Role of the microenvironment in ovarian cancer metastasis

微环境在卵巢癌转移中的作用

• 批准号: 10670556
• 负责人: Katherine Cynthia Fuh
• 金额: $ 42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670556
• 关键词: Abdomen; Address; Binding; Cancer Etiology; Cancer Patient; Cause of Death; Cells; Cessation of life; Clinical Trials; Collagen; Colorectal Cancer; Data; Diffuse; Disease; Extracellular Domain; Extracellular Matrix; Extracellular Matrix Proteins; FDA approved; Fibroblasts; Fibronectins; Goals; Human; Imaging Device; In Vitro; Injections; Intestines; Knockout Mice; Knowledge; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mediating; Mesothelial Cell; Mesothelium; Metalloproteases; Mus; Neoplasm Metastasis; Omentum; Organ; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphotransferases; Play; Proliferating; Proteins; Publishing; Receptor Protein-Tyrosine Kinases; Risk; Role; Serous; Small Interfering RNA; Stromal Cells; Stromal Neoplasm; Testing; Tumor Cell Invasion; Tyrosine Kinase Inhibitor; Wild Type Mouse; Woman; Work; cancer recurrence; cancer type; chemotherapy; discoidin domain receptor 2; fluorescence imaging; imaging platform; improved; inhibitor; intraperitoneal; malignant stomach neoplasm; mouse model; neoplastic cell; novel; novel marker; novel therapeutics; ovarian neoplasm; overexpression; patient derived xenograft model; preclinical study; prevent; response; small molecule; statistics; targeted treatment; treatment response; tumor; tumor microenvironment

PROJECT SUMMARY / ABSTRACT Half of all ovarian cancer patients die within five years. This is largely because their tumors recur after chemotherapy and metastasize within the intraperitoneal cavity, eventually blocking function of organs such as the bowel. Additionally, no FDA-approved drugs block the steps of intraperitoneal metastasis. Thus, new strategies are needed to prevent ovarian cancer metastasis. This proposal focuses on the receptor tyrosine kinase Discoidin Domain Receptor 2 (DDR2) as a candidate target to prevent ovarian cancer metastasis for the following reasons. First, DDR2 is overexpressed in 74% of advanced-stage, high-grade serous human ovarian tumors and 100% of metastases. Second, patients whose tumors had higher levels of DDR2 had shorter survival than those with lower levels of DDR2. Third, preliminary data shows that, after tumor cell injection, tumors formed in syngeneic DDR2 knockout mice were smaller and contained less collagen (the ligand for DDR2) than those in DDR2 wild-type mice. Fourth, promising small molecule DDR2 inhibitors have been developed that, unlike all other receptor tyrosine kinase inhibitors, bind and allosterically inhibit the extracellular domain of DDR2. This proposal will test the central hypothesis that DDR2 in stromal cells promotes steps of metastasis by acting through its ligand collagen to alter the microenvironment. Aim 1 will build on strong preliminary data showing that DDR2 in the stroma promotes metastasis by identifying the particular stromal cells (fibroblasts and mesothelial cells) and steps in which DDR2 contributes to metastasis. This aim will make use of a large bank of human primary omental stromal cells and ovarian tumor cells. Aim 2 will test the hypothesis that DDR2 in the mesothelial cells, fibroblasts, or both is activated by collagen I, leading to increased matrix metalloprotease 2 activity and fibronectin cleavage. Additionally, this aim will test the hypothesis that DDR2 regulates collagen amount and organization in the microenvironment and will identify proteins secreted by DDR2-expressing fibroblasts that promote ovarian tumor cell invasion. Aim 3 will assess the ability of a novel DDR2 inhibitor to enhance response to chemotherapy, and identify tumor microenvironment components that correlate with response. In addition to testing a novel DDR2 inhibitor in mouse syngeneic and patient-derived xenograft models of ovarian cancer, this aim will use a novel, multi-parameter fluorescent imaging tool to define tumor/stromal cell expression patterns and extracellular matrix signatures that correlate with treatment response in mouse and human tumors. Completion of these aims will uncover novel mechanisms by which the tumor microenvironment contributes to intraperitoneal metastasis and reveal new potential targets for therapy.

项目总结/摘要 一半的卵巢癌患者在五年内死亡。这主要是因为他们的肿瘤复发后， 化疗和腹腔内转移，最终阻断器官的功能， 肠子此外，没有FDA批准的药物阻断腹膜内转移的步骤。因此，新 需要策略来预防卵巢癌转移。这项建议的重点是受体酪氨酸 激酶盘状结构域受体2（DDR2）作为预防卵巢癌转移的候选靶点， 以下原因。首先，DDR2在74%的晚期、高级别浆液性人卵巢癌中过表达。 肿瘤和100%的转移。其次，肿瘤中DDR2水平较高的患者生存期较短， 而DDR2水平较低的人更少。第三，初步数据显示，肿瘤细胞注射后， 同基因DDR2敲除小鼠的体积更小，胶原蛋白（DDR2的配体）含量更少， 在DDR2野生型小鼠中。第四，已经开发了有前景的小分子DDR2抑制剂，与所有的DDR2抑制剂不同， 其它受体酪氨酸激酶抑制剂结合并变构抑制DDR2的胞外结构域。这 一项提案将检验中心假设，即基质细胞中的DDR2通过作用于肿瘤细胞， 通过其配体胶原蛋白来改变微环境。目标1将建立在强有力的初步数据基础上，这些数据表明， 间质中的DDR2通过鉴定特定的间质细胞（成纤维细胞和间皮细胞）来促进转移 细胞）和其中DDR2有助于转移的步骤。这一目标将利用一个庞大的人类银行， 原代网膜基质细胞和卵巢肿瘤细胞。目的2将检验DDR2在间皮瘤中 细胞、成纤维细胞或两者被胶原蛋白I激活，导致基质金属蛋白酶2活性增加， 纤连蛋白裂解。此外，这一目的将检验DDR2调节胶原蛋白量的假设， 组织在微环境中，并将确定蛋白分泌的DDR2表达成纤维细胞， 促进卵巢肿瘤细胞的侵袭。目的3将评估新型DDR2抑制剂增强应答的能力 化疗，并确定与反应相关的肿瘤微环境成分。除了 在小鼠同基因和患者来源的卵巢癌异种移植模型中测试新型DDR2抑制剂， aim将使用一种新的多参数荧光成像工具来确定肿瘤/基质细胞的表达模式 以及与小鼠和人肿瘤中的治疗反应相关的细胞外基质特征。 这些目标的完成将揭示肿瘤微环境有助于肿瘤发生的新机制。 腹膜内转移和揭示新的潜在治疗靶点。