Targeting Neuropilin 2 with Semaphorin 3F during Pancreatic Carcinoma Progression

在胰腺癌进展过程中使用 Semaphorin 3F 靶向 Neuropilin 2

基本信息

批准号：
8191261
负责人：
DIANE Renee BIELENBERG
金额：
$ 18.89万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-10 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8191261
关键词：
Adenocarcinoma Cell Angiogenesis Inhibitors Area Biology Blood Vessels Blood capillaries Carcinoma Cause of Death Cell Surface Receptors Disease Disseminated Malignant Neoplasm Distant Ductal Endocrine Glands Endothelial Cells Enzymes Epithelial Cells Exocrine Glands Family Hormones Human Infection Injection of therapeutic agent Isogenic transplantation Laboratories Ligands Liver Lymph Lymphangiogenesis Lymphatic Endothelial Cells Lymphatic vessel Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediator of activation protein Metastatic Neoplasm to the Liver Modeling Molecular Mus Neoplasm Metastasis Neoplasms Neuropilin-2 Organ Pancreas Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pancreatic carcinoma Patients Proliferating Proteins Pump Recruitment Activity Regulation Reporting Research Role Sampling Semaphorin-3 Semaphorins Signal Transduction Site Survival Rate Testing Transfection Transgenic Organisms Tumor Angiogenesis Tumor Biology Tumorigenicity United States Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors angiogenesis antitumor agent autocrine cancer cell capillary cell growth cell type effective therapy fighting in vivo migration neoplastic cell neovascularization neuronal guidance novel strategies novel therapeutic intervention novel therapeutics overexpression pancreatic cancer cells preclinical study receptor receptor binding tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Research in the Bielenberg laboratory focuses on studying the biology of cancer metastasis, the spread of malignant tumor cells from one site in the body to another, through blood vessels and lymphatic vessels. Pancreatic adeno-carcinoma is a devastating disease with only a 4% 5-year survival rate due to the lack of effective therapies. We propose a novel therapeutic approach to pancreatic carcinoma treatment that involves using neuronal guidance molecules called Semaphorins to inhibit neoplastic growth and progression. We have identified a common cell surface receptor that is expressed on pancreatic cancer cells, pancreatic carcinoma-associated endothelial cells (blood vessels), and lymphatic endothelial cells (lymphatic vessels) called Neuropilin 2 (NRP2). It is unusual to find a common target on several cell types within the tumor microenvironment. Therefore, NRP2 is an excellent target for therapy in pancreatic adenocarcinoma. We hypothesize that NRP2 is acting as a VEGF-reservoir in the cancer cells and as an enhancing co-receptor with VEGFR in the endothelial cells. We will test this hypothesis by examining the role of NRP2 in cancer cells as a reservoir for VEGF or as an autocrine mediator of VEGF signaling by overexpressing NRP2 in pancreatic carcinoma cells. In addition, we will test the necessity of NRP2 in tumor-associated angiogenesis and lymphangiogenesis in murine orthotopic pancreatic carcinoma models and in transgenic (K-ras+) pancreatic carcinoma models using NRP2-deficient mice. We predict that mice lacking NRP2 in the endothelial cells will have decreased tumor size, decreased proliferating capillaries (angiogenesis), decreased lymphatic vessel area, and decreased metastatic potential. Lastly, we hypothesize that Semaphorin 3F (SEMA3F), an inhibitory ligand of NRP2, will inhibit (lymph)-angiogenesis and metastasis in vivo. We propose preclinical trials in pancreatic carcinoma (both human and murine orthotopic models) to test SEMA3F purified proteins delivered as daily injections or in slow-release pumps. In addition, we will test SEMA3F retroviral infection to obliterate pancreatic cancer metastasis in the liver. Overall, our plans are to investigate a novel approach and a new target in pancreatic cancer. PUBLIC HEALTH RELEVANCE: Our proposed studies will explore the biology of cancer metastasis and the molecular mechanisms involved in pancreatic adenocarcinoma. Our preclinical trials with Semaphorin 3F may have broader impact on many angiogenic and metastatic cancers.

描述（由申请人提供）：Bielenberg实验室的研究重点是研究癌症转移的生物学，恶性肿瘤细胞从体内一个部位通过血管和淋巴管传播。胰腺腺癌是一种毁灭性疾病，由于缺乏有效的疗法，其生存率仅为4％。我们提出了一种用于胰腺癌治疗的新型治疗方法，该方法涉及使用称为信号素的神经元引导分子抑制肿瘤的生长和进展。我们已经确定了一种公共细胞表面受体，该受体在胰腺癌细胞，胰腺癌相关的内皮细胞（血管）和淋巴内皮细胞（淋巴细胞）（淋巴管）（NRYROPILIN 2（NRP2））中表达。在肿瘤微环境中找到几种细胞类型的共同靶标是不寻常的。因此，NRP2是胰腺腺癌治疗的绝佳靶标。我们假设NRP2在癌细胞中充当VEGF-reserervoir，并且是内皮细胞中与VEGFR的增强的共受体。我们将通过研究NRP2在癌细胞中作为VEGF的储层或作为VEGF信号的自分泌介质的作用来检验这一假设，通过在胰腺癌细胞中过表达NRP2来检验NRP2。此外，我们将使用NRP2缺乏的小鼠在鼠的原位胰腺癌模型以及转基因（K-RAS+）胰腺癌模型中测试NRP2在肿瘤相关的血管生成和淋巴管生成中的必要性。我们预测，内皮细胞中缺乏NRP2的小鼠将减少肿瘤的大小，减少增殖毛细血管（血管生成），淋巴管降低和转移潜能降低。最后，我们假设Semaphorin 3F（SEMA3F）是NRP2的抑制性配体，将抑制（淋巴）血管生成和体内转移。我们提出了胰腺癌（人和鼠矫正模型）中的临床前试验，以测试以每日注射或缓释泵中输送的SEMA3F纯化蛋白质。此外，我们将测试SEMA3F逆转录病毒感染，以消除肝脏中的胰腺癌转移。总体而言，我们的计划是调查一种新颖的方法和胰腺癌的新目标。公共卫生相关性：我们提出的研究将探讨癌症转移的生物学以及胰腺腺癌涉及的分子机制。我们使用Semaphorin 3F的临床前试验可能会对许多血管生成和转移性癌症产生更大的影响。