Anti-angiogenic drug scheduling optimisation with application to colorectal cancer

Sci Rep. 2018 Jul 25;8(1):11182. doi: 10.1038/s41598-018-29318-5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bevacizumab / therapeutic use
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / drug therapy*
  • Cytotoxins / therapeutic use
  • Drug Administration Schedule*
  • Fluorouracil / therapeutic use
  • Humans
  • Leucovorin / therapeutic use
  • Models, Theoretical
  • Neovascularization, Pathologic / drug therapy*
  • Organoplatinum Compounds / therapeutic use

Substances

  • Angiogenesis Inhibitors
  • Cytotoxins
  • Organoplatinum Compounds
  • Bevacizumab
  • Leucovorin
  • Fluorouracil

Supplementary concepts

  • Folfox protocol