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Targeting of Mitochondrial Lon Protease as a Novel Therapy for Glioblastoma

靶向线粒体 Lon 蛋白酶作为胶质母细胞瘤的新疗法

基本信息

批准号：
10832278
负责人：
Daniela Annenelie Bota
金额：
$ 7.83万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10832278
关键词：
Adult Animal Model Apoptosis Automobile Driving Binding Biochemical Bioenergetics Biogenesis Biological Biology Brain Brain Neoplasms CRISPR/Cas technology Cell Culture Techniques Cell Cycle Cell Death Induction Cell Line Cell Survival Cells Cervical Chemotherapy and/or radiation Clinical Trials Colorectal Cues DNA biosynthesis Development Disease Drug Targeting Equilibrium Excision FDA approved Glioblastoma Glioma Goals Growth Heat shock proteins Homeostasis Human Hypoxia Immunodeficient Mouse In Vitro Inbred BALB C Mice Knock-out Lead Libraries Link Malignant Glioma Malignant Neoplasms Maximum Tolerated Dose Measures Mesenchymal Metabolic Mitochondria Mitochondrial DNA Mitochondrial Proteins Modeling Molecular Molecular Chaperones Neoplasm Metastasis Normal Cell Operative Surgical Procedures Oral Pathway interactions Patients Peptide Hydrolases Phenotype Primary Brain Neoplasms Process Prognosis Prognostic Factor Proteins Publishing RNA Radiation therapy Recurrence Recurrent tumor Regulation Resistance Respiration Role Small Interfering RNA Structure-Activity Relationship Study models Survival Rate System Testing Therapeutic Toxic effect Up-Regulation Xenograft Model anti-cancer blood-brain barrier crossing chemotherapeutic agent chemotherapy clinical application cytotoxic endopeptidase La epithelial to mesenchymal transition gene therapy glioma cell line in vivo in vivo Model inhibitor interest knock-down melanoma meter mitochondrial DNA mutation mitochondrial dysfunction mitochondrial metabolism novel novel strategies novel therapeutics nutrient deprivation overexpression pharmacologic protein degradation response small molecule stable cell line standard of care stem cells stem-like cell synergism temozolomide therapy resistant tumor tumor growth tumor initiation

项目摘要

PROJECT SUMMARY Glioblastoma (GBM) is the most aggressive primary brain tumor with a two years survival rate of less than 50% following surgical resection, radiation, and chemotherapy. Recurrence is nearly universal after the first-line treatment, and there is currently no therapy proven to prolong survival after tumor recurrence. Thus, there is an urgent need for more effective GBM therapies. The overarching goal of this project is to further develop and validate new chemotherapeutic agents for the treatment of GBM. GBM's resistance to radiation and chemotherapy heavily correlates with extensive hypoxia-induced, mitochondria-dependent phenotypic changes such as glycolytic respiration, decreased the ability to undergo apoptosis and extensive invasiveness. Mitochondrial LonP1 is an ATP-stimulated protease, directly up-regulated by HIF-1α. LonP1 is overexpressed in human malignant gliomas and its elevated expression levels are associated with high glioma tumor grade and poor patient survival. Therefore, regulation of mitochondrial function by inhibiting LonP1 protease could represent a novel approach for GBM and potentially other fast-growing malignancies which heavily depend on hypoxic adaptation. The proposed project is based on our published and preliminary results obtained from in vitro (cell- based) studies with LonP1 inhibition using siRNA and the inhibitor compounds CC4 and BT317 and in vivo LonP1-overexpression xenograft models studies. BT317 is a small molecule compound, able to cross the blood- brain barrier and to achieve promising concentrations in the brain. BT317 is highly effective in inducing cell death in multiple glioma lines and patient-derived glioblastoma stem cell cultures, with an IC50 value of 60-100 µM (temozolomide – the main FDA approved therapy and has minimal toxicity in normal lines. identifying BT317 as a potentially new therapy for this universally fatal disease. In this project, we propose to: (1) examine the effect of mitochondrial LonP1 knockout in distinct patient-derived primary glioma stem-like cells (GSC), glioblastoma cell lines and xenograft models, (2) identify microenvironment cues and LonP1-induced mitochondrial changes that drive GSC invasiveness, and (3) examine the drug-target inhibition and molecular mechanisms for anti- cancer efficacy of the LonP1 inhibitor, BT317. The studies outlined here are the first to explore a very promising avenue – mitochondrial Lon protease inhibition – as a treatment for GBM.

项目概要胶质母细胞瘤 (GBM) 是最具侵袭性的原发性脑肿瘤，两年生存率低于 50% 手术切除、放疗和化疗后。一线治疗后复发几乎是普遍的治疗，目前尚无任何治疗方法被证明可以延长肿瘤复发后的生存期。因此，有一个迫切需要更有效的 GBM 治疗方法。该项目的总体目标是进一步开发和验证用于治疗 GBM 的新化疗药物。 GBM 的抗辐射能力和化疗与广泛的缺氧诱导的线粒体依赖性表型变化密切相关例如糖酵解呼吸，降低了细胞凋亡和广泛侵袭的能力。线粒体 LonP1 是一种 ATP 刺激的蛋白酶，受 HIF-1α 直接上调。 LonP1 过表达于人类恶性胶质瘤及其表达水平升高与高胶质瘤肿瘤级别和患者生存率低。因此，通过抑制 LonP1 蛋白酶来调节线粒体功能可以代表一种治疗 GBM 和其他潜在快速增长的恶性肿瘤的新方法，这些恶性肿瘤严重依赖于缺氧适应。拟议的项目基于我们已发表的体外（细胞- 基于）使用 siRNA 和抑制剂化合物 CC4 和 BT317 进行 LonP1 抑制研究以及体内研究 LonP1 过度表达异种移植模型研究。 BT317是一种小分子化合物，能够穿过血液- 脑屏障并在大脑中达到有希望的浓度。 BT317 非常有效地诱导细胞死亡在多种胶质瘤系和患者来源的胶质母细胞瘤干细胞培养物中，IC50 值为 60-100 µM （替莫唑胺 – FDA 批准的主要疗法，在正常细胞系中具有最小的毒性。将 BT317 确定为针对这种普遍致命疾病的潜在新疗法。在本项目中，我们建议：（1）检验效果不同患者来源的原代胶质瘤干细胞 (GSC)、胶质母细胞瘤中线粒体 LonP1 敲除的影响细胞系和异种移植模型，(2) 识别微环境线索和 LonP1 诱导的线粒体变化驱动 GSC 侵袭性，(3) 检查药物靶标抑制和抗- LonP1 抑制剂 BT317 的癌症功效。这里概述的研究是第一个探索非常有前途的研究途径——线粒体 Lon 蛋白酶抑制——作为 GBM 的治疗方法。