Stromal modulation of response to Thymidylate synthase inhibitors

描述（由申请人提供）：抗癌治疗通常针对肿瘤细胞。胸苷酸合成酶（TS）的抑制剂，特别是氟嘧啶，已在各种癌症的临床治疗中使用多年。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增加肿瘤对这些药物的反应。肿瘤被异质的非肿瘤细胞浸润。这些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。它们通过分泌一系列细胞因子、生长因子、激素等，在肿瘤的生长和进展以及对治疗药物的反应中起着关键作用。在这个提议中，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学敏感性控制的假设。我们将利用易患小肠和结肠腺瘤性肿瘤的ApcMin/+小鼠。通过骨髓移植，我们将产生嵌合小鼠，其中基质细胞的化学敏感性与肿瘤的化学敏感性不同。我们预测这些小鼠的肿瘤将显示出反映基质细胞化学敏感性的药物反应。基于初步结果，Aim 1将确定TS抑制剂对间质室细胞的影响，以确定对TS抑制剂有反应的基质介质。目的2，将研究基质细胞中TS下调对肿瘤对TS抑制剂反应的影响。在Aim 3中，我们将直接对TS抑制剂进行致敏，特别是对肿瘤相关的基质细胞。总之，在这个项目中测试的假设将为开发新的治疗方式铺平道路，使用基质细胞来改善针对肿瘤细胞的治疗方法，以确保药物诱导癌细胞死亡。

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.