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Role of the microenvironment in ovarian cancer metastasis

微环境在卵巢癌转移中的作用

基本信息

批准号：
10020913
负责人：
Katherine Cynthia Fuh
金额：
$ 43.32万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10020913
关键词：
Abdomen Address Binding Cancer Etiology Cancer Patient Cause of Death Cells Cessation of life Cleaved cell 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 Xenograft Model Xenograft procedure cancer recurrence cancer type chemotherapy discoidin domain receptor 2 fluorescence imaging imaging platform improved inhibitor/antagonist intraperitoneal malignant stomach neoplasm mouse model neoplastic cell novel novel marker novel therapeutics ovarian neoplasm overexpression preclinical study prevent response small molecule statistics targeted treatment treatment response tumor tumor microenvironment

项目摘要

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.

项目摘要/摘要