Antisecretory factor as a novel therapeutic agent in human glioblastoma

抗分泌因子作为人胶质母细胞瘤的新型治疗剂

基本信息

批准号：
8840674
负责人：
Per Anders Ingemar Persson
金额：
$ 19.8万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2016-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8840674
关键词：
Adult Alkylating Agents Animals Apoptosis Biology Bioluminescence Bioreactors Blood Vessels Brain Neoplasms Cell Death Cell Density Cell Proliferation Cell division Cells Cholera Toxin Cleaved cell Data Diet Disease Dose Doxorubicin Drainage procedure Electrophysiology (science)Fluids and Secretions Fluorescence Genes Glioblastoma Goals Health Human Hydrostatic Pressure Immunocompromised Host Immunohistochemistry Implant In Vitro Injection of therapeutic agent Intercellular Fluid Intestines Intracranial Hypertension Intracranial Pressure Laboratories Lead Liquid substance Luciferases Magnetic Resonance Imaging Malignant Neoplasms Measurement Measures Mechanical Stress Mediating Methodology Methods Modeling Mus Normal tissue morphology Operative Surgical Procedures Organ Osmotic Pressure Patients Peptides Pharmaceutical Preparations Plasma Polyribosomes Property Radiation therapy Relative (related person)Resistance Rodent Role Slice Solid Solid Neoplasm Stromal Cells Swelling Tail Testing Therapeutic Agents Time Transplantation Tumor Cell Biology Tumor Cell Invasion Vascular remodeling Veins Work Xenograft procedure antisecretory factor caspase-3 chemotherapeutic agent chemotherapy chloride-cotransporter potassium cytotoxic improved in vivo interest interstitial neoplastic cell novel novel therapeutics outcome forecast pressure prevent release factor sensor subcutaneous temozolomide therapeutic target tumor tumor growth tumor progression uptake

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is among the most aggressive cancers. The prognosis for GBM patients is dismal, with average survival of 12-15 months. High interstitial fluid pressure (IFP) represents a major obstacle in solid cancers and a barrier for drg uptake. Solid tumors are associated with increased IFP due to vascular leakiness and drainage resistance via stromal cell mediated release of factors and contraction of the interstitial matrix. Fluid accumulation and high cell density compresses tumor and surrounding normal tissue and promotes osmotic swelling of tumor cells. Although studies have clarified the role of tumor vasculature, it is still unclear how mechanical stresses and osmotic changes regulate tumor cell biology. Our laboratory has developed a novel method that enables precise measurements of IFP in xenografted GBMs during tumor progression. Intriguingly, our preliminary data suggest that elevated IFP drives tumor growth. Extended studies in vitro confirmed that elevated hydrostatic pressure increases GBM cell proliferation. In this proposal, we will use novel in vitro and in vivo methodology to study the effects of hydrostatic and osmotic pressures on GBM biology. We will study the relationship between elevated IFP on 1) tumor growth and 2) uptake of chemotherapeutics in human GBM xenografts. Using 3D-cultures and tumor slices, we will then test if increased hydrostatic or osmotic pressure components regulate 1) GBM cell proliferation and 2) the cytotoxic effects of chemotherapy. Early efforts to identify a treatment that prevents cholera toxin-induced hypersecretion from the intestine resulted in the identification of antisecretory factor (AF). AF-induction is safe in patients, reduces elevated intracranial pressure in rodents, and lowers IFP in subcutaneous solid tumors. In two aims, we will test if AF lowers IFP in GBM xenografts, leading to reduced tumor growth and increased uptake of chemotherapies in tumors. Mechanistic studies in 3D-cultures and tumor slices will test if AF can regulate GBM cell proliferation and the cytotoxic effects of chemotherapies under conditions of elevated hydrostatic or osmotic pressures. Our work will establish a role for mechanical stresses and osmotic changes as potential therapeutic targets in solid cancers. As a novel IFP-reducing therapy, we firmly believe that AF induction represents an attractive strategy to improve overall survival in GBM patients.

描述（由申请人提供）：胶质母细胞瘤（GBM）是最具侵袭性的癌症之一。 GBM患者的预后很差，平均生存期为12-15个月。高间质液压力（IFP）是实体癌的主要障碍和药物吸收的障碍。由于基质细胞介导的因子释放和间质基质收缩导致血管渗漏和引流阻力，实体瘤与 IFP 增加相关。液体积聚和高细胞密度压迫肿瘤和周围正常组织并促进肿瘤细胞的渗透性肿胀。尽管研究已经阐明了肿瘤血管系统的作用，但仍不清楚机械应力和渗透压变化如何调节肿瘤细胞生物学。我们的实验室开发了一种新方法，可以在肿瘤进展过程中精确测量异种移植 GBM 中的 IFP。有趣的是，我们的初步数据表明，IFP 升高会促进肿瘤生长。体外扩展研究证实，静水压升高会促进 GBM 细胞增殖。在本提案中，我们将使用新颖的体外以及研究静水压和渗透压对 GBM 生物学影响的体内方法。我们将研究人类 GBM 异种移植物中 IFP 升高与 1) 肿瘤生长和 2) 化疗药物摄取之间的关系。然后，我们将使用 3D 培养物和肿瘤切片来测试增加的静水压或渗透压成分是否调节 1) GBM 细胞增殖和 2) 化疗的细胞毒性作用。早期努力寻找一种方法来预防霍乱毒素引起的肠道分泌过多，最终发现了抗分泌因子（AF）。 AF 诱导对患者来说是安全的，可以降低啮齿动物的颅内压升高，并降低皮下实体瘤的 IFP。在两个目标中，我们将测试 AF 是否会降低 GBM 异种移植物中的 IFP，从而减少肿瘤生长并增加肿瘤对化疗的吸收。 3D 培养物和肿瘤切片的机制研究将测试 AF 是否可以在静水压或渗透压升高的条件下调节 GBM 细胞增殖和化疗的细胞毒性作用。我们的工作将确定机械应力和渗透压变化作为实体癌潜在治疗靶点的作用。作为一种新型的 IFP 减少疗法，我们坚信 AF 诱导是提高 GBM 患者总生存率的一种有吸引力的策略。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

STAT3 Blockade Inhibits Radiation-Induced Malignant Progression in Glioma.

DOI：
10.1158/0008-5472.can-14-3331
发表时间：
2015-10-15
期刊：
Cancer research
影响因子：
11.2
作者：
Lau J;Ilkhanizadeh S;Wang S;Miroshnikova YA;Salvatierra NA;Wong RA;Schmidt C;Weaver VM;Weiss WA;Persson AI
通讯作者：
Persson AI

Deregulated proliferation and differentiation in brain tumors.

DOI：
10.1007/s00441-014-2046-y
发表时间：
2015-01
期刊：
CELL AND TISSUE RESEARCH
影响因子：
3.6
作者：
Swartling, Fredrik J.;Cancer, Matko;Frantz, Aaron;Weishaupt, Holger;Persson, Anders I.
通讯作者：
Persson, Anders I.