More Mouse Models of Cancer, Still Not Human
There have been many attempts to reproduce human cancers in mice. The nude mouse lacked the FOX1 gene, the SCID mouse was created with a very deficient immune system, and there have been many more. All have failed to predict human response and have misled researchers. When I say things like that, the vested interest groups go wild accusing me a of being an antiscience, misanthropic, lunatic, animal rights activist.
In the April 1, 2010 issue of The Scientist some scientists apparently missed the memo warning them not to agree with me. The article is about yet another effort to make mice into humans. But interestingly, the article says:
Most of the time, in order to test a cancer therapy, researchers simply transplant human cancer tissue into a mouse. But those experiments rarely predict how a human will respond to the same treatment . . . Mouse models that use transplants of human cancer have not had a great track record of predicting human responses to treatment in the clinic. It’s been estimated that cancer drugs that enter clinical testing have a 95 percent rate of failing to make it to market, in comparison to the 89 percent failure rate for all therapies . . . Indeed, we had loads of models that were not predictive, that were [in fact] seriously misleading,” says NCI’s Marks, also head of the Mouse Models of Human Cancers Consortium, a network of cancer researchers (including Pandolfi) who set goals, meet regularly, and collaborate in their search for a better mouse model. In 2001, researchers at the NCI looked at the xenograft data from 39 cancer drugs that had already successfully completed Phase II trials in humans. Only one of the xenograft models showed a similar response to the cancer drug as the patients who received it (Br J Cancer, 84:1424–31, 2001) . . . Scientists and companies compound the problem by putting too much stock in the results from these troubled models. [1] (Emphasis added.)
Historically researchers who use mice have defended the practice saying the mouse models were invaluable for informing about the human disease. I guess they were engaging in a bit of irrational exuberance there. No matter. Now they are saying the new mouse models will be great. Of course, not everyone is saying that:
The National Cancer Institute awarded the trial more than $4 million in stimulus funds, but Cheryl Marks, the director of the NCI’s division of cancer biology, isn’t entirely convinced that these [new] genetically modified mice will prove more predictive than the standard human transplant model. “This [trial] is the first thing that would make a believer out of you,” she says. “To me, the jury is out” . . . But will this model, or any other, predict human experiences of toxicity, recurrence, drug response, metastasis? “It’s a very challenging question,” says Marks. [1]
At some point society must hold responsible the researchers whose failures cost precious money that could have gone into studying humans with cancer. These scientists told society cures were coming from the mouse models and that the mouse models could predict human response. Likewise, society must also call into question current claims being made by essentially the same people.
Instead of using mice, scientists could study humans with cancer and the cancerous tissues from those humans. What a novel idea; study the species you want to cure. But until society realizes lives are being lost and demands an end to white coat welfare, the status quo is unlikely to change.
(For more in cancer and animal models see Animal Models in Light of Evolution.)
References
1. Zielinska E: Building a better mouse. The Scientist 2010, 24:34-38.
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Dr. Greek appears to be missing the bigger picture. The mouse subcutaneous xenograft tumour model is probably the easiest target there is for anti-vivisectionists, it's not even considered to be a real animal model by the vast majority of cancer researchers. It's probably best to think of the standard sub-cutaneous xenograft mouse models as a kind of half way house , occupying groung somewhere between in vitro models of cancer and real animal models. Sub-cutaneous xenograft mouse models of cancer have played and continues to play a very useful role in cancer research but has for decades been viewed with extreme caution as a predictor of success in human clinical trails.
The article in The Scientist http://www.the-scientist.com/2010/4/1/34/1 / points out one of the problems with the mouse xenograft models of cancer is that the human cancer cell lines used in them are often not very accurate representations of real human cancers. In many cases they have been modified from the original cancer tissue sample and the tumours they produce are very homogenous, unlike most cancers found in real patients which show great variation. It's hardly surprising that a drug that will stop tumour grouth or kill the majority of tumour cells in a mouse xenograft model will often only kill a minority of cancer cells in a patient and have little effect on the progression of the disease.
Incidently the same problem of inadequate or unrepresentative cancer cell lines also affects the overwhelming majority of in-vitro cancer research, which most drugs are tested in and need to "pass" before they even get to be tested in mice.
As the report in The Scientist indicates many researchers are well aware of the weaknesses in the techniques that are usually used to evaluate new cancer drugs , and many are working on better models such as GM mice and xenografts that use tumour tissue taken directly from patients rather than homogenous cell lines, thereby better representing the kind of tumour cells found in human cancer. These will provide both useful models for basic cancer research and hopefully prove to be more predicitiv models when used in the translational evaluation of new anti-cancer drugs .
Another sign of progress is the news that the NIH is reviewing its rules for the testing and approval of multidrug combinations http://www.thebody.com/content/news/art55898.html . This is timely since over the past decade it has become increasingly obvious that to kill many cancers you need to attack them from several directions at once, not least because the diversity of cells in many tumours been that each drug might only kill a portion of the cancer cells. Also in many cases cancer drugs have been found to work better in combination, for example by combining an anti-angiogenic drug with a cytotoxic drug. In the near future I expect that combination therapy for cancer will become the standard, and that many cancer drugs will be developed with use in combinations in mind right from the outset.
Everyone working in cancer research is well aware that the field has its flaws, but to blame most of them on animal research would be missing the point; there are more important problems such as the use of unrepresentative cancer cell lines used in both in vitro and in vivo cancer research. This is something that needs to be got right, since drugs need to be evaluated in some way, either in vitro or in animals , and usually in both, before going into human trials.
