IntroductionIn oncological drug development, animal studies continue to play a central role in which the volume of subcutaneous tumours is monitored to assess the efficacy of new drugs. The tumour volume is estimated by taking the volume to be that of a regular spheroid with the same dimensions. However, this method is subjective, insufficiently traceable, and is subject to error in the accuracy of volume estimates as tumours are frequently irregular.Methods & resultsThis paper reviews the standard technique for tumour volume assessment, calliper measurements, by conducting a statistical review of a large dataset consisting of 2,500 tumour volume measurements from 1,600 mice by multiple operators across 6 mouse strains and 20 tumour models. Additionally, we explore the impact of six different tumour morphologies on volume estimation and the detection of treatment effects using a computational tumour growth model. Finally, we propose an alternative method to callipers for estimating volume–BioVolumeTM, a 3D scanning technique. BioVolume simultaneously captures both stereo RGB (Red, Green and Blue) images from different light sources and infrared thermal images of the tumour in under a second. It then detects the tumour region automatically and estimates the tumour volume in under a minute. Furthermore, images can be processed in parallel within the cloud and so the time required to process multiple images is similar to that required for a single image. We present data of a pre-production unit test consisting of 297 scans from over 120 mice collected by four different operators.ConclusionThis work demonstrates that it is possible to record tumour measurements in a rapid minimally invasive, morphology-independent way, and with less human-bias compared to callipers, whilst also improving data traceability. Furthermore, the images collected by BioVolume may be useful, for example, as a source of biomarkers for animal welfare and secondary drug toxicity / efficacy.

Xenografts -as simplified animal models of cancer- differ substantially in vasculature and stromal architecture when compared to clinical tumours. This makes mathematical model-based predictions of clinical outcome challenging. Our objective is to further understand differences in tumour progression and physiology between animal models and the clinic.To achieve that, we propose a mathematical model based upon tumour pathophysiology, where oxygen -as a surrogate for endocrine delivery- is our main focus. The Oxygen-Driven Model (ODM), using oxygen diffusion equations, describes tumour growth, hypoxia and necrosis. The ODM describes two key physiological parameters. Apparent oxygen uptake rate () represents the amount of oxygen cells seem to need to proliferate. The more oxygen they appear to need, the more the oxygen transport. gathers variability from the vasculature, stroma and tumour morphology. Proliferating rate (k p) deals with cell line specific factors to promote growth. The K H,K N describe the switch of hypoxia and necrosis. Retrospectively, using archived data, we looked at longitudinal tumour volume datasets for 38 xenografted cell lines and 5 patient-derived xenograft-like models.Exploration of the parameter space allows us to distinguish 2 groups of parameters. Group 1 of cell lines shows a spread in values of and lower k p, indicating that tumours are poorly perfused and slow growing. Group 2 share the value of the oxygen uptake rate () and vary greatly in k p, which we interpret as having similar oxygen transport, but more tumour intrinsic variability in growth.However, the ODM has some limitations when tested in explant-like animal models, whose complex tumour-stromal morphology may not be captured in the current version of the model. Incorporation of stroma in the ODM will help explain these discrepancies. We have provided an example. The ODM is a very simple -and versatile- model suitable for the design of preclinical experiments, which can be modified and enhanced whilst maintaining confidence in its predictions.

A 2‐day meeting was held by members of the UK Quantitative Systems Pharmacology Network () in November 2018 on the topic of Translational Challenges in Oncology. Participants from a wide range of backgrounds were invited to discuss current and emerging modeling applications in nonclinical and clinical drug development, and to identify areas for improvement. This resulting perspective explores opportunities for impactful quantitative pharmacology approaches. Four key themes arose from the presentations and discussions that were held, leading to the following recommendations: Evaluate the predictivity and reproducibility of animal cancer models through precompetitive collaboration. Apply mechanism of action (MoA) based mechanistic models derived from nonclinical data to clinical trial data. Apply MoA reflective models across trial data sets to more robustly quantify the natural history of disease and response to differing interventions. Quantify more robustly the dose and concentration dependence of adverse events through mathematical modelling techniques and modified trial design.

BackgroundThe tumour stroma -or tumour microenvironment- is an important constituent of solid cancers and it is thought to be one of the main obstacles to quantitative translation of drug activity between the preclinical and clinical phases of drug development. The tumour-stroma relationship has been described as being both pro- and antitumour in multiple studies. However, the causality of this complex biological relationship between the tumour and stroma has not yet been explored in a quantitative manner in complex tumour morphologies.MethodsTo understand how these stromal and microenvironmental factors contribute to tumour physiology and how oxygen distributes within them, we have developed a lattice-based multiscalar cellular automaton model. This model uses principles of cytokine and oxygen diffusion as well as cell motility and plasticity to describe tumour-stroma landscapes. Furthermore, to calibrate the model, we propose an innovative modelling platform to extract model parameters from multiple in-vitro assays. This platform provides a novel way to extract meta-data that can be used to complement in-vivo studies and can be further applied in other contexts.ResultsHere we show the necessity of the tumour-stroma opposing relationship for the model simulations to successfully describe the in-vivo stromal patterns of the human lung cancer cell lines Calu3 and Calu6, as models of clinical and preclinical tumour-stromal topologies. This is especially relevant to drugs that target the tumour microenvironment, such as antiangiogenics, compounds targeting the hedgehog pathway or immune checkpoint inhibitors, and is potentially a key platform to understand the mechanistic drivers for these drugs.ConclusionThe tumour-stroma automaton model presented here enables the interpretation of complex in-vitro data and uses it to parametrise a model for in-vivo tumour-stromal relationships.Electronic supplementary materialThe online version of this article (doi:10.1186/s12911-017-0461-1) contains supplementary material, which is available to authorized users.

No abstract

15In oncological drug development, animal studies continue to play a central role in which the 16 volume of subcutaneous tumours is monitored to assess the efficacy of new drugs. Tumour 17 volume is currently estimated by measuring length and width with callipers and then 18 estimating the volume of the tumour as if it were a regular spheroid. However, this method is 19 subjective, insufficiently traceable, and is subject to error in the accuracy of volume 20 estimates as tumours frequently are irregular. 21This paper explores the extent of inconsistencies in calliper measurements by conducting a 22 statistical review of a large dataset consisting of 2,500 tumour volume measurements from 23 1,600 mice by multiple operators across 6 mouse strains and 20 tumour models. We also 24 explore the impact of six different tumour morphologies on volume estimation and the 25 detection of treatment effects using a computational tumour growth model. Finally, we 26 propose an alternative method to callipers for estimating volume -BioVolume TM , a 3D 27 scanning technique. BioVolume simultaneously captures both stereo RGB (Red, Green and 28 Blue) images from different light sources and infrared thermal images of the tumour. It 29 detects the tumour region automatically and estimates the tumour volume in under a second. 30 BioVolume has been tested on a dataset of 297 scans from over 120 mice collected by four 31 different operators. 32 This work demonstrates that it is possible to record tumour measurements in a rapid, 33 minimally invasive, morphology-independent way, and with less human-bias compared to 34 callipers, whilst also improving data traceability. Furthermore, the images collected by 35 BioVolume may be useful, for example, as a source of biomarkers for animal welfare and 36 secondary drug toxicity / efficacy. 3 37