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

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.

IGFBP-3 治疗男性前列腺癌的进展 在利用 SPORE 资助获得的初步数据中，我们证明了 IGFBP-3