GLIPR1-ATM Protein Therapy for Prostate Cancer

广泛的研究已将GLIPRI(胶质瘤发病机制相关蛋白)定义为一种分泌型、细胞抑制型/亲细胞型蛋白。 在前列腺癌进展过程中下调的凋亡性肿瘤抑制蛋白 表观遗传机制。机制研究表明GLIPRI具有肿瘤抑制功能 通过协调细胞类型的特定活动，包括直接的、肿瘤细胞选择性的、促凋亡的活动 通过活性氧(R0S)-c-Jun-NH2激酶(JNK)信号转导。最近我们展示了 GLIPRI的表达导致特异性蛋白1(SPL)的下调。进一步的分析显示 GLIPR1通过依赖SPL的转录抑制抑制c-myc的表达 C-myc启动子中有反应的GC/GT位点并导致额外的SPL靶点下调 铜锌超氧化物歧化酶和锰超氧化物歧化酶基因 歧化酶(MnS0D/S0D2)。这些数据与之前的发现一致，即SPL直接刺激 铜锌超氧化物歧化酶、锰超氧化物歧化酶和胞外超氧化物歧化酶等多种抗氧化蛋白的表达 歧化酶(EcSOD/SOD3)。C-myc靶蛋白的Western blotting分析表明GLIPRI过表达 导致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活性的抑制代表着一种削弱抗氧化剂的分子开关 阻止ROS介导的癌细胞“自毁”和抑制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 多发性前列腺癌的治疗导致肿瘤细胞选择性生长停滞和/或细胞凋亡 体外培养的细胞系。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蛋白抑制肿瘤生长和增加肿瘤细胞凋亡 瘤内或腹膜内给药。此外，还观察到了对基质细胞的影响 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GLIPRI蛋白疗法治疗前列腺癌的第一步是测试改良的 GLIPRI蛋白(GLIPR1-ATM)。本次1b期临床试验将实现两个重要目标：(1)建立 这种治疗性蛋白在临床环境中的安全性(根治前的前列腺内治疗 前列腺切除术)；(2)建立系统使用GLIPRI-ATM的原则证据。 相关性(请参阅说明)： 该项目将进一步分析一种新的癌症治疗蛋白GLIPRI-ATM的作用机制， 并利用这些信息开发局部和系统反应的预测性生物标记物。进一步的临床应用 涉及前列腺内注射GLIPRI-ATM的研究将通过广泛的 组织分析。GLIPRI-ATM有可能用于前列腺癌的局部和全身治疗。

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.