Data-driven QSP software for personalized colon cancer treatment

用于个性化结肠癌治疗的数据驱动 QSP 软件

基本信息

批准号：
10227447
负责人：
SUVRA PAL
金额：
$ 15.99万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227447
关键词：
Adopted Affect Algorithms Alternative Therapies Animals Biological CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cancer Etiology Cell Density Cells Cessation of life Characteristics Chemicals Clinical Clinical Research Colon Carcinoma Colonic Neoplasms Combined Modality Therapy Complex Computer software Data Data Science Data Set Dendritic Cells Differential Equation Epithelial Cells Equation Expression Profiling Fluorouracil Gender Gene Expression Genetic Goals Immune Immune response In Vitro Individual Inflammatory Interferons Interleukin-2 Interleukin-4 Interleukin-6 Killer Cells Laws Least-Squares Analysis Leucovorin Mathematics Measures Methods Modeling Molecular Necrosis Patients Pattern Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pilot Projects Primary Neoplasm Process Proteins Race Radial Running STAT4 gene STAT6 gene Sampling Signal Transduction Source Statistical Methods System T-Cell Activation T-Lymphocyte Techniques Time Treatment outcome Uncertainty United States Variant Woman base biological systems cancer therapy cancer type cell type colon cancer patients colon cancer treatment cytokine density drug action drug testing effective therapy effector T cell efficacy study experimental study in vivo individual patient individualized medicine innovation interest irinotecan macrophage mathematical methods mathematical model men model building mutant novel optimal treatments patient subsets personalized cancer therapy personalized medicine research and development response systems of equations targeted treatment tool treatment strategy tumor tumor growth

项目摘要

Abstract Colon cancer is the third leading cause of cancer-related deaths in the United States in both men and women. A major clinical challenge is to obtain an effective treatment strategy for each patient or at least identify a subset of patients who could beneﬁt from a particular treatment. Since each colon cancer has its own unique features, it is very important to obtain personalized cancer treatments and ﬁnd a way to tailor treatment strategies for each patient based on each individual's characteristics, including race, gender, genetic factors, immune response variations. Recently, Quantitative and Systems Pharmacology (QSP) has been commonly used to discover, validate, and test drugs. QSP models are a system of differential equations that model the dynamic interactions between drug(s) and a biological system. These mathematical models provide an integrated “systems level” approach to determining mechanisms of action of drugs and ﬁnding new ways to alter complex cellular networks with mono or combination therapy to obtain effective treatments. Since QSP models are a complex system of nonlinear equations with many unknown parameters, estimating the values of the model's parameters is extremely difﬁcult. Existing parameter estimation methods for QSP models often use assembled data from various sources rather than a single curated dataset. These datasets are usually obtained through various biological experiments, in vitro and in vivo animal studies, thus rendering QSP models hard to be practicable for personalized treatments. To the best of our knowledge, no QSP model has been developed for personalized colon cancer treatments. In this project, we propose a unique approach to develop a data-driven QSP software to suggest effective treatment for each patient based on gene expression data from the primary tumor samples. Since signatures of main characteristics of tumors, such as immune response variations, can be found in gene expression proﬁling of primary tumors, we use gene expression data as input. We develop an innovative framework to systematically employ a combination of data science, mathematical, and statistical methods to obtain personalized colon cancer treatment. We employ novel inverse problem techniques to estimate the values of parameters of the model and statistical methods to perform sensitivity analysis. We will use these techniques to propose an optimal treatment strategy for each patient and predict the efﬁcacy of the proposed treatment. The model might also suggest alternative therapies in case of low efﬁcacy for some patients.

抽象的结肠癌是美国男性和女性癌症相关死亡的第三大原因。一个主要的临床挑战是为每个患者获得有效的治疗策略或至少确定一个子集可以从特定治疗中受益的患者由于每种结肠癌都有其独特的特征，获得个性化的癌症治疗并找到量身定制治疗策略的方法非常重要根据每个患者的个人特征，包括种族、性别、遗传因素、免疫反应变化。最近，定量和系统药理学 (QSP) 已普遍用于发现、验证、 QSP 模型是一个微分方程组，用于模拟药物之间的动态相互作用。这些数学模型提供了一种集成的“系统级”方法。确定药物的作用机制并寻找改变复杂细胞网络的新方法或联合治疗以获得有效的治疗，因为 QSP 模型是一个复杂的非线性系统。由于方程具有许多未知参数，估计模型参数的值极其困难。现有的 QSP 模型参数估计方法通常使用来自各种来源的组装数据，而不是这些数据集通常是通过各种生物实验获得的。体外和体内动物研究，因此使得 QSP 模型难以用于个性化治疗。据我们所知，尚未开发出用于个性化结肠癌治疗的 QSP 模型。在这个项目中，我们提出了一种独特的方法来开发数据驱动的 QSP 软件，以提出有效的建议根据原发肿瘤样本的基因表达数据对每位患者进行治疗。肿瘤的主要特征，例如免疫反应变化，可以在基因表达谱中找到对于原发性肿瘤，我们使用基因表达数据作为输入，我们开发了一个创新框架来系统地进行研究。结合数据科学、数学和统计方法来获得个性化的结肠癌我们采用新颖的逆问题技术来估计模型的参数值和我们将使用这些技术来进行敏感性分析的统计方法提出最佳治疗方案。该模型还可以建议每个患者的策略并预测所提议的治疗的效果。替代疗法，以防某些患者效率低下。