GLIPR1-ATM Protein Therapy for Prostate Cancer

GLIPR1-ATM 蛋白治疗前列腺癌

基本信息

批准号：
7743202
负责人：
Timothy Charles Thompson
金额：
$ 25.43万
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：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7743202
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 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 Reproduction spores 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.

广泛的研究已将Glipri（神经胶质瘤发病机理相关蛋白）定义为分泌的，细胞抑制剂/促疾病凋亡肿瘤抑制蛋白，在前列腺癌进展过程中下调表观遗传机制。机械研究表明，Glipri表现出肿瘤抑制功能通过协调的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）的下调。其他分析表明 GLIPR1表达通过转录抑制抑制了C-MYC，这取决于SPL C-MYC启动子中响应敏感的GC/GT位点，导致其他SPL目标下调包括铜/锌超氧化物歧化酶（Cuznsod/Sodi）和锰超氧化物在内的基因验证酶（MNS0D/S0D2）。这些数据与先前直接刺激SPL的发现一致多种抗氧化剂蛋白的表达，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- Q谷氨酸 - 半胱氨酸的显着抑制合成酶，催化谷胱甘肽合成[1]的第一次限制步骤。总体而言，格里普里 SPL活性的抑制代表一种分子开关，使抗氧化剂衰弱防止癌细胞介导的“自我毁灭”并抑制c-myc-的机制/途径介导的癌细胞增殖。在临床前研究中，我们发现重组GLIPRI蛋白治疗导致多种前列腺癌中肿瘤细胞选择性生长停滞和/或凋亡细胞死亡体外细胞系。使用VCAP和/或PC-3异种移植模型进一步的临床前研究表明，重组GLIPRI蛋白抑制肿瘤的生长并增加肿瘤细胞凋亡在肿瘤内或腹膜内进行施用。此外，在处理的肿瘤包括对血管生成和巨噬细胞浸润的明显抑制。我们开发Glipri蛋白治疗前列腺癌的第一步是测试改良的现场递送 Glipri蛋白（GLIPR1-ATM）。该阶段LB临床试验将实现两个重要目标：（1）建立该治疗蛋白在临床环境中的安全性（从根本上治疗前列腺切除术）；（2）建立全身使用Glipri-ATM的原理证明。相关性（请参阅说明）：该项目将进一步分析新型癌症蛋白治疗性Glipri-ATM的作用机理并使用此信息来开发用于本地和系统性响应的预测生物标志物。进一步的临床涉及肉体内注射GLIPRI-ATM的研究将通过广泛测试其毒性和功效组织分析。 Glipri-ATM具有用于前列腺癌的局部和系统用途的潜力。