

This actually seems to work. Using breast cancer xenografts in mice (two different models) and paclitaxel/taxol therapy, the effects are actually very impressive. In up to 80% of the animal, they ended up being dosed only once every few weeks to keep things stable, with no treatment at all in between. The tumor tissues were monitored by NMR imaging, and this information was used to adjust the dosing schedules. Biopsies show that there seems, over time, to be some vascular normalization taking place, which might help account for the improvements over time.

Now, there are things here that are going to have to be worked out. Mouse xenograft models are notorious for being poor predictors of clinical efficacy – but that said, these seem to be well-chosen cell lines, and treating such patients with taxol is exactly what you’d do in the clinic. And this evolutionary approach might be more translatable from the model as well (wouldn’t that be nice), since some of the disconnects might be due to that regrowth-of-the-resistant problem. At any rate, this seems very much worth following up on, and I hope that this paper creates as much of a stir in the oncology community as it seems ready to. Doing a human trial like this is going to take some serve, but the potential benefits are large.

The implications for drug discovery are worth thinking about, too. Traditionally, the framework for drug discovery in this area has been the hit-it-with-everything-you’ve-got paradigm (taxol is certainly part of that). This paper takes a mighty hammer like that compound and adjusts it to use in an evolutionary framework by careful dosing (thus the NMR monitoring, which would seem to be essential for this idea to work). Another approach might be more regular dosing of a less ferocious compound, which is not something that we’ve been thinking about much in drug discovery.

Why would you take a sort of medium-effective chemotherapy drug forward? Well, this latest paper might be the answer to that question. I don’t know if that approach would be equivalent to the one used here, but it’s worth thinking about. Alternatively, you might imagine a period of whacking the tumor population into shape a bit with high-dose chemotherapy of the traditional sort (or worse), followed by a switch to something less vicious for maintenance. There’s a lot to think about here, and if you’re doing cancer research, you should definitely set aside some time to think about it.

20 comments on “A New Chemotherapy Idea”

  1. anonao says:

    The approach is interesting, but yes, running a clinical trial for it is not going to be easy. The endpoint is not cure of cancer (present or not present), but the fact that it is first reduced then stayed under control.
    “Future”, self-monitoring device in the body and alert when need to take a dose of a cancer drug to maintain everything in a good way (or at least to avoid a critical situation).

    1. “The approach is interesting, but yes, running a clinical trial for it is not going to be easy. The endpoint is not cure of cancer (present or not present), but the fact that it is first reduced then stayed under control.”

      Yes, so survival is the endpoint, not tumor burden reduction or shrinkage of the tumor. Ditching the surrogate endpoints won’t be painless, but simply running a straight survival trial isn’t radical.

  2. Tim Carlton says:

    I wonder if this could extrapolate to antibiotic treatment as well?

  3. Dr. Manhattan says:

    “I wonder if this could extrapolate to antibiotic treatment as well?”

    Bacteria replicate at a faster rate than tumor cells. Infections with serious pathogens can be fast moving and patients can go downhill very quickly, especially if sepsis sets in. Not much room to back off on treatment, and if there are already resistant organisms in the infecting population, it probably won’t help. Unfortunately many hospitals (especially tertiary care facilities) come with their own sets of resistant organisms in house, despite the best efforts of staff and infection control measures. Some nice studies on development of resistance have studied resistance development under antibiotic pressure (see e.g., Roy Kishony’s & Bruce Levin’s work).

    A separate case is dormant bacterial cells. There have been studies (see work by Kim Lewis, among others) on modifying antibiotic regimens to try to catch dormant cells as they emerge from dormancy and cause infection rebound.

  4. Rule (of 5) Breaker says:

    I always thought there is just as much to be done clinically as there is on the R&D side of things like dosing amounts, schedule, combos, etc. Obviously this is extremely difficult just from the vast number of permutations and combinations that are possible, not to mention the costs associated with doing so. Great to see novel clinical approaches. Those of us in R&D come up with the tools, and it is nice to see some creative clinicians thinking outside traditional dogma on how to use those tools. I hope at the very least their approach uncovers new understandings about tumor cell biology.

    1. Robert Gillies says:

      (I am author on the paper). Because of the complexity, we are making extensive use of mathematical modeling to conduct “iTrials”.

