The role of mouse tumour models in the discovery and development of anticancer drugs

Ireson, Christopher R.; Alavijeh, Mohammad S.; Palmer, Alan M.; Fowler, Emily; Jones, Helen M.F.

doi:10.1038/s41416-019-0495-5

Cited by 135 publications

(114 citation statements)

References 62 publications

(54 reference statements)

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“…37 An alternative is to use syngeneic or allograft mouse tumour systems in which mouse tumour tissues or cell lines are implanted into animals from the same genetic background, thus retaining an intact immune system. 38 Patient-derived xenograft (PDX) models, in which fragments of fresh tumours are transplanted and propagated in immunodeficient mice, have received considerable interest and have been utilised for both basic and translational cancer research, biomarker discovery, personalised drug screening and understanding the mechanisms of drug resistance. 24,39,40 Unlike cell line or organoid xenografts, PDX models have been suggested to retain the architecture and morphology of the original transplanted tumours, 41 even after serial propagation, although there is some evidence that clonal selection occurs over time, 42 so that the heterogeneity of the tumours may be lost.…”

Section: In Vitro Modelsmentioning

confidence: 99%

Patient-derived explants (PDEs) as a powerful preclinical platform for anti-cancer drug and biomarker discovery

et al. 2020

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Preclinical models that can accurately predict outcomes in the clinic are much sought after in the field of cancer drug discovery and development. Existing models such as organoids and patient-derived xenografts have many advantages, but they suffer from the drawback of not contextually preserving human tumour architecture. This is a particular problem for the preclinical testing of immunotherapies, as these agents require an intact tumour human-specific microenvironment for them to be effective. In this review, we explore the potential of patient-derived explants (PDEs) for fulfilling this need. PDEs involve the ex vivo culture of fragments of freshly resected human tumours that retain the histological features of original tumours. PDE methodology for anti-cancer drug testing has been in existence for many years, but the platform has not been widely adopted in translational research facilities, despite strong evidence for its clinical predictivity. By modifying PDE endpoint analysis to include the spatial profiling of key biomarkers by using multispectral imaging, we argue that PDEs offer many advantages, including the ability to correlate drug responses with tumour pathology, tumour heterogeneity and changes in the tumour microenvironment. As such, PDEs are a powerful model of choice for cancer drug and biomarker discovery programmes.

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Section: In Vitro Modelsmentioning

confidence: 99%

Patient-derived explants (PDEs) as a powerful preclinical platform for anti-cancer drug and biomarker discovery

et al. 2020

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“…For decades, the most basic and frequently employed mouse models used to assess tumor growth and screen conventional chemotherapy or candidate drugs have been simple xenografted or syngeneic mice. Typically, these mouse models involve subcutaneous administration of human (xenograft) and mouse (syngeneic) tumor cells without regard to the organ of tumor origin (heterotopic) or via implantation of tumor tissue or cells into the tissue corresponding to the site of the tumors origin (orthotopic) [55]. Cell culture-derived xenograft mice and syngeneic mice require less technical skill and time to establish but they are less predictive of a patient's response to therapeutics compared with genetically engineered mouse models (GEMMs) or patient-derived xenograft (PDX) mice, which are discussed in subsequent sections [56].…”

Section: Xenograft and Syngeneic Mouse Modelsmentioning

confidence: 99%

Current methods in translational cancer research

Lee

Miljanic

Triplett

et al. 2020

Cancer Metastasis Rev

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Recent developments in pre-clinical screening tools, that more reliably predict the clinical effects and adverse events of candidate therapeutic agents, has ushered in a new era of drug development and screening. However, given the rapid pace with which these models have emerged, the individual merits of these translational research tools warrant careful evaluation in order to furnish clinical researchers with appropriate information to conduct pre-clinical screening in an accelerated and rational manner. This review assesses the predictive utility of both well-established and emerging pre-clinical methods in terms of their suitability as a screening platform for treatment response, ability to represent pharmacodynamic and pharmacokinetic drug properties, and lastly debates the translational limitations and benefits of these models. To this end, we will describe the current literature on cell culture, organoids, in vivo mouse models, and in silico computational approaches. Particular focus will be devoted to discussing gaps and unmet needs in the literature as well as current advancements and innovations achieved in the field, such as co-clinical trials and future avenues for refinement.

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“…Overall, the mouse has been highly instructive in determining genes involved and their mechanistic contribution to the origin and development of cancer [51]. However, the limitations of this model, in particular the differences in environment and microbiome, life span, tumor etiology and genetic status may be the reason why certain aspects are not reflected closely in this model, resulting in only 11% of oncology drugs that work in mice being approved for human use [52].…”

Section: Preclinical Modelsmentioning

confidence: 99%

Companion Animals as Models for Inhibition of STAT3 and STAT5

Kieslinger

Swoboda

Kramer

et al. 2019

Cancers

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The use of transgenic mouse models has revolutionized the study of many human diseases. However, murine models are limited in their representation of spontaneously arising tumors and often lack key clinical signs and pathological changes. Thus, a closer representation of complex human diseases is of high therapeutic relevance. Given the high failure rate of drugs at the clinical trial phase (i.e., around 90%), there is a critical need for additional clinically relevant animal models. Companion animals like cats and dogs display chronic inflammatory or neoplastic diseases that closely resemble the human counterpart. Cat and dog patients can also be treated with clinically approved inhibitors or, if ethics and drug safety studies allow, pilot studies can be conducted using, e.g., inhibitors of the evolutionary conserved JAK-STAT pathway. The incidence by which different types of cancers occur in companion animals as well as mechanisms of disease are unique between humans and companion animals, where one can learn from each other. Taking advantage of this situation, existing inhibitors of known oncogenic STAT3/5 or JAK kinase signaling pathways can be studied in the context of rare human diseases, benefitting both, the development of drugs for human use and their application in veterinary medicine.

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The role of mouse tumour models in the discovery and development of anticancer drugs

Cited by 135 publications

References 62 publications

Patient-derived explants (PDEs) as a powerful preclinical platform for anti-cancer drug and biomarker discovery

Patient-derived explants (PDEs) as a powerful preclinical platform for anti-cancer drug and biomarker discovery

Current methods in translational cancer research

Companion Animals as Models for Inhibition of STAT3 and STAT5

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