21 October 2020
by Humane Society International
In recent years many scientists have questioned why animals are still being used for testing potential drugs aimed at treating human diseases, including cancer. There is an increasing body of evidence showing that the predictive value of animals to attest safety and efficacy of medicines for humans is very low. In fact, animal testing represents a major obstacle in the drug development pipeline and is the main reason drug attrition rates are so high. For cancer, in particular, more than 95% of potential drugs fail in clinical trials.
But are failing animal models truly being replaced by the more predictive, human biology-based tools? To investigate this, a group of researchers at Humane Society International, led by Dr Lindsay Marshall, analyzed research funding, numbers of papers published and clinical trials for breast, lung and colorectal cancers across the European Union and in the US between 2014 and 2019. The group compared research using animal-dependent methods—so-called “xenograft” models in which patient tumor biopsies are injected into an animal—and human “organoids”, which use patient tumor samples to create in vitro models that more closely resemble a patient’s tumor. Their preliminary analysis showed that for human organoids, there has been a modest increase in outputs, as measured by number of publications, funding, and publications associated with clinical trial. However, when the authors compared this to xenograft research, they found that animal-dependent research is still favored and that publications, funding and clinical trials associated with xenografts all outnumber organoids by at least 10 to 1.
Overall, it appears that the transition to more effective and more human-relevant non-animal technologies, is proceeding at a very slow pace. The authors make several recommendations to accelerate this change, including the establishment of training programs for researchers and greater transparency regarding the use of organoids/other human cell-based tools to develop drug testing regimes for patients.
The authors contend that, “There is a great need to level the ‘playing field’ for the human cell-based technologies compared to animals, given that, in the European Union, only 0.036% of the research budget is dedicated to these more human relevant, non-animal approaches. This deficit is adding hugely to the obstacles preventing animal replacement in human health research.” They go on to say “We would like to stress that funding should be made available to assess the capacity of the organoids in predicting patient responses or for evaluating novel, possibly combination therapies, and not for comparative studies aiming to ‘validate’ organoids against animals, given that the animal models are, and remain, unvalidated.” A number of studies have described the pitfalls of using animal xenografts as a proxy model for a patient’s tumor. These models are time-consuming, very expensive, and some studies have shown that they do not faithfully replicate the changes and abnormalities first seen in the original tumor, but rather create new ones.
On the other hand, human organoid models recapitulate key characteristics of the original cancer and maintain the structure seen in the patient’s tumor. This makes human organoid models better for studying how the patient will respond to specific drugs, and how the tumor will progress. Considering this, and the promise of human organoids for studying cancer, the authors expressed their disappointment in learning that the U.S. National Institutes of Health awarded over five times more funding to animal xenograft-based research programs than to those involving human organoids. Importantly, the study also shows that despite a rise in funding for research in cancer over the last years, regardless of the technology used, this increase does not seem to translate into benefits for patients.
With at least half of European cancer research funding coming from the public via charity donations, and U.S. taxpayers contributing heavily to their own government’s research budget, there is certainly a case to be made for the responsibility scientists and researchers have to the public. Given the disaproval of many citizens concerning the use of animal in research, this might include reducing reliance on animal testing and accelerating the discovery and development of new, effective and affordable medicines.
The work of Marshall et al. indicates that this is entirely possible but that it will require dedicated support for human biology-based approaches, a more agile regulatory approach and smarter clinical trials. With lung, colorectal and breast cancers accounting for almost a third of all cancer mortality annually worldwide and cancer research consuming millions of animals’ lives, these would surely be small changes for the potential gains to be made.
The paper entitled “Patient-Derived Xenograft vs. Organoids: A Preliminary Analysis of Cancer Research Output, Funding and Human Health Impact in 2014–2019” is available here.
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