      1. Hello Dr. Gillies,

        I wonder if by chance you did genomic sequencing of the tumors under the treatment regimens? The genetic diversity could be examined to test the degree of heterogeneity that develops over time in different regimens, including looking for signs of developing resistance to chemotherapeutic agents.

  5. watcher says:

    While I know this does not mean giving specifically paclitaxel/taxol, but it could be a short term result, and we all know in cancer that short term intentions are often hard to displace, And if you’ve ever been on paclitaxel/taxol, then you’d know that the side effects are cumulative and extremely tiring. Many people I know would not, could not “live” that way for prolonged periods, or for the rest of ones life, and would opt for an option that tries to “cure” rather than to use very generically toxic compounds a palliative treatment. Yes, it’s an interesting study with provocative results, but we need a goal to not be satisfied with such toxic treatments and work toward more tolerable ones that actually help more folks become truly cancer free and cured.

  6. Anon electrochemist says:

    Are there not dozens of medium-low efficacy compounds from decades of cancer trials that flopped? Perhaps there are a handful with good PK and tox, but lost out by not hitting as hard as taxol.

  7. Anon postdoc says:

    If this does take off as a therapeutic option, the industry will have to be very careful how they frame their arguments for it. Historically, any time that big pharma has tried to offer a maintenance therapy for cancer instead of a cure, it gets slammed for being money-grubbing and not interested in patient health. An unfortunate pitfall, but one they’ll have to manage.

    Perhaps it will be easier for the public to swallow if the therapies being used are generic?

  8. Mark Thorson says:

    If you can get an effective therapeutic effect from a dose below that which triggers the cascade of drug-clearance mechanisms (mainly P-glycoprotein and CYP3A4) triggered by activating the steriod and xenobiotic receptor (SXR), that would be big news. Those are the mechanisms which always result in the ultimate failure of chemotherapy. For inoperable cancers, chemotherapy is a rough road that ends in death. Most of the time, chemotherapy buys you a few more years of life, but at a high cost in dollars and quality of life. It doesn’t eradicate the cancer, but suppresses it until drug resistance kicks in, followed by death shortly thereafter.

    It’s hard to believe that simply throttling back the dosing protocol could solve this problem. If it was really that simple, why was it not found sooner? These drugs have been around a long time.

  9. DanielT says:

    I was under the impression this is exactly what oncologists do with older patients. If they have a 85 year old they just low dose the patient to slow growth of the tumour rather than hit the cancer hard trying for a cure.

    What would be interesting here is combining this approach with low dose anti-VGRF to normalise the vascular before hitting to get a 90% volume reduction, then dosing to hold before repeating. This way you might be able to walk the tumour back slowly without selecting for resistant mutants.

  10. steve says:

    It’s hard to believe this will work clinically; I’d be in Stockholm if everything that worked in mice worked in people. The answer to the heterogeneity of cancer is the immune system, which is equally adaptive.

    1. Mo Shoreibah says:

      Couldn’t agree more on with both points you made!

  11. Jose says:

    I hope the volumetric measurements (+/- SD?) are more impressive than the survival analyses. In Figure 3 all those comparisons are wholly inappropriate- crossing survival curves invalidate the Mantel-Cox test. Moreover, these experiments are *massively* underpowered to see any difference in survival.

  12. oncodoc says:

    Oncology is full of great hypotheses but not so full of great results. As an old guy this study is quite reminiscent of ” metromonic ” chemotherapy efforts that date back decades. Small frequent doses of taxanes have also been described as antiangiogenic when angiogenesis was a big idea in our field. I think we should be very sparing in the use of the word “new” and maintain a degree of caution about results in mice models.

    1. me says:

      LOL – my impression of these mouse tumour models is that the xenografts die after low doses of country music, let alone chemotherapy!! So I would have thought your warning about them is pretty spot-on.

  13. Matt says:

    This is not new (they are basically repurposing maintenance therapy as front-line). The problem is that low-dose chemo might suppress growth, but not invasiveness, and low-dose chemo isn’t going to regulate tumors that metastasize to a privileged site such as brain mets.

  14. Joel Lord says:

    So tangentially from something in your second paragraph, might there be value in research in to strengthening cellular adhesion proteins in cancer cells, in an attempt to reduce the risk of metastasis? Make ’em stick together better, and at least treatment only has to focus on one known location.

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