Key Points
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Advanced fluorescence-based imaging, three-dimensional intermediate systems and intravital mouse models can be integrated into the standard drug project operating model (DPOM) to better inform the development and selection of new candidate drugs.
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Intermediate systems provide initial three-dimensional imaging early in the drug discovery process to support translational cancer research in more physiologically relevant in vitro settings and identify deficient or ineffective drug strategies earlier in the drug discovery pipeline.
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In vivo advanced imaging techniques can be used to assess more complex questions, such as transient protein–protein interactions or molecular, cell or tissue-specific dynamics in response to drug treatment in live tissue.
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Biosensors are now providing dynamic and reversible fluorescence-based readouts of drug targeting, allowing drug turnover, clearance and dissociation to be monitored in real-time.
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Stromal targeting of the tumour microenvironment is a vital aspect of cancer drug development, which can be quantified using advanced imaging techniques, such as second harmonic generation (SHG), third harmonic generation (THG) and fluorescence lifetime imaging microscopy (FLIM).
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Longitudinal imaging through intravital imaging windows can give quantitative functional information from repeated, non-invasive imaging and drug endpoint analysis in real-time.
Abstract
Integrating biological imaging into early stages of the drug discovery process can provide invaluable readouts of drug activity within complex disease settings, such as cancer. Iterating this approach from initial lead compound identification in vitro to proof-of-principle in vivo analysis represents a key challenge in the drug discovery field. By embracing more complex and informative models in drug discovery, imaging can improve the fidelity and statistical robustness of preclinical cancer studies. In this Review, we highlight how combining advanced imaging with three-dimensional systems and intravital mouse models can provide more informative and disease-relevant platforms for cancer drug discovery.
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Acknowledgements
The authors thank H. Bennett, D. Herrmann, A. Magenau, A. Burgess, M. Pajic, B. Browne and C. Vennin. This work was supported by the Australian Research Council (ARC), Cancer Institute New South Wales (CINSW) and National Health and Medical Research Council (NHMRC) funding. N.O.C. is supported by a Research Councils United Kingdom (RCUK) fellowship.
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Glossary
- Phenotypic screening
-
Assay systems that enable quantifiable measurements of cell phenotype or function that can be used to guide compound selection or iterative chemical design, often in the absence of any prior knowledge of an intended drug target.
- First-in-class small molecule medicines
-
Newly approved medicines that have novel mechanisms of action, distinct from anything else on the market.
- Target-directed drug discovery
-
A contemporary strategy for the identification and optimization of lead molecules and candidate drugs based on achieving high levels of potency and specificity against a nominated target that is implicated in disease progression.
- Anisotropy
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The anisotropy of a molecule is assessed through the simultaneous measurement of orthogonally polarized fluorescence relative to the polarization of the excitation light. Factors that determine the degree of anisotropy are protein mobility and molecular orientation. As a consequence, anisotropy can be used as a powerful and sensitive readout for binding and screening assays of protein behaviour and interactions.
- Extracellular matrix
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(ECM). A reinforced composite of structural proteins that is primarily composed of collagen and tissue-specific inclusions (for example, fibronectin and laminin), as well as other metabolites secreted by cells. The ECM provides structural support and biochemical signals for multicellular tissue and organ systems.
- Intravital imaging windows
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Windows that are surgically implanted in a mouse to allow repeated, non-invasive imaging over a long time course.
- Organotypic 3D collagen I matrix
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Fibroblast-driven contraction of acid-extracted collagen I is used to produce matrices with high in vivo fidelity for analysis of cell behaviour in a live in vitro setting.
- Multiphoton intravital microscopy
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This method reduces interference from the background by using more than one photon as a multiple of the excitation wavelength of the sample, effectively restricting interactions to the focal plane and allowing deep imaging within live tissue.
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Conway, J., Carragher, N. & Timpson, P. Developments in preclinical cancer imaging: innovating the discovery of therapeutics. Nat Rev Cancer 14, 314–328 (2014). https://doi.org/10.1038/nrc3724
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DOI: https://doi.org/10.1038/nrc3724
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