Stromal modulation of response to Thymidylate synthase inhibitors

描述(申请人提供)：抗癌治疗通常针对的是肿瘤细胞。胸苷酸合成酶(TS)的抑制剂，特别是氟嘧啶类化合物，多年来一直用于各种癌症的临床治疗。尽管对控制肿瘤对TS抑制剂反应的遗传和分子因素进行了广泛的研究，但其临床疗效仍然有限。在这个项目中，我们提出了一种新的方法来提高肿瘤对这些药物的反应。肿瘤中有大量异质性的非肿瘤细胞。这些细胞包括宿主来源的细胞，如成纤维细胞、巨噬细胞、淋巴细胞、内皮细胞等。与细胞外基质一起，构成肿瘤间质或微环境。通过分泌一系列细胞因子、生长因子、激素等，它们在肿瘤的生长和发展以及对治疗药物的反应中发挥关键作用。在这个方案中，我们将检验肿瘤对TS抑制剂的反应是由浸润性基质细胞的化疗敏感性决定的假设。我们将利用易发生小肠和结肠腺瘤瘤的ApcMin/小鼠。通过骨髓移植，我们将产生嵌合小鼠，其中基质细胞的化疗敏感性与肿瘤的不同。我们预测，这些小鼠的肿瘤将表现出反映基质细胞化疗敏感性的药物反应。根据初步结果，AIM 1将确定TS抑制剂对间质间质细胞的影响，以确定对TS抑制剂反应的间质介质。目的2，研究TS在基质细胞中的下调对肿瘤对TS抑制剂反应的影响。在目标3中，我们将针对肿瘤相关的间质细胞定向增敏TS抑制剂。总而言之，该项目中正在测试的假设将为开发使用基质细胞的新治疗模式铺平道路，以改进针对肿瘤细胞的治疗，以确保药物诱导的癌细胞死亡。

DESCRIPTION (provided by applicant): Anti-cancer therapy has typically been targeted on neoplastic cells. Inhibitors of the enzyme thymidylate synthase (TS), particularly fluoropyrimidines, have been used for many years in the clinical management of a variety of cancers. In spite of the extensive research on the genetic and molecular factors governing tumor response to TS inhibitors, its clinical efficacy remains limited. In this project, we propose a novel approach to increase tumor response to these agents. Tumors are infiltrated with a heterogeneous population of non-neoplastic cells. These include host-derived cells such as fibroblasts, macrophages, lymphocytes, endothelial cells, etc. Together with extracellular matrix, make up the tumor stroma or microenvironment. By secreting an array of cytokines, growth factors, hormones, etc., they play a critical role in tumor growth and progression, as well as response to therapeutic agents. In this proposal, we will test the hypothesis that tumor response to TS inhibitors is governed by the chemosensitivity of infiltrating stromal cells. We will utilize the ApcMin/+ mouse which is predisposed to the development of adenomatous tumors of the small intestine and the colon. By bone marrow transplantation we will generate chimeric mice wherein the chemosensitivity of stromal cells is distinct from that of the tumor. We predict that tumors in these mice will show a drug response that reflects the chemosensitivity of stromal cells. Based on preliminary results, Aim 1 will determine the impact of TS inhibitors on cells in the stromal compartment to identify stromal mediators of response to TS inhibitors. Aim 2, will examine the effect of TS down regulation in stromal cells on tumor response to TS inhibitors. In Aim 3, we will direct sensitization to TS inhibitors specifically to tumor associated stromal cells. In all, the hypothesis being tested in this project will pave the way for development of new treatment modalities using stromal cells to improve therapies targeted at tumor cells to ensure drug induced cancer cell death.