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Mouse “avatars”: New predictors of response to chemotherapy?

Over the years, I’ve written a lot about “personalized medicine, mainly in the context of how the breakthroughs in genomic medicine and data pouring in from the Cancer Genome Atlas is providing the raw information necessary for developing truly personalized cancer therapy. The problem, of course, is analyzing it and figuring out how to apply it. Another problem, of course, is developing the necessary targeted drugs to attack the pathways that are identified as being dysregulated in cancer cells. Oh, and there’s that pesky evolution of resistance to antitumor therapies. Indeed, most recently, the Cancer Genome Atlas is bearing fruit in breast cancer (a study that I’ve been meaning to blog about).

One problem with modeling the pathways based on next generation sequencing data and expression profiling is testing whether therapies predicted to work from these analyses actually do work without actually testing potentially toxic drugs on patients. Cell culture is notoriously unreliable as a predictor. However, there is another way that’s intriguing. Unfortunately, as intriguing as it is, it has numerous problems, and, unfortunately, it’s being prematurely marketed to patients. Although I had heard of this technique as a research tool before, I learned about its marketing to patients when I came across an article by Andrew Pollack in the New York Times entitled Seeking Cures, Patients Enlist Mice Stand-Ins. Basically, it’s about a trend in science and among patients to use custom, “personalized’ mouse xenograft models in order to do “personalized” therapy:

Megan Sykes, a medical researcher, has a mouse with a human immune system — her own. She calls it “Mini-Me.”

There are also mice containing a part of 9-year-old Michael Feeney — a cancerous tumor extracted from his lungs. Researchers have tested various drugs on the mice, hoping to find the treatment that would work best for Michael.

In what could be the ultimate in personalized medicine, animals bearing your disease, or part of your anatomy, can serve as your personal guinea pig, so to speak. Some researchers call them avatars, like the virtual characters in movies and online games.

“The mice allow you the opportunity to test drugs to find out which ones will be efficacious without exposing the patient to toxicity,” said Colin Collins, a professor at the University of British Columbia.

Well, yes and no.

My first reaction to this story was a massive yawn. Scientists have been removing bits of patient’s tumors and implanting them into immunosuppressed mice for decades. As I pointed out, I had heard of implanting bits of patient tumors into mice a long time ago. I’ve even known investigators who did such work. Certainly, such models have their uses and can be moderately predictive of at least initial human response (namely, tumor shrinkage), but they have been less successful at being predictive of what therapies will actually prolong human life or cure disease. It’s been fairly hit or miss. So what’s different about these mouse models in this story? Two things. First, instead of using a cancer cell line, these tumors are derived from a patient’s own tumor. In essence, they are chunks of the patient’s tumor implanted under the skin of the appropriate mouse strain; i.e., the strain with the “human” immune system.

As “un-novel” as this all is, what was novel (and to me somewhat alarming) is that companies are apparently already marketing these sorts of animal models to patients. It might very well be that combining the use of genomics to identify specific genetic abnormalities in cancer cells, matching them with targeted drugs, and then testing these drugs in mouse models of the patient’s very own tumor could revolutionize cancer therapy. After all, one problem with using just genomics is that the first test of whether the prediction is right is in patients, and using cell culture models has been quite unreliable to predict whether a given patient’s tumor will be sensitive to a given drug. On the other hand, it’s incredibly labor-intensive and expensive. In other words, avatars are an interesting research tool that could become very useful over time when combined with the genomics revolution. One example is the Breast Cancer Genome Guided Therapy Study (BEAUTY) project (which has the most god-awful contrived acronym I’ve seen in a very long time), which is being carried out at the Mayo Clinic’s Center for Individualized Medicine.

There’s more on this study here:

And here. It’s a fascinating, systematic study that is likely to provide very useful information. Basically, the investigators will not only do next generation sequencing (NGS) on patient’s tumors before and after chemotherapy, but they will keep the patient’s tumor cells alive and grow them in mice to test the predictions that these NGS techniques lead to. The whole thing is likely to be hideously expensive; although the cost of NGS sequencing techniques is plummeting, the cost of keeping a large colony of mice is skyrocketing. That’s why, right now, this sort of combination of techniques is (and should probably only be) limited to cutting edge research laboratories. It’s not something that just anyone can do, nor has it been validated yet in clinical trials.

