GLIPR1-ATM Protein Therapy for Prostate Cancer

GLIPR1-ATM 蛋白治疗前列腺癌

基本信息

批准号：
8380586
负责人：
Timothy Charles Thompson
金额：
$ 25.94万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8380586
关键词：
6 year old Accounting Agreement Antioxidants Apoptosis Apoptotic Autophagocytosis Biochemical Biological Biological Markers Bone Marrow Bone Marrow Diseases Cancer Center Cancer Patient Cause of Death Cell Cycle Proteins Cell Death Cell Proliferation Cells Cessation of life Clinical Clinical Research Clinical Trials Communication Cysteine Cytostatics Data Development Distant Dose Down-Regulation Drug Kinetics Epigenetic Process Epithelial Gene Expression Gene Targeting Gene Transfer Genetic Glioma Glutathione Goals Growth Heart Diseases Human Immune In Situ In Vitro Infiltration Injection of therapeutic agent Instruction JUN gene Ligase Local Therapy Malignant Neoplasms Malignant neoplasm of prostate Manganese Superoxide Dismutase Mediating Metastatic Prostate Cancer Modality Molecular Molecular Profiling Mus Nature Necrosis Neoplasm Metastasis Newly Diagnosed PC3 cell line Pathogenesis Pathologic Pathway interactions Phase Phosphotransferases Population Primary Neoplasm Principal Investigator Prostate Prostate Cancer therapy Protein Overexpression Proteins Radiation therapy Radical Prostatectomy Reactive Oxygen Species Recombinants Safety Serum Markers Signal Transduction Site Specificity Stromal Cells Superoxide Dismutase Systemic Therapy Techniques Testing Therapeutic Effect Tissues Toxic effect Treatment Efficacy Tumor Suppressor Proteins Urogenital Cancer VCaP Western Blotting Xenograft Model Xenograft procedure angiogenesis anticancer research ataxia telangiectasia mutated protein c-myc Genes cancer cell cell type copper zinc superoxide dismutase cytotoxicity disorder control effective therapy efficacy testing extracellular gene repression hormone therapy indexing intraperitoneal lymph nodes macrophage man men mortality neoplastic cell novel palliative preclinical study prevent prognostic promoter protein expression research study response standard care therapeutic protein tumor tumor growth tumor progression

项目摘要

Extensive studies have defined GLIPRI (glioma pathogenesis-related protein) as a secreted, cytostatic/pro- apoptotic tumor suppressor protein that is down-regulated during prostate cancer progression through epigenetic mechanisms. Mechanistic studies have shown that GLIPRI manifests tumor suppressor functions through coordinated cell type specific activities, including direct, tumor cell selective, pro-apoptotic activities mediated through reactive oxygen species (R0S)-c-jun-NH2 kinase (JNK) signaling. Recently we showed that GLIPRI expression leads to down-regulation of specificity protein 1 (Spl). Additional analysis showed that GLIPR1 expression suppressed c-myc through transcriptional repression that was dependent on Spl responsive GC/GT sites in the c-myc promoter and resulted in down-regulation of additional Spl target genes including copper/zinc superoxide dismutase (CuZnSOD/SODI) and manganese superoxide dismutase (MnS0D/S0D2). These data are in agreement with previous findings that Spl directly stimulates expression of multiple anti-oxidant proteins including CuZnSOD, MnSOD, and extracellular superoxide dismutase (ECSOD/SOD3). Western blotting analysis of c-myc targets showed that GLIPRI overexpression resulted in significant suppression of key cell cycle regulatory proteins and also y-Qlutamyl-cysteine synthetase, which catalyzes the first rate-limiting step in the synthesis of glutathione [1]. Overall, GLIPRI suppression of Spl activities represents a molecular switch that debilitates the anti-oxidant mechanisms/pathways that prevent cancer cells from ROS mediated "self-destruction" and inhibits c-myc- mediated cancer cell proliferation. In preclinical studies we have found that recombinant GLIPRI protein treatment results in tumor cell selective growth arrest and/or apoptotic cell death in multiple prostate cancer cell lines in vitro. Further preclinical studies using VCaP and/or PC-3 xenograft models demonstrated that recombinant GLIPRI protein suppressed tumor growth and increased tumor cell apoptosis when administered intratumorally or intraperitoneally. In addition, effects on stromal cells effects were observed in treated tumors including significant suppression of angiogenesis and macrophage infiltration. Our first step in developing GLIPRI protein therapy for prostate cancer is to test in situ delivery of a modified GLIPRI protein (GLIPR1-ATM). This Phase lb clinical trial will accomplish two important goals: (1) Establish the safety of this therapeutic protein in a clinical setting (intraprostatic treatment prior to radical prostatectomy); (2) Establish proof of principle for systemic use of GLIPRI-ATM. RELEVANCE (See instructions): This project will further analyze the mechanism of action of a novel cancer protein therapeutic, GLIPRI-ATM, and use this information to develop predictive biomarkers for local and systemic response. Further clinical studies that involve intraprostatic injection of GLIPRI-ATM will test its toxicity and efficacy through extensive tissue analysis. GLIPRI-ATM has the potential for local and systemic use for prostate cancer.

