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Table 1: The five determinants of success that form the 5R framework RIGHT TARGET


Uncover, select and validate new targets with a strong link to the disease


Ensure new drug candidates have good bioavailability and display the right effect in the intended tissue


RIGHT TISSUE RIGHT SAFETY


Establish safety as far as possible in humanised systems before initiating clinical trials


RIGHT PATIENT


Recognise patients have unique genetic, molecular and functional disease profiles and target medicines to populations who will derive the greatest benefit


RIGHT COMMERCIAL


Develop a unique value proposition for new medicines based on the size and unmet needs of the target patient population


(MSI) to gather vast datasets on multiple predictive criteria; and humanised models that realistically simulate the tissue environment in vitro.


Humanised models While in vivo animal systems provide a lifelike sys- tem in terms of architecture and complex physio- logical interactions, in many cases the effects of drugs on animal tissue are not translatable to humans. This lack of translatability is one reason for drug trial failures. Humanised models bridge this gap, providing an environment in which human cells behave more closely to how they would in the body. These technologies have the added advantage over 2D and 3D cell culture in that they mimic aspects of the tissue environment to provide human-relevant data on multiple parameters including toxicity, efficacy and PK/PD determination prior to compounds ever being test- ed in patients.


Patient-derived xenograft (PDX) models Clinical cancers often have complex, hard-to-pre- dict phenotypes that are not adequately reflected in available cell lines. Tumour complexity and hetero- geneity can, however, be recreated using PDX models – in vivo disease models made by grafting tumour tissue directly into immunodeficient mice. This provides a translatable system for testing drugs in the ‘right tissue’, giving a stronger predic- tion of how drugs might behave in a real human tumour than classical human in vitro or animal in vivo models. PDX models are of particular value in studying


late-stage cancers and modelling resistance mecha- nisms. Samples taken from late-stage tumours and patients relapsing on available therapies provide new models to explore next-generation approaches that could treat or even prevent resistance emer-


Drug Discovery World Summer 2018


gence. As part of an academic collaboration, we recently published a study using a series of PDX models of colorectal cancer. We showed that a novel inhibitor of DNA damage repair protein, ATM, could resensitise chemotherapy-resistant tumours to respond to therapy in preclinical models4. This is an encouraging lead, and supports further research into the inhibitor as part of a combination therapy. As part of a wider collaboration with several


partners, we are testing drugs in a biobank of breast cancer PDX models5. These heterogeneous models can also be used to generate short-term organ cultures to test drug response at higher throughput. These systems enable us to measure drug effects across a diverse cancer model popula- tion, simulating a clinical trial population. To further these innovative approaches to candi-


date screening, we are currently researching ways to incorporate a human immune system into mouse models. Immune interactions are funda- mental in shaping cancer progression and response to therapy, so this would provide a translatable preclinical model that will support the develop- ment of next-generation immuno-oncology drugs. PDX models provide a unique means of simulat-


ing multiple aspects of real-world heterogeneity and tumour behaviour outside of the patient. The predictability of these models when considering the behaviour of therapeutic candidates is already proving to be superior when compared to homoge- nous cell lines, or cell line-derived xenografts. As improvements are made to model the tumour envi- ronment they will provide even stronger validation packages for innovative treatments and combina- tions, especially in the arena of drug resistance.


Organs-on-Chips technology Organs-on-Chips, also known as microphysiologi- cal systems, are in vitro systems that recreate the in


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