Out of curiosity, I wandered over to the website of the company mentioned in the NYT article, Champions Oncology, which markets its test under the name Personalized Champions TumorGrafts™ as “empowering patients and physicians using an in vivo mouse avatar-based diagnostic model that has shown to be predictive of a patients’ clinical response to anticancer therapies.” TumorGrafts are further described thusly:

A piece of the patient’s living tumor is removed during surgery or biopsy and is implanted in mice. By implanting the tumor together with it’s microenvironment, TumorGrafts continue to very closely resemble the patient’s tumor with 94% genetic correlation to the tumor in the patient. Our TumorGrafts successfully grow over 80% of all tumors implanted.

And:

Our scientists work closely with treating physicians to determine which drugs to test on the patient’s TumorGrafts. Our labs will administer these treatments to the TumorGrafted mice and measure the living tumor’s response to each drug regimen. Physicians receive a robust report on the effectiveness of each tested therapy on the TumorGrafts. With this information in hand, physicians can personalize each patient’s cancer treatment.

It sound suspiciously to me like making educated guesses and throwing them at the mouse tumor models. In the article, a boy named Michael Feeney is described. Michael has Ewing’s sarcoma, and his parents paid over $25,000 to have a bit of his tumor sent to Champions Oncology for its TumorGraft test. The results came back suggesting gemcitabine, docetaxel, Avastin and Afinitor as a combination of drugs to use, which is described by Michael’s oncologist as “not something oncologists would typically choose.” It’s probably for the same reason that the combinations that Stanislaw Burzynski chooses based on a gene test that he uses are not combinations that oncologists would typically choose because of the potential for synergistic toxicity. In any case, I have to wonder how Champions Oncology came up with the idea of testing that combination in the first place. At least with NGS, there is the guidance of specific mutations uncovered through sequencing. In the case of the BEAUTY study, those mutations will guide testing in mouse avatars. In the case of the TumorGraft test, there are a practically uncountable number of potential drug combinations that can be tested, each taking a certain number of mice. How does one prioritize? I’m surprised it only cost the Feeneys $25,000!

This made me wonder what the evidence base for this test was. I was disturbed by what I found. What I would normally expect to find would be well-designed basic science, animal studies, and clinical trials supporting the hypothesis that using TumorGraft-guided therapy improves response rates or, better yet, survival rates. That is the minimum that I would expect. What I found were preliminary studies, some of which weren’t even based on the company’s test, and then, under a section called Our Experience was nothing of the sort. What I found was a single case report of a man with pancreatic cancer who survived over five years with pancreatic cancer. Unfortunatley, one case study does not adequate evidence make, and I note that this particular patient also had his tumor genome sequenced, as described in this case report. In other words, this case report is much like the BEAUTY trial than it is like what is described on the company website for what it does. In other words, it’s not exactly a fair comparison. Champions narrowed down its choices of therapies to try based on sequencing of the patient’s cancer cells, not the way that the test is described. If the company is routinely sequencing patient tumors and then testing combinations in its TumorGraft test, that would be less questionable to me, although I would still consider it way premature to offer such a test to patients. Way premature.

Nor do testimonials, which are the other main type of evidence on the Champions Oncology website. I can’t help but notice in these testimonials that there doesn’t seem to be any testimonials stating that the results of the TumorGraft test has actually saved a life that wouldn’t have been saved using conventional methods. There are, however, testimonials like this:

A combination of world-class advice and the data from the mice is ensuring that my oncologist has far more information about the potential effectiveness of various treatments than would normally be the case. I feel more in control and not a passive victim of my condition.

Or

Working with Champions’ experts has provided my physician, my family and me with a hopeful path to treat my disease… using Champions TumorGrafts™, [they] identified a novel drug combination that has provided promising results and an improved quality of life.

