Am J Transl Res 2014;6(2):114-118
`www.ajtr.org /ISSN:1943-8141/AJTR1312010
`
`Review Article
`Lost in translation: animal models and clinical trials in
`cancer treatment
`
`Isabella WY Mak1,2, Nathan Evaniew1,2, Michelle Ghert1,2
`
`1Department of Surgery, McMaster University, Hamilton, Ontario, Canada; 2Juravinski Cancer Centre, Hamilton
`Health Sciences, Hamilton, Ontario, Canada
`Received December 20, 2013; Accepted December 5, 2013; Epub January 15, 2014; Published January 30, 2014
`
`Abstract: Due to practical and ethical concerns associated with human experimentation, animal models have been
`essential in cancer research. However, the average rate of successful translation from animal models to clinical
`cancer trials is less than 8%. Animal models are limited in their ability to mimic the extremely complex process of
`human carcinogenesis, physiology and progression. Therefore the safety and efficacy identified in animal studies is
`generally not translated to human trials. Animal models can serve as an important source of in vivo information, but
`alternative translational approaches have emerged that may eventually replace the link between in vitro studies and
`clinical applications. This review summarizes the current state of animal model translation to clinical practice, and
`offers some explanations for the general lack of success in this process. In addition, some alternative strategies to
`the classic in vivo approach are discussed.
`
`Keywords: Animal models, translational studies, clinical trials, cancer, review
`
`Introduction
`
`Prior to embarking on cancer drug trials, phar-
`maceutical companies and independent inves-
`tigators conduct extensive pre-clinical studies.
`In vitro (test tube or cell culture) and in vivo (ani-
`mal experiments) studies examine preliminary
`efficacy, toxicity and pharmacokinetics. Early in
`vivo testing specifically aims to demonstrate
`safety, which assists investigators to determine
`whether a candidate drug has scientific merit to
`justify further development. Both the Food and
`Drug Administration (FDA) and Health Canada
`require that animal tests be conducted before
`humans are exposed to a new molecular entity
`[1, 2].
`
`The ultimate goal of cancer researchers is to
`translate scientific findings into practical clini-
`cal applications. Experimental discoveries are
`thought to begin at “the bench” with basic
`research, progress through pre-clinical animal
`studies, then show therapeutic efficacy in
`human clinical trials. Although animal models
`continue to play a large role in the evaluation of
`efficacy and safety of new cancer interventions,
`genetic, molecular, and physiological limita-
`
`tions often hinder their utility. Despite success-
`ful pre-clinical testing, 85% of early clinical tri-
`als for novel drugs fail; of those that survive
`through to phase III, only half become approved
`for clinical use [3]. The largest proportion of
`these failures occurs in trials for cancer drugs
`[4]. Furthermore, fewer than one in five cancer
`clinical trials find their way to the peer-reviewed
`literature, generally due to negative findings [5].
`Although logistical and study design issues are
`often identified as the root cause of clinical trial
`failures, most futilities in fact originate from
`molecular mechanisms of the drug(s) tested
`[6].
`
`The overall result is that promising pre-clinical
`animal studies that require extensive resources
`both in time and money rarely translate into
`successful treatments. This review provides a
`critical evaluation of pre-clinical animal models
`and their role in translation to clinical practice
`for cancer patients.
`
`Limitations of animal models in cancer re-
`search
`
`Animal models have not been validated as a
`necessary step in biomedical research in the
`
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`Animal models and clinical trials for cancer
`
`scientific literature [7]. Instead, there is a grow-
`ing awareness of the limitations of animal
`research and its inability to make reliable pre-
`dictions for human clinical trials [8]. Indeed,
`animal studies seem to overestimate by about
`30% the likelihood that a treatment will be
`effective because negative results are often
`unpublished [9]. Similarly, little more than a
`third of highly cited animal research is tested
`later in human trials [10]. Of the one-third that
`enter into clinical trials, as little as 8% of drugs
`pass Phase I successfully [11].
`
`The major pre-clinical tools for new-agent
`screening prior to clinical testing are experi-
`mental tumors grown in rodents. Although mice
`are most commonly used, they are actually
`poor models for the majority of human diseas-
`es [12]. Crucial genetic, molecular, immunolog-
`ic and cellular differences between humans
`and mice prevent animal models from serving
`as effective means to seek for a cancer cure
`[13]. Among 4,000+ genes in humans and
`mice, researchers found that transcription fac-
`tor binding sites differed between the species
`in 41% to 89% of cases [14]. In many cases,
`mouse models serve to replicate specific pro-
`cesses or sets of processes within a disease
`but not the whole spectrum of physiological
`changes that occur in humans in the disease
`setting [15].
