Anti-angiogenic drug scheduling optimisation with application to colorectal cancer

M Sturrock,A Barat,A T Byrne,A C O’Farrell,N Hannis Arba’Ie,J H Prehn,G Kang,G Marston,P L Coletta,I S Miller

doi:10.1038/s41598-018-29318-5

M Sturrock, A Barat + Show 8 more

Open Access

https://doi.org/10.1038/s41598-018-29318-5

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Abstract

Bevacizumab (bvz) is a first choice anti-angiogenic drug in oncology and is primarily administered in combination with chemotherapy. It has been hypothesized that anti-angiogenic drugs enhance efficacy of cytotoxic drugs by “normalizing” abnormal tumor vessels and improving drug penetration. Nevertheless, the clinical relevance of this phenomenon is still unclear with several studies over recent years suggesting an opposing relationship. Herein, we sought to develop a new computational tool to interrogate anti-angiogenic drug scheduling with particular application in the setting of colorectal cancer (CRC). Specifically, we have employed a mathematical model of vascular tumour growth which interrogates the impact of anti-angiogenic treatment and chemotherapeutic treatment on tumour volume. Model predictions were validated using CRC xenografts which underwent treatment with a clinically relevant combinatorial anti-angiogenic regimen. Bayesian model selection revealed the most appropriate term for capturing the effect of treatments on the tumour size, and provided insights into a switch-like dependence of FOLFOX delivery on the tumour vasculature. Our experimental data and mathematical model suggest that delivering chemotherapy prior to bvz may be optimal in the colorectal cancer setting.

Highlights

Bevacizumab is a first choice anti-angiogenic drug in oncology and is primarily administered in combination with chemotherapy
We sought to further explore anti-angiogenic drug scheduling within the setting of CRC. To address this question experimentally, we employed the gold-standard HCT116 CRC xenograft model which underwent treatment with a paradigmatic folinic acid, fluorouracil and oxaliplatin (FOLFOX) chemotherapy + anti-vascular endothelial growth factor (VEGF) regimen commonly employed in the clinical management of metastatic colorectal cancer
It is not clear which functional form the degradation of tumour volume via FOLFOX should take, we investigated two different physiologically feasible chemotherapy function forms

Summary

Introduction

Bevacizumab (bvz) is a first choice anti-angiogenic drug in oncology and is primarily administered in combination with chemotherapy. The tumour mass may reach a critical point of transition from the avascular to vascular phase and develop an intrinsic blood supply network (angiogenesis) which supports further growth and metastases During this process, tumour cells secrete angiogenic factors such as vascular endothelial growth factor (VEGF) in response to diminished oxygen levels and the ‘angiogenic switch’ occurs. We sought to further explore anti-angiogenic drug scheduling within the setting of CRC To address this question experimentally, we employed the gold-standard HCT116 CRC xenograft model which underwent treatment with a paradigmatic folinic acid, fluorouracil and oxaliplatin (FOLFOX) chemotherapy + anti-VEGF (bvz) regimen commonly employed in the clinical management of metastatic colorectal cancer (mCRC). Our joint experimental-computational approach as illustrated in Fig. 1, suggests that delivery of antiangiogenic therapy after chemotherapy may deliver optimal treatment results in the setting of colorectal cancer

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