Dynamics of Tumor Stem Cells in Cancer Initiation, Therapy, and Resistance

描述（由申请人提供）：人类癌症的生长是由正常成人干细胞的病理对应物，癌症干细胞维持的。这个概念最初是在人类髓性白血病中被描述的，后来被扩展到实体肿瘤，如乳腺癌和脑癌。对癌症干细胞的定量理解需要一个数学框架来描述癌症的发生和进展、对治疗的反应和耐药性的演变。在这个建议中，我们建议使用数学和实验技术来研究癌症干细胞的生物学。我们将推导数学模型来研究人类癌症的细胞起源，癌症干细胞在治疗过程中的行为，以及对抗癌药物的耐药性演变。我们将使用ABL酪氨酸激酶抑制剂治疗慢性髓性白血病（CML）作为一个特殊的例子，并将在CML的小鼠模型中验证数学模型的预测。我们的方法将提供对癌症干细胞的有效定量理解，并允许我们将癌症干细胞的数学建模应用于生物学和临床重要问题，包括对靶向治疗的反应和耐药性的演变。

DESCRIPTION (provided by applicant): Human cancers are sustained in their growth by a pathological counterpart of normal adult stem cells, cancer stem cells. This concept was first described in human myeloid leukemias and has later been extended to solid tumors such as breast and brain cancer. A quantitative understanding of cancer stem cells requires a mathematical framework to describe the dynamics of cancer initiation and progression, the response to treatment, and the evolution of resistance. In this proposal, we suggest to use mathematical and experimental techniques to investigate the biology of cancer stem cells. We will derive mathematical models to investigate the cell of origin of human cancers, the behavior of cancer stem cells during therapy, and the evolution of resistance to anti-cancer drugs. We will use chronic myeloid leukemia (CML) treated with ABL tyrosine kinase inhibitors as a particular example and will validate the predictions of the mathematical models in a murine model of CML. Our approach will provide a validated quantitative understanding of cancer stem cells, and allow us to apply mathematical modeling of cancer stem cells to biologically and clinically important issues including response to targeted therapies and evolution of drug resistance. The Specific Aims are 1. To design a mathematical framework of CML stem cells. 2. To validate the predictions derived in Aim 1 in a murine model of CML. 3. To study the dynamics of resistance to anti-cancer therapy. 4. To investigate the cell of origin of CML. The research program outlined in this proposal will establish a quantitative understanding of tumor stem cells in cancer initiation, progression, treatment, and resistance and will provide theoretical frameworks indispensable for the understanding of cancer stem cell biology and the optimum administration of therapies. We will also test our mathematical models in an in vivo system, in order to demonstrate the relevance of our mathematical models to an experimental model. Although outside the scope of this proposal, the ultimate goal of this research program is to use mathematical models to develop a general framework for evaluating the role of cancer stem cells in oncogenesis, and to develop specific therapies which target cancer stem cells for human malignancies.