大量研究已将 GLIPRI（神经胶质瘤发病机制相关蛋白）定义为一种分泌型、细胞抑制/促凋亡肿瘤抑制蛋白，在前列腺癌进展过程中下调表观遗传机制。机制研究表明GLIPRI表现出抑癌功能通过协调细胞类型特异性活动，包括直接、肿瘤细胞选择性、促凋亡活动通过活性氧 (R0S)-c-jun-NH2 激酶 (JNK) 信号传导介导。最近我们展示了 GLIPRI 表达导致特异性蛋白 1 (Spl) 下调。附加分析显示 GLIPR1 表达通过依赖于 Spl 的转录抑制来抑制 c-myc c-myc 启动子中的响应性 GC/GT 位点并导致其他 Spl 靶点的下调基因包括铜/锌超氧化物歧化酶 (CuZnSOD/SODI) 和锰超氧化物歧化酶（MnS0D/S0D2）。这些数据与之前的研究结果一致，即 Spl 直接刺激多种抗氧化蛋白的表达，包括 CuZnSOD、MnSOD 和细胞外超氧化物歧化酶（ECSOD/SOD3）。 c-myc 靶标的蛋白质印迹分析表明 GLIPRI 过表达导致关键细胞周期调节蛋白和 y-Qlutamyl-半胱氨酸的显着抑制合成酶，催化谷胱甘肽合成中的第一个限速步骤[1]。总体而言，格力普利 Spl 活性的抑制代表了一种削弱抗氧化剂的分子开关防止癌细胞免受 ROS 介导的“自我毁灭”并抑制 c-myc- 的机制/途径介导癌细胞增殖。在临床前研究中我们发现重组GLIPRI蛋白治疗导致多发性前列腺癌中肿瘤细胞选择性生长停滞和/或细胞凋亡体外细胞系。使用 VCaP 和/或 PC-3 异种移植模型的进一步临床前研究表明重组 GLIPRI 蛋白抑制肿瘤生长并增加肿瘤细胞凋亡瘤内或腹膜内施用。此外，还观察到对基质细胞的影响治疗肿瘤包括显着抑制血管生成和巨噬细胞浸润。我们开发前列腺癌 GLIPRI 蛋白疗法的第一步是测试修饰的原位递送 GLIPRI 蛋白 (GLIPR1-ATM)。本次lb期临床试验将实现两个重要目标：（1）建立这种治疗性蛋白质在临床环境中的安全性（根治性治疗之前的前列腺内治疗）前列腺切除术）； (2) 建立系统使用 GLIPRI-ATM 的原理证明。相关性（参见说明）：该项目将进一步分析新型癌症蛋白疗法 GLIPRI-ATM 的作用机制，并利用这些信息来开发局部和全身反应的预测生物标志物。进一步临床涉及前列腺内注射 GLIPRI-ATM 的研究将通过广泛的测试来测试其毒性和功效。组织分析。 GLIPRI-ATM 具有局部和全身用于治疗前列腺癌的潜力。