Stromal modulation of response to Thymidylate synthase inhibitors

对胸苷酸合酶抑制剂反应的基质调节

• 批准号: 8902022
• 负责人: MARIA Marjorette PENA
• 金额: $ 29.06万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-25 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8902022
• 关键词: Adverse effects; Affect; Animal Model; Antimetabolites; Antineoplastic Agents; ApcMin/+ mice; Attenuated; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Death; Cell Therapy; Cells; Chimera organism; Clinical; Clinical Management; Colon; Colonic Neoplasms; Combined Modality Therapy; Data; Development; Down-Regulation; Drug Sensitization; Drug resistance; Endothelial Cells; Ensure; Environment; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Extracellular Matrix; Fibroblasts; Genetic; Goals; Growth Factor; Hematopoietic; Hormones; Intestinal Neoplasms; Lead; Lymphocyte; Malignant Neoplasms; Marrow; Mediator of activation protein; Modality; Modification; Molecular Genetics; Mus; Neoplasm Metastasis; Neoplastic Stromal Cell; Normal Cell; Normal tissue morphology; Pharmaceutical Preparations; Pharmacotherapy; Play; Population Heterogeneity; Primary Neoplasm; Recruitment Activity; Recurrence; Research; Resistance; Role; Signal Pathway; Site; Small Intestinal Neoplasm; Specificity; Stromal Cells; TYMS gene; Testing; Therapeutic; Therapeutic Agents; Thymidylate Synthase; Thymidylate Synthase Inhibitor; Tissues; Toxic effect; Transplantation; anticancer activity; base; cancer cell; cancer therapy; cell type; chemotherapeutic agent; clinical efficacy; clinically relevant; cytokine; fluoropyrimidine; improved; macrophage; mouse model; neoplastic cell; novel strategies; response; targeted treatment; tumor; tumor growth; tumor microenvironment; tumor progression

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.

描述（由申请人提供）：抗癌治疗通常针对肿瘤细胞。胸苷酸合酶 (TS) 抑制剂，特别是氟嘧啶，已在多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群浸润。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基质或微环境。通过分泌一系列细胞因子、生长因子、激素等，它们在肿瘤生长和进展以及对治疗药物的反应中发挥着关键作用。在本提案中，我们将测试肿瘤对 TS 抑制剂的反应受浸润基质细胞的化学敏感性控制的假设。我们将利用 ApcMin/+ 小鼠，该小鼠易于形成小肠和结肠腺瘤肿瘤。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表现出反映基质细胞化学敏感性的药物反应。根据初步结果，目标 1 将确定 TS 抑制剂对基质室中细胞的影响，以确定对 TS 抑制剂反应的基质介质。目标 2 将检查基质细胞中 TS 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 TS 抑制剂特别针对肿瘤相关基质细胞进行敏化。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方式铺平道路，以改进针对肿瘤细胞的疗法，以确保药物诱导的癌细胞死亡。