Hutchinson L G, Mueller H-J, Gaffney E A, Maini P K, Wagg J, Phipps A, Boetsch C, Byrne H M, Ribba B
Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, UK.
Pharma Research and Early Development, Roche Innovation Centre Munich, Munich, Germany.
CPT Pharmacometrics Syst Pharmacol. 2016 Nov;5(11):636-645. doi: 10.1002/psp4.12142. Epub 2016 Nov 14.
Experimental evidence suggests that antiangiogenic therapy gives rise to a transient window of vessel normalization, within which the efficacy of radiotherapy and chemotherapy may be enhanced. Preclinical experiments that measure components of vessel normalization are invasive and expensive. We have developed a mathematical model of vascular tumor growth from preclinical time-course data in a breast cancer xenograft model. We used a mixed-effects approach for model parameterization, leveraging tumor size data to identify a period of enhanced tumor growth that could potentially correspond to the transient window of vessel normalization. We estimated the characteristics of the window for mice treated with an anti-VEGF antibody (bevacizumab) or with a bispecific anti-VEGF/anti-angiopoietin-2 antibody (vanucizumab). We show how the mathematical model could theoretically be used to predict how to coordinate antiangiogenic therapy with radiotherapy or chemotherapy to maximize therapeutic effect, reducing the need for preclinical experiments that directly measure vessel normalization parameters.
实验证据表明，抗血管生成疗法会产生一个短暂的血管正常化窗口，在此窗口内，放疗和化疗的疗效可能会增强。测量血管正常化成分的临床前实验具有侵入性且成本高昂。我们根据乳腺癌异种移植模型中的临床前时间进程数据，开发了一个血管肿瘤生长的数学模型。我们使用混合效应方法进行模型参数化，利用肿瘤大小数据来确定肿瘤生长增强的时期，这可能与血管正常化的短暂窗口相对应。我们估计了用抗VEGF抗体（贝伐单抗）或双特异性抗VEGF/抗血管生成素-2抗体（凡西珠单抗）治疗的小鼠的窗口特征。我们展示了该数学模型理论上如何用于预测如何将抗血管生成疗法与放疗或化疗进行协调，以最大化治疗效果，从而减少直接测量血管正常化参数的临床前实验的需求。