Oh, sure, there are scientific studies listed. They’re all fairly small and definitely preliminary. One was carried out by Bayer Schering Pharma AG, which didn’t really demonstrate that TumorGraft or TumorGraft-like tests improve patient outcomes. There was, as I pointed out, the aforementioned case report of the man with pancreatic cancer who had a prolonged remission. I’m not saying that the technique of sequencing a patient’s tumor and then testing targeted therapies identified by that sequencing doesn’t have promise; I am saying that it’s not ready for prime time and that offering it to patients before it’s been validated (and charging patients for it) is the same thing as charging patients for an experimental test or therapy, which is what TumorGraft is. Even if it turns out to be the be-all and end-all of personalized cancer therapy, charging patients for it right now is in my opinion at best highly dubious and at worst completely wrong. In other words, count me as one of the critics:

Critics are numerous and have a lot to say. The total length of the procedure is long and patients have died waiting for their mice to be done growing their tumors. Sometimes the tumors do not grow at all. Mice can die during the transplant or when undergoing treatment. The tumor may not behave the same in mice. Treatments that are effective in mice may not have the same effect in humans. Critics are unsure whether it will prolong patients’ lives and the process is very financially draining; it can cost upwards of tens of thousands of dollars, which insurance does not cover. Skeptics say that a randomized trial would need to occur in order to prove that people with avatars would do better than more traditional methods.

Exactly. Although I now count myself as a critic, I’m a hopeful critic, though. There are studies, for instance, that suggest that the use of these animal models in which patients’ own tumors are grown in mice do correlate pretty closely with patient response to the chemotherapy tested. For instance, this study, which is the main study touted by Champions Oncology, involved testing 63 drugs in 232 treatment regimens, and only a few of the tumors were subjected to gene expression profiling. Interestingly, in the conclusion the authors write something that I completely agree with:

The limitations to this approach certainly challenge the broad clinical application of the process and will need to be resolved before this can be first tested in a randomized clinical trial. The process requires large amounts of fresh tumor material and intense resources to generate the tumorgraft. Even in the best conditions, 25 to 30% of implants fail, and those that engraft require 6 to 8 months of additional propagation to be useful for treatment.

This paper was published in 2011 and was done in collaboration with scientists associated with Champions Biotechnology. One wonders why a year later Champions thinks that it’s OK to charge patients for this test. Believe it or not, I do think that sequencing cancer genomes and doing expression profiling, then using mouse models like this, could hold considerable promise for predicting individual patient response to different regimens. I just don’t think the contention that this approach does has been documented. I also view this as a test that will not be helpful to a lot of cancer patients because it just takes too long and is way more expensive than most insurance plans and governments would be willing to pay for without slam dunk evidence that it does a lot better than what we’re doing now. In the NYT article, Dr. Ronnie Morris, the president of Champions, noted that the company has had about 160 patients so far and has tested drugs on mice for 60 of them. However, the other patients “either died too soon, or the tumor did not grow in the mice, or the patients are too new to have reached the drug testing stage.”

So in the end, what we have here is an animal model that very well might be predictive of human response in a way that is more direct and individualized. Unfortunately, it’s not ready for prime time, and might never be. Personally, I tend to view this sort of test as a better research tool than actual diagnostic and predictive test, given its expense, how labor intensive it is, and how long it takes. It could, however, be potentially quite useful in testing whether findings in NGS and/or expression profiling data are predictive of response to specific targeted therapies and, in turn, whether response in the mice is predictive of response in humans. In its current form, however, avatars seem far too cumbersome, labor-intensive, and expensive for routine use, even if it’s limited only to patients with advanced tumors.

NOTE: I’m in Chicago right now attending the American College of Surgeons annual meeting, and didn’t have time to produce a new post up to the usual high standards we demand here at SBM. Since several of you requested a discussion of this study, I figured I’d retool a post that I did over at my not-so-super-secret other blog. I’ll be back next week with a new magnum opus.

Posted in: Basic Science, Cancer, Clinical Trials, Diagnostic tests & procedures

Leave a Comment (8) ↓

8 thoughts on “Mouse “avatars”: New predictors of response to chemotherapy?

  1. Valya says:

    The story of 9-year-old Michael Feeney made me very sad, especially after I read this in the NYT article:

    “The results came back in July. A combination of four drugs — gemcitabine, docetaxel, Avastin and Afinitor — was “astonishingly active” in shrinking the tumor in the mice, said Michael’s oncologist, Dr. Leonard H. Wexler of the Memorial Sloan-Kettering Cancer Center. Dr. Wexler said that the combination was not something oncologists would typically choose.