I'll end by pointing out an essay by one of Dario Ringach's colleagues at Speaking of Research http://speakingofresearch.com/2010/03/25/rnai-send-in-the-nanobots / which highlights the importance of animals in the basic research and pre-clinical evaluation of the novel nanotechnology and RNA interference-based cancer treatments that are now entering clinical trials.
Ray Greek is just attempting to co-opt the thoughtful attitude of cancer researchers for his own misleading propaganda.
Everybody knows that UCLA's notorious animal experiments have nothing to do with real science . They're done to gain lucrative grant funds (duh) and perhaps to give puppy-punchers a playground. UCLA researchers love to manipulate the public with cheap slogans such as “Animal research saves lives" (to imply if you don't support it, you don't care about people, especially kids ) and "Campus terrorism is not OK” (to perpetuate the Green Scare and kill our civil liberties by muffling all dissent).
No surprise that often exploiters reward their own with prizes. Doesn't change the fact that animal models are not predictive for humans. Just because some folks insist on saying mice are furry little men, doesn't make it so. But I guess it's like a George W. tactic, keep repeating a lie forcefully until people give in or give up.
If a person cares about the well-being of people, then it is unconscionable to support animal research and impede real medical progress.
Dr. Fuster’s credentials and premises are excellent. His awards and honors includes the following:
Fellowship Jaime Balmes, 1954
Fellowship Gregorio Del Amo, 1956
Career Investigator Award (NIMH), 1960
Career Development Award (NIMH), 1965
Research Scientist Award (NIMH), 1970
Senior Scientist Award (NIMH), 1990
The Magoun Lecturer, University of California, 1991
The Ojemann Lecturer, University of Iowa , 1995
Spanish Royal Academy of Medicine (elected Member of Honor, 1997)
The Elsevier Lecturer, European Brain and Behavior Society, 1997
JeanLouis Signoret Prize, (Paris), 2000
Fyssen International Prize, (Paris), 2000
The Elliot Lecture, University of Pennsylvania, 2002
European Brain and Behavior Society (elected Member of Honor, 2002)
Doctor Honoris Causa, Universidad Miguel Hernández, Alicante, Spain (2004)
The Goldman-Rakic Price for Cognitive Neuroscience NARSAD (2006)
George Miller Prize, Cognitive Neuroscience Society (2007)
Earl Usdin Award (2008)
Doctor Honoris Causa, Univesidad Autónoma, Madrid, Spain (2008)
http://www.joaquinfuster.com /
This is a common logical fallacy. Expert A says B so B must be true. But the theoretical underpinnings of animal modeling of human biology are not part of Fuster's expertise, at least his publication list at PubMed doesn't demonstrate that he has an expertise in this area. So his credentials and awards for other topics have little bearing on whether his opinion on this matter is correct. For that determination, one has to actually read what he has written and compare his claims and conclusions to the known facts.
If you'd actually read the information on Fuster's homepage you would have noticed that he conducts research on animals AND on human subjects in his work on memory and cognition, so he is very well placed to judge the quality of the information that the animal models he uses provides.
I suppose Fuster could have done what Dr. Greek did a few years ago and appointed himself as an "expert" on the "theoretical underpinnings of animal modelling of human biology", but I''d still pay a lot more attention to whether or not he has a good research record...and there's no doubting that Fuster has an excellent research record.
Please clarify your comment. Are you claiming that Fuster's experiments on monkeys have led to improvements in human clinical care? I do not see evidence of that on Fuster's homepage, but maybe I missed it?
Please point to this evidence if it exists. If there is such evidence it would bolster your claim that Fuster is a reasonable judge of the consilience of the interspecies data he has gathered. In the area of animal models of human biology, data that does not lead to clinical application is of little value.
If such evidence doesn't exist, then Fuster's claims regarding Greek's conclusions are no more reliable than yours or mine, and we must rely on the published scientific evaluations of the efficacy of animal models.
Fuster operates from the faulty premise—as most animal faux researchers tend to do--that animal models are predictive for humans. Sorry, but they simply aren't. Just look at the huge history of animal experiments. Let's just say, major FAIL.
One of the best responses to Dr. Greek’s views of animal research (imo) was written by Joaquín M. Fuster, M.D., Ph.D., Professor, UCLA School of Medicine back in 2009. That letter can be read in its entirety at:
http://speakingofresearch.com/2009/08/24/open-letter-to-dr-greek /
letter was written in 2003
Animal researchers usually like to claim AZT (used to treat HIV ) was developed through animal testing . But AZT was actually created in a TEST TUBE around the mid-Sixties. Back then it was applied in cancer treatments. About two decades later, scientists figured out AZT could be used in the treatment of HIV. Thanks to animal testing? Hell no. Thanks to real science conducted in, yes, the trusty test tube. This is just one example.
The propaganda of the billion-dollar animal testing industry has 70% of the general public eating up the deadly lie that animal testing is necessary. Not only is animal testing plain torture for the animals , it's dangerous for people. For instance, drugs not toxic to animals can be lethal to humans. As Dr. Greek has pointed out, mice and rats are not furry little humans. Animal testing trips up medical progress, and people suffer and die unnecessarily while hoping for a real cure. Talk about unethical....
Believing in animal testing as a science in this century is like believing the earth has no moon . Animal testing is only a tradition of ruthless profiteering disguised as “legitimate research for the common good of humanity.”
Thanks for defending the truth, Dr. Greek.