`
`The failure to translate from animals to humans
`is likely due in part to poor methodology and
`failure of the models to accurately mimic the
`human disease condition. The core of the prob-
`lem may be rooted in the animal modeling
`itself. Unlike in human clinical trials, no best-
`practice standards exist for animal testing [14].
`Moreover, the laboratory environment can have
`a significant effect on experimental results, as
`stress is a common factor in caged mice [16]. It
`has been recommended that therapeutic
`agents should not only be evaluated in rodents,
`but also in higher animal species, and that ran-
`domization and outcomes assessor blinding
`should be performed. In addition, experiments
`should be designed in both genders and in dif-
`ferent age groups of animals and all data, both
`positive and negative, should be published [3].
`
`Notable examples of failed clinical cancer tri-
`als initiated due to successful animal models
`
`A well-known example of a successful animal
`model that did not translate into clinical trials is
`
`the TGN1412 trial [17]. The drug TGN1412,
`developed by the company TeGenero, was
`described as an immunomodulatory human-
`ized agonistic anti-CD28 monoclonal antibody
`developed for the treatment of immunological
`diseases such as multiple sclerosis, rheuma-
`toid arthritis and certain cancers. Before con-
`ducting human trials, TGN1412 was tested on
`different animals including mice, to ensure
`safety and efficacy in preclinical animal models
`[17]. These toxicity studies demonstrated that
`doses hundred times higher than that adminis-
`tered to humans did not induce any toxic reac-
`tions. In the first human clinical trials of
`TGN1412, the drug caused catastrophic sys-
`temic organ failure in patients, despite being
`administered at a sub-clinical dose that was
`500 times lower than the dose found safe in
`animal studies [18].
`
`In a recent report, a Phase II randomized clini-
`cal trial of the Hedgehog pathway antagonist
`IPI-926 (saridegib) in patients with advanced
`chondrosarcoma was stopped early for futility
`[19]. The Hedgehog pathway is dysregulated in
`a variety of solid tumors and provides key
`growth and survival signals to tumor cells.
`Mutations resulting in constitutive Hedgehog
`signaling are causal in cartilage tumors such as
`chondrosarcoma [20]. The Phase II clinical trial
`for IPI-926 translated from a successful animal
`model of IPI-926 on a malignant solid brain
`tumor [21]. IPI-926 treated mice with the
`advanced brain tumors gained a fivefold
`increase in survival [21]. However, IPI-926
`showed no effect compared to placebo in the
`human trial [19]. Therefore even a targeted
`molecular approach did not result in clinical
`efficacy despite remarkable success in mice.
`
`Matrix metalloproteinases (MMPs) are a family
`of zinc-dependent proteinases involved in the
`degradation and remodeling of extracellular
`matrix proteins and are associated with the
`tumorigenic process. MMPs promote tumor
`invasion and metastasis,
`regulating host
`defense mechanisms and normal cell function
`[22]. Cancer and arthritis were once regarded
`as the prime indications for the use of MMP
`inhibitors (MMPIs) and results from multiple
`animal studies indeed indicated that MMP inhi-
`bition would be an effective therapeutic
`approach in the management of cancer and
`other diseases [15]. However, multiple failed
`clinical trials in humans have had the effect of
`
`115
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`Animal models and clinical trials for cancer
`
`seriously reducing interest in MMP inhibition as
`a valid therapeutic option [22].
`
`Among the more-than 16 MMPIs that pro-
`gressed to clinical testing, only Periostat (doxy-
`cycline hyclate, a nonspecific MMPI) has been
`approved for clinical use in periodontal disease
`[15]. The serious safety problems in clinical tri-
`als have been attributed to poor selectivity of
`the MMPIs, poor target validation for the tar-
`geted therapy and poorly defined predictive
`preclinical animal models for safety and effica-
`cy [23]. The failure and indeed resulting dam-
`age of all anti-MMP drugs in clinical trials indi-
`cated that MMPs as a class have useful
`functions in normal tissue, and therefore inhibi-
`tion would result in toxicities in the human host
`not identified in the animal models in which
`they were tested.
`
`Therapeutic cancer vaccines are becoming
`increasingly popular in the approach to cancer
`treatment. The concept of stimulating the
`body’s immune system to fight tumors, repre-
`senting an alternative approach to the use of
`traditional cytotoxic cancer therapies, is indeed
`compelling [24]. A typical therapeutic vaccine
`against cancer contains a cancer-specific pep-
`tide, or protein fragment, that is injected under
`the skin of either the tested animals or humans.
`It is assumed that the immune system would
`recognize the peptide as something to be
`attacked and boosts the population of cancer-
`fighting T-cells in the bloodstream [25]. These
`vaccines must first be tested in animals to con-
`firm efficacy prior to entering into human clini-
`cal trials [26]. In the particular case of cancer,
`preclinical animal models have provided new
`knowledge regarding vaccine-induced immune
`responses and the central importance of T cell-
`mediated cellular responses in cancer treat-
`ment [25].
`
`Although therapeutic cancer vaccines have
`been effective
`in
`initiating
`the
`immune
`response in animal models, they have pro-
`duced mixed results in human clinical trials. In
`a recent review article, it was reported that out
`of 23 Phase II/III clinical trials testing 17 dis-
`tinct therapeutic anticancer vaccines, 18 of
`these studies had failed [27]. Some examples
`are Merck’s Stimuvax (failed a phase III trial on
`non-small cell
`lung cancer)
`[28], Glaxo-
`SmithKline’s MAGE-A3 (failed a phase III mela-
`noma trial) [29], Vical’s Allovectin (failed a
`
`phase III metastatic melanoma trial) [30], and
`KAEL-GemVax’s TeloVac (failed a phase III pan-
`creatic cancer trial) [31]. It has been postulated
`that most of the cancer vaccine trials have
`failed due to elevated levels of circulating
`immunosuppressive cytokines and various
`immunological checkpoints in humans that
`may not be present in rodents [25].
`
`Critical re-evaluation of animal models and
`alternative strategies
`
`Despite the general lack of success in translat-
`ing animal models to clinical studies, animals
`are still prevalently used in laboratories all over
`the world to test the safety, toxicity and effec-
`tiveness of drugs [32]. Animal models have
`been essential in cancer research for obvious
`practical and ethical concerns associated with
`human experimentation. Animal research is
`similar to in vitro assays, epidemiological inves-
`tigations, and computer simulations. All
`attempt to derive probabilistic knowledge in
`one context that will generalize to humans. All
`are forms of modeling that will map onto the
`whole population with less than perfect preci-
`sion and predict with even less precision the
`fate of any individual. Notwithstanding, these
`methods risk missing some important knowl-
`edge, or risk finding knowledge that doesn’t
`hold up in the clinical setting even to a point
`that is actually harmful once widely deployed.
`
`Ultimately, we come into the question as to
`whether we should spare resources and bypass
`animal models to evaluate therapy in humans
`directly. In the last decade, the FDA and the
`European Medicines Agency introduced guide-
`lines for testing very small ‘micro-doses’ of
`drugs in humans [33]. These are concentra-
`tions less than a one-hundredth of the thera-
`peutic dose. Because the concentrations are
`so low, the drugs can be tested in a small num-
`ber of patients without the level of safety data
`normally required before a phase I study. These
`early ‘phase 0’ studies collect human data
`quickly by showing how the drug is distributed
`and metabolized in the body, and whether it
`hits the right molecular target. Approximately
`one-quarter of the molecules entering clinical
`trials fail due to pharmacological issues such
`as lack of absorption or penetration into the
`target organ [33]. With a direct test in humans,
`pharmaceuticals can determine earlier wheth-
`er the drug is worth investing both time and
`
`116
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`

`Animal models and clinical trials for cancer
`
`Address correspondence to: Dr. Michelle Ghert,
`Department of Surgery, McMaster University, 711
`Concession Street, Hamilton, On L8V 1C3. Tel: 905-
`387-9495 Ext. 64089; Fax: 905-381-7071; E-mail:
`Michelle.Ghert@jcc.hhsc.ca
`
`References
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`money into clinical research. Phase 0 trials may
`be small in scope, but they require very sensi-
`tive tests to detect the minute quantities of the
`drug in the body and possibly its mechanism of
`action.
`
`Aside from phase 0 studies, a wide range of
`alternatives
`to
`animal-based preclinical
`research has emerged. These include epidemi-
`ological studies, autopsies, in vitro studies, in
`silico computer modelling, “human organs on a
`chip” - creating living systems on chips by mim-
`icking a micro- biological environment with cells
`of a certain organ implanted onto silicon and
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`automation of over a hundred cell cultures or
`other experiments on a tiny rubbery silicone
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`The National Institutes of Health of the United
`States suspended all new grants for biomedical
`and behavioural research on chimpanzees
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`the US National Research Council recommends
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`
`In summary, animal models have been the
`basic translational model in the preclinical set-
`ting in elucidating key biochemical and physio-
`logic processes of cancer onset and propaga-
`tion in a living organism. Experimental tumors
`raised in animals, particularly in rodents, con-
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`process of human carcinogenesis. The vast
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`between mice and humans, may lead to trans-
`lational limitations. Even though animal models
`still remain a unique source of in vivo informa-
`tion, other emerging translational alternatives
`may eventually replace the link between in vitro
`studies and clinical applications.
`
`Disclosure of conflict of interest
`
`None.
`
`117
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`Am J Transl Res 2014;6(2):114-118
`
`Abraxis EX2086
`Cipla Ltd. v. Abraxis Bioscience, LLC
`IPR2018-00162; IPR2018-00163; IPR2018-00164
`
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