Opportunities for Quantitative Translational Modeling in Oncology.

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.

An innovative non-invasive technique for subcutaneous tumour measurements.

INTRODUCTION: In 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 & RESULTS: This 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. CONCLUSION: This 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.

Oxygen-Driven Tumour Growth Model: A Pathology-Relevant Mathematical Approach.

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 (k'R) represents the amount of oxygen cells seem to need to proliferate. The more oxygen they appear to need, the more the oxygen transport. k'R gathers variability from the vasculature, stroma and tumour morphology. Proliferating rate (kp) deals with cell line specific factors to promote growth. The KH,KN 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 k'R and lower kp, indicating that tumours are poorly perfused and slow growing. Group 2 share the value of the oxygen uptake rate (k'R) and vary greatly in kp, 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.