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）定义为一种分泌的细胞抑制剂/促炎性因子