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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，即恶性肿瘤细胞通过血管和淋巴管从身体的一个部位扩散到另一个部位。胰腺腺癌是一种毁灭性的疾病，由于缺乏有效的治疗方法，5年生存率只有4%。我们提出了一种新的胰腺癌治疗方法，包括使用称为信号蛋白的神经元引导分子来抑制肿瘤的生长和进展。我们已经确定了一种常见的细胞表面受体，它在胰腺癌细胞、胰腺癌相关内皮细胞（血管）和淋巴内皮细胞（淋巴管）上表达，称为Neuropilin 2 （NRP2）。在肿瘤微环境中发现几种细胞类型的共同靶点是不寻常的。因此，NRP2是治疗胰腺腺癌的一个很好的靶点。我们假设NRP2在癌细胞中充当vegf的储存库，并在内皮细胞中充当VEGFR的增强共受体。我们将通过研究NRP2在癌细胞中作为VEGF的储存库或通过在胰腺癌细胞中过表达NRP2作为VEGF信号传导的自分泌介质的作用来验证这一假设。此外，我们将在小鼠原位胰腺癌模型和NRP2缺陷小鼠转基因（K-ras+）胰腺癌模型中测试NRP2在肿瘤相关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的小鼠会出现肿瘤大小减小、毛细血管增生（血管生成）减少、淋巴管面积减少和转移潜力降低的情况。最后，我们假设信号蛋白3F (SEMA3F)，一种NRP2的抑制配体，会在体内抑制（淋巴）血管生成和转移。我们建议在胰腺癌（人类和小鼠原位模型）中进行临床前试验，以测试每日注射或缓释泵递送的SEMA3F纯化蛋白。此外，我们将测试SEMA3F逆转录病毒感染是否能消除胰腺癌在肝脏的转移。总的来说，我们的计划是研究胰腺癌的新方法和新靶点。