Kraut Anna K, Garvey Colleen M, Strelez Carly, Mumenthaler Shannon M, Foo Jasmine
School of Mathematics, University of Minnesota-Twin Cities, Minneapolis, MN, USA.
Department of Mathematics, Statistics, and Computer Science, St. Olaf College, Northfield, MN, USA.
NPJ Syst Biol Appl. 2025 Feb 6;11(1):16. doi: 10.1038/s41540-025-00495-0.
Complex interactions between stromal cells, tumor cells and therapies can influence environmental factors that in turn impact anticancer treatment efficacy. Disentangling these phenomena is critical for understanding treatment response and designing effective dosing strategies. We propose a mathematical model for a common tumor-stromal interaction motif where stromal cells secrete factors that promote drug resistance. We demonstrate that the presence of this interaction modulates the therapeutic dose window of efficacy and can lead to nonmonotonic treatment response. We consider combination strategies that target stromal cells and their secretome, and identify strategies that constrain drug concentrations within the efficacious window for long-term response. We explore an experimental dataset from colorectal cancer cells treated with anti-EGFR targeting therapy, cetuximab, where cancer-associated fibroblasts increase epidermal growth factor secretion under treatment. We apply our general approach to identify a critical drug concentration threshold and study effective dosing regimens for single-drug and combination therapies.
基质细胞、肿瘤细胞和治疗方法之间的复杂相互作用会影响环境因素，而这些环境因素反过来又会影响抗癌治疗的疗效。理清这些现象对于理解治疗反应和设计有效的给药策略至关重要。我们提出了一个针对常见肿瘤-基质相互作用基序的数学模型，其中基质细胞分泌促进耐药性的因子。我们证明这种相互作用的存在会调节疗效的治疗剂量窗口，并可能导致非单调的治疗反应。我们考虑针对基质细胞及其分泌组的联合策略，并确定将药物浓度限制在有效窗口内以实现长期反应的策略。我们研究了一个来自用抗表皮生长因子受体（EGFR）靶向治疗药物西妥昔单抗治疗的结肠癌细胞的实验数据集，其中癌症相关成纤维细胞在治疗下会增加表皮生长因子的分泌。我们应用我们的通用方法来确定临界药物浓度阈值，并研究单药和联合治疗的有效给药方案。