    Michael has not tried the combination yet because he is participating in a clinical trial of an experimental drug. But if that drug does not work, his mother said, “we have the home run in the back pocket.”

    The mother thinks her child is cured no matter what. It makes me sick that Champions Oncology thinks it’s alright to sell this level of what could be false hope to a child and their family. If avatars were touted as the experimental procedure they are, patients would probably keep a reasonable expectation of treatment outcome. Also, no one should have to pay for experimental therapy.

  2. passionlessDrone says:

    Hi Dr. Gorski –

    I saw this @ RI and meant to comment how much I appreciated this post. Very interesting stuff. Thank you.

    - pD

  3. rork says:

    I think I’ve listed other companies where they offer to test cell lines but am having a hard time finding that today. Then there are companies that just sequence your tumor.
    None of these people are proposing trials though, which seems terribly wrong. Try just one tumor type, and perhaps just one targeted therapy, and see if you can predict who will be helped by that more than conventional treatment – that’s the way we usually do research. It’s slow, but you end up with knowledge that is instrumental.

    Aside: I am starting to have a problem with the word “predict” and “predictive” out there in the wild. Always say what you mean – predictive of what. I’m not saying that wasn’t done here, just grabbing my teachable moment. A marker can be associated with outcome (be prognostic), and we might say it predicts outcome. Statisticians often mean something much stronger though when they say a marker is predictive: they mean that high marker means more difference (or less) between two treatments than for low marker – it’s an interaction between a marker and the treatment effects. When true, it can be useful for saying what treatment you should get. Note that if a marker is prognostic, that doesn’t mean it is predictive in the strong sense – you don’t have data to demonstrate that usually, and need to do a study. (For example, should “bad” folks be treated more, or “good” folks less, or even good folks more – we don’t know. We can guess, but that’s not evidence, and the docs will often disagree about what we should try.) Conversely, if a marker is not prognostic, that doesn’t mean it is not predictive in the strong sense (useless to assign treatment). I see seasoned researchers make mistakes about this all the time, and discredit themselves (to perhaps 10-30% of the people who know better). There’s also often an assumption that a marker (or set of markers) that is prognostic is a good bet to be predictive in two particular arms of a trial – even if it was not designed to be useful in the particular case of those two treatments. That’s just trying to get lucky. Yet people ask me to do exactly that rather often (I forgive them somewhat – we want a function of the markers that is pre-specified before we do the study if possible, so we can randomize based on that function, as opposed to hunting for associations among perhaps hundreds of markers post-hoc.)
    Anyway, watch it when people say “predict” and you aren’t sure what they mean.

  4. DavidRLogan says:

    This is so cool! Thanks for adding a bit of moderation, Dr. G.

    I wish I had the money to run some of these experiments…

    Best,
    -David

  5. WilliamLawrenceUtridge says:

    Why is it getting more expensive to maintain a pool of lab animals?

  6. asolis says:

    Redox Signaling Molecules and ASEA

    ASEA
    Let’s start at the beginning.The human body is made up of somewhere in the range of 100 trillion cells. Within each cell are mitochondria, which are responsible for the creation of energy by way of what is called the Krebs Cycle. This process entails the conversion of glucose to ATP. The byproducts of the Krebs Cycle along the Electron Transport Chain are what are known as redox signaling molecules (“RSM”). Originally, scientists perceived these byproducts as metabolic waste – oxidants and reductants that must be purged from the cell in order to remain healthy. However, current research suggests otherwise. That in fact a proper homeostatic balance of oxidants and reductants is absolutely necessary for maintaining cellular health, including virtually all of the functions of the immune system and tissue regeneration response.

    In the most simplistic terms, they provide a means by which cells
    participate in intra- and inter-cellular damage-control
    communications, activation of antioxidants, cellular protection and
    defense against toxins and free radicals, and in the healing
    response. The human body is constantly working to maintain cellular health by balancing these redox signaling molecules to rid the body of harmful components and to clean up the oxidative stress and free radical damage that occurs at the cellular level, while simultaneously ensuring the cell’s ability to maintain proper
    communication with its environment. When these reactive molecules are in the proper balance, the immune system and healing process function at their optimal level.

