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

描述(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。这一概念最早是在人类髓系白血病中描述的，后来扩展到实体肿瘤，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发生和发展的动力学、对治疗的反应以及耐药性的演变。在这项建议中，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。我们将建立数学模型来研究人类癌症的起源细胞，癌症干细胞在治疗过程中的行为，以及抗癌药物耐药性的演变。我们将使用ABL酪氨酸激酶抑制剂治疗慢性粒细胞白血病(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量化理解，并允许我们将癌症干细胞的数学模型应用于生物学和临床上的重要问题，包括对靶向治疗的反应和耐药性的演变。 具体目标是 1.设计慢性粒细胞白血病干细胞的数学框架。 2.在慢性粒细胞白血病小鼠模型中验证目标1中的预测。 3.研究抗癌药物耐药的动态变化。 4.探讨慢性粒细胞白血病的细胞来源。 这项建议中概述的研究计划将建立对肿瘤干细胞在癌症发生、发展、治疗和耐药中的定量理解，并将为理解癌症干细胞生物学和最佳治疗方法提供不可或缺的理论框架。我们还将在活体系统中测试我们的数学模型，以演示我们的数学模型与实验模型的相关性。虽然超出了这项建议的范围，但这项研究计划的最终目标是使用数学模型来开发一个评估癌症干细胞在肿瘤发生中的作用的一般框架，并开发针对人类恶性肿瘤的癌症干细胞的特定疗法。

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.