Evaluating the Role of IGFBP-3 in Men with Prostate Cancer

评估 IGFBP-3 在男性前列腺癌患者中的作用

• 批准号: 7679545
• 负责人: ALLAN J PANTUCK
• 金额: $ 20.64万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7679545
• 关键词: Angiogenesis Inhibition; Apoptosis; Biological Assay; Biological Markers; Clinical; Clinical Research; Clinical Trials; Data; Development; Disease; Dose; Epidermal Growth Factor Receptor; Event; Genomics; Goals; Grant; Histopathology; Induction of Apoptosis; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Receptor; Insulin-Like Growth-Factor-Binding Proteins; Malignant neoplasm of prostate; Mitochondria; Molecular; Mus; Neoadjuvant Therapy; Nuclear; Nuclear Receptors; Nutritional; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phosphorylation; Property; Proteins; Proteomics; Reproduction spores; Resources; Role; Somatomedins; Staining method; Stains; Surrogate Markers; Tissue Microarray; Tissues; Toxic effect; Translations; Tumor Suppression; Work; Xenograft procedure; in vivo; inhibitor/antagonist; men; mouse model; outcome forecast; response; tool; tumor; Angiogenesis Inhibition; Apoptosis; Biological Assay; Biological Markers; Clinical; Clinical Research; Clinical Trials; Data; Development; Disease; Dose; Epidermal Growth Factor Receptor; Event; Genomics; Goals; Grant; Histopathology; Induction of Apoptosis; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Receptor; Insulin-Like Growth-Factor-Binding Proteins; Malignant neoplasm of prostate; Mitochondria; Molecular; Mus; Neoadjuvant Therapy; Nuclear; Nuclear Receptors; Nutritional; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phosphorylation; Property; Proteins; Proteomics; Reproduction spores; Resources; Role; Somatomedins; Staining method; Stains; Surrogate Markers; Tissue Microarray; Tissues; Toxic effect; Translations; Tumor Suppression; Work; Xenograft procedure; in vivo; inhibitor/antagonist; men; mouse model; outcome forecast; response; tool; tumor

DEVELOPMENT OF IGFBP-3 THERAPY IN MEN WITH PROSTATE CANCER In preliminary data derived with this SPORE grant, we demonstrated interactions of IGFBP-3 with mitochondria! and nuclear apoptosis-related proteins and showed that IGFBP-3's action requires rapid internalization, phosphorylation, and association with the multi-compartmental nuclear receptors RXRa and Nur77 leading to both rapid induction of apoptosis pathways. Particularly, we described that the nucleo- mitochondrial translocation of Nur77 in response to IGFBP-3 treatment is a key event in the IGFBP-3 cascade and could serve as a biomarkerfor IGFBP-3 responsiveness. Importantly, we have also shown that the in vivo administration of IGFBP-3 to xenograft bearing mice results in substantial tumor suppression and inhibition of angiogenesis and that the effects of IGFBP-3 in vivo are observed when given as a single therapy, and are enhanced in combination with other agents. Our work has been instrumental in advancing this field to its current state, and in this SPORE renewal we propose to further investigate the role of IGFBP- 3 as a therapy for men with prostate cancer. Our specific aims are to (1) Develop histopathology assays for IGFBP-3 pathway molecules in prostate cancer and evaluate of their role in determining disease prognosis and their ability to serve as surrogate tissue biomarkers of IGFBP-3 activity on prostate cancer in vivo, (e. g. Nur77 subcellular localization); and to determine, using the SPORE tissue array resource, if baseline intra tumor staining levels of IGFBP-3, Nur77, and RXRa predict the clinical outcome of patients with prostate cancer. (2) Conduct a a Phase 1 b dose response neoadjuvant trial of IGFBP-3 in men with CaP. The primary goals of the study are to assess toxicity and to identify an active dose as defined by molecular induction of apoptosis using assays that include those developed in Aim 1. Secondary goals will be to use genomic and proteomic analyses to identify additional surrogate markers of treatment. (3) Optimize IGFBP-3 treatment of prostate cancer in in vivo mouse models, prior to initiating a larger phase 2 study. This Aim is a reverse translation that will build upon the preceding clinical study. Our goals are to identify drugs that synergize with IGFBP-3, such as IGF receptor inhibitors, EGF receptor antagonists and nutritional agents including Pom X. Together, these efforts will serve to promote the development of rational IGFBP-3-related therapies and tools to assess its efficacy in prostate cancer. As the first clinical trials targeting other components of the IGF axis are already underway, we believe that IGFBP-3 will have additional tumor suppressive effects given its IGF-dependent and -independent apoptosis-promoting properties. If successful, our findings may provide new avenues for the treatment of this disease and pave the way towards larger clinical studies involving IGFBP-3.

前列腺癌男性的IGFBP-3疗法的发展 在此孢子赠款中得出的初步数据中，我们证明了IGFBP-3与 线粒体！和与核凋亡相关的蛋白质，表明IGFBP-3的作用需要快速 内在化，磷酸化以及与多室核受体RXRA和 NUR77导致凋亡途径的快速诱导。特别是，我们描述了核 - NUR77对IGFBP-3处理的线粒体易位是IGFBP-3的关键事件 级联，可以作为IGFBP-3反应性的生物标志物。重要的是，我们还表明 体内给药的体内给予小鼠的异种移植物会导致大量肿瘤抑制和 抑制血管生成和IGFBP-3在体内的作用时，当给出单个时。 治疗，并与其他药物结合使用。我们的工作在进行前进方面发挥了作用 该领域达到当前状态，在这种孢子更新中，我们建议进一步研究IGFBP-的作用 3作为前列腺癌男性的疗法。我们的具体目的是（1）开发组织病理学测定法 前列腺癌中的IGFBP-3途径分子评估其在确定疾病预后的作用 以及它们充当IGFBP-3活性对前列腺癌活性的替代组织生物标志物的能力（例如。 NUR77亚细胞定位）；并确定使用孢子组织阵列资源，如果基线 IGFBP-3，NUR77和RXRA的肿瘤染色水平预测了前列腺患者的临床结果 癌症。 （2）在具有CAP的男性中进行IGFBP-3的A期1 B剂量反应新辅助试验。这 该研究的主要目标是评估毒性并确定由分子定义的活性剂量 使用包括在AIM 1中开发的测定法的诱导凋亡。次要目标是使用 基因组和蛋白质组学分析以鉴定其他治疗的替代标记。 （3）优化IGFBP-3 在启动大型2期研究之前，在体内小鼠模型中治疗前列腺癌。这个目标是 反向翻译将基于前面的临床研究。我们的目标是确定药物 与IGFBP-3协同作用，例如IGF受体抑制剂，EGF受体拮抗剂和营养剂 包括POM X。一起，这些努力将有助于促进与理性IGFBP-3相关的发展 评估其在前列腺癌中的疗效的疗法和工具。作为针对其他的第一个临床试验 IGF轴的组件已经在进行中，我们认为IGFBP-3将有其他肿瘤 鉴于其IGF依赖性和非依赖性细胞凋亡特性的抑制作用。如果 成功，我们的发现可能为治疗这种疾病提供新的途径，并为方式铺平道路 涉及涉及IGFBP-3的较大临床研究。