GLIPR1-ATM Protein Therapy for Prostate Cancer

GLIPR1-ATM 蛋白治疗前列腺癌

• 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
• 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

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.

广泛的研究已经将GLIPRI（胶质瘤发病相关蛋白）定义为分泌的、细胞抑制的/促细胞凋亡的蛋白。 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表现出肿瘤抑制功能 通过协调的细胞类型特异性活性，包括直接、肿瘤细胞选择性、促凋亡活性 通过活性氧（ROS）-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。其他分析显示， GLIPR1的表达通过转录抑制抑制c-myc，这依赖于Spl 在c-myc启动子中的GC/GT响应位点，并导致额外的Spl靶点的下调 铜锌超氧化物歧化酶（CuZnSOD/SODI）和锰超氧化物歧化酶（MnO2）基因 歧化酶（MnS0D/S0D2）。这些数据与先前的研究结果一致，即Spl直接刺激 表达多种抗氧化蛋白，包括CuZnSOD、MnSOD和胞外超氧化物 歧化酶（ECSOD/SOD 3）。c-myc靶蛋白的蛋白质印迹分析显示GLIPRI过表达 导致对关键细胞周期调节蛋白和γ-谷氨酰-半胱氨酸的显著抑制 合成酶，催化谷胱甘肽合成的第一个限速步骤[1]。总体而言，GLIPRI Spl活性的抑制代表了削弱抗氧化剂的分子开关 防止癌细胞ROS介导的"自我毁灭"和抑制c-myc- 介导的癌细胞增殖。在临床前研究中，我们发现重组GLIPRI蛋白 治疗导致多发性前列腺癌中肿瘤细胞选择性生长停滞和/或凋亡性细胞死亡 体外细胞系。使用VCaP和/或PC-3异种移植物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， 肿瘤内或腹膜内施用。此外，观察到对基质细胞的影响， 治疗的肿瘤，包括显著抑制血管生成和巨噬细胞浸润。 我们开发GLIPRI蛋白治疗前列腺癌的第一步是测试原位递送修饰的 GLIPRI蛋白（GLIPR1-ATM）。该Ib期临床试验将实现两个重要目标： 这种治疗性蛋白质在临床环境中的安全性（根治性前列腺切除术前的前列腺内治疗 （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治疗剂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研究来测试其毒性和有效性。 组织分析GLIPRI-ATM具有局部和全身用于前列腺癌的潜力。