Sorbonne Université, CNRS, Université de Paris, Laboratoire Jacques-Louis Lions UMR 7598, 4 place Jussieu, 75005 Paris, France.
Sorbonne Université, CNRS, Université de Paris, Inria, Laboratoire Jacques-Louis Lions UMR 7598, 4 place Jussieu, 75005 Paris, France.
J Theor Biol. 2024 Dec 7;595:111957. doi: 10.1016/j.jtbi.2024.111957. Epub 2024 Oct 5.
We present a mathematical model of the evolutionary dynamics of a metastatic tumour under chemotherapy, comprising non-local partial differential equations for the phenotype-structured cell populations in the primary tumour and its metastasis. These equations are coupled with a physiologically-based pharmacokinetic model of drug administration and distribution, implementing a realistic delivery schedule. The model is carefully calibrated from the literature, focusing on BRAF-mutated melanoma treated with Dabrafenib as a case study. By means of long-time asymptotic and global sensitivity analyses, as well as numerical simulations, we explore the impact of cell migration from the primary to the metastatic site, physiological aspects of the tumour tissues and drug dose on the development of chemoresistance and treatment efficacy. Our findings provide a possible explanation for empirical evidence indicating that chemotherapy may foster metastatic spread and that metastases may be less impacted by the chemotherapeutic agent.
我们提出了一个转移性肿瘤在化疗下的进化动力学的数学模型，该模型由原发性肿瘤及其转移灶中表型结构细胞群体的非局部偏微分方程组成。这些方程与药物给予和分布的基于生理的药代动力学模型耦合，实施了现实的给药方案。该模型是根据文献仔细校准的，以 BRAF 突变黑色素瘤用 Dabrafenib 治疗作为案例研究。通过长时间渐近和全局敏感性分析以及数值模拟，我们探讨了细胞从原发性肿瘤向转移性肿瘤部位迁移、肿瘤组织的生理方面以及药物剂量对化疗耐药性和治疗效果发展的影响。我们的研究结果为一些经验证据提供了一种可能的解释，这些证据表明化疗可能促进转移扩散，并且转移灶可能受化疗药物的影响较小。
