Vishwanath Krithik, Choi Hoon, Gupta Mamta, Zhou Rong, Sorace Anna G, Yankeelov Thomas E, Lima Ernesto A B F
Department of Aerospace Engineering and Engineering Mechanics, The University of Texas at Austin, Austin, Texas, 78712.
Department of Mathematics, The University of Texas at Austin, Austin, Texas, 78712.
bioRxiv. 2025 Jan 3:2025.01.03.631015. doi: 10.1101/2025.01.03.631015.
We seek to establish a parsimonious mathematical framework for understanding the interaction and dynamics of the response of pancreatic cancer to the NGC triple chemotherapy regimen (mNab-paclitaxel, gemcitabine, and cisplatin), stromal-targeting drugs (calcipotriol and losartan), and an immune checkpoint inhibitor (anti-PD-L1). We developed a set of ordinary differential equations describing changes in tumor size (growth and regression) under the influence of five cocktails of treatments. Model calibration relies on three tumor volume measurements obtained over a 14-day period in a genetically engineered pancreatic cancer model (KrasLSLG12D-Trp53LSLR172H-Pdx1-Cre). Our model reproduces tumor growth in the control and treatment scenarios with an average concordance correlation coefficient (CCC) of 0.99±0.01. We conduct leave-one-out predictions (average CCC=0.74±0.06), mouse-specific predictions (average CCC=0.75±0.02), and hybrid, group-informed, mouse-specific predictions (average CCC=0.85±0.04). The developed mathematical model demonstrates high accuracy in fitting the experimental tumor data and a robust ability to predict tumor response to treatment. This approach has important implications for optimizing combination NGC treatment strategies.
我们试图建立一个简约的数学框架，以理解胰腺癌对NGC三联化疗方案（mNab-紫杉醇、吉西他滨和顺铂）、基质靶向药物（骨化三醇和氯沙坦）以及免疫检查点抑制剂（抗PD-L1）的反应的相互作用和动态变化。我们开发了一组常微分方程，描述在五种治疗组合影响下肿瘤大小的变化（生长和消退）。模型校准依赖于在一个基因工程胰腺癌模型（KrasLSLG12D-Trp53LSLR172H-Pdx1-Cre）中14天内获得的三次肿瘤体积测量值。我们的模型在对照和治疗场景中重现肿瘤生长，平均一致性相关系数（CCC）为0.99±0.01。我们进行留一法预测（平均CCC = 0.74±0.06）、小鼠特异性预测（平均CCC = 0.75±0.02）以及混合的、群体信息的、小鼠特异性预测（平均CCC = 0.85±0.04）。所开发的数学模型在拟合实验肿瘤数据方面显示出高精度，并且具有预测肿瘤对治疗反应的强大能力。这种方法对优化NGC联合治疗策略具有重要意义。