    Virtually all disease and bodily challenges are caused by what is
    called oxidative stress – a increasingly salient reality of living
    in modern times attributable to a wide variety of factors, including
    sun damage, excessive exercise, electromagnetic radiation, food
    additives and preservatives, x-ray radiation, prescription drugs,
    heavy metals, stress, anxiety, air & water pollution, lack of
    sleep, and toxic industrialized chemicals to name a few. These
    factors cause our cells to produce an excess of oxidants in
    comparison to reductants – thus throwing off the cell’s
    homeostatic balance of RSMs and promoting the proliferation of
    harmful free radicals. But this imbalance is how the cell detects
    damage and is signaled to repair itself. The immune system is
    summoned, prompting repair, or replacement of the cell via mitosis (cell division) of a neighboring healthy cell. Without this excess of oxidants indicating oxidative stress, the cell wouldn’t know to reach out for restorative help. Too many oxidants leads to a proliferation of damaged cells. But too few oxidants impairs the cell’s ability to signal an immune response and to repair damage. Therefore, balance – homeostasis – is key.

    However, chronic oxidative stress leads to a
    proliferation of free radicals that unless neutralized, lead to cell
    damage that will continue to worsen – damaging the cell walls,
    vessel walls, proteins, fats and even the DNA nucleus of our cells
    until the cell can no longer properly function. The result advances
    the aging of tissues, leading to poor health and the potentiality for
    degenerative disease.

    It is for this reason that we are constantly inundated with the
    health benefits of anti-oxidants. The idea is that these molecules
    combat the proliferation of free radicals in an effort to bring the
    cell back to healthy homeostasis. But herein lies the rub. First,
    most antioxidant supplements are molecules far too large to pass
    through the cell wall, averaging about 200 atoms in diameter.

    Therefore, most (some scientists estimate about 90%) are denied entry to the place where they are needed most – inside the cell where the free radicals are found. Second, one anti-oxidant molecule is empowered to combat one free radical molecule before becoming essentially inert. It is thus a 1:1 ratio. However, the body generally harbors about 100 sextillion free radicals a day. That’s a heck of a lot! Due to this restrictive 1:1 ratio, scientific studies show that your body can’t possibly ingest enough antioxidants to eliminate the number of free radicals your body makes every day. For example, you would have to eat 32 pounds of strawberries, 31 pounds of raspberries, AND 15 pounds of dark chocolate per day to achieve the antioxidant power that it would take to eliminate the free radicals that are created naturally in the body.
    ASEA

    This is where ASEA comes in – as the first and only RSM
    supplement. As stated above, stable RSMs are central to the body’s healing mechanisms, mediating multiple cellular defense, repair & replacement signaling pathways. ASEA purports to have determined a completely stable, balanced, bio-available and entirely non-toxic formula of RSMs native to the body that can effectively penetrate the cell wall (unlike most anti-oxidant supplements), efficiently combat free radicals, stimulate the body’s production of its own anti-oxidant defenses, and stabilize the proper homeostasis of oxidants to reductants to optimize cellular communication, repair, and replacement, thus enhancing the body’s ability to properly function, recover, and simply work as designed.

    Moreover, independent studies show that ASEA when in contact with living cells increased the efficiency of some of our body’s most important native antioxidants inside living cells – such as
    glutathione peroxidase and superoxide dismutase (SOD) — more than 500%. In other words, ASEA is purported to significantly stimulate the cell’s own production of the master antioxidants inside the cells without causing an inflammatory immune system response.

    What does this mean?

    It means that the body becomes empowered to
    neutralize approximately 70,000,000 free radicals per second — the rate at which native Glutathione Peroxidase is able to process
    oxidative free radicals. Quite an improvement over the results that can be achieved by a diet rich in anti-oxidants.

    “Asea merely enhances the body’s innate ability to repair itself”
    Article obtain from http://pure-healing.info/redox_signaling_molecules_and_asea/

  7. Harriet Hall says:

    @aeolis,

    You posted this on the magnesium thread also. Please take your commercials elsewhere. If you have any actual evidence that ASEA is anything more than salt water or that it has actual clinical benefits to patients, please post your comments on the ASEA thread.

  8. weing says:

    I think that ASEA has about as much science behind it as Radithor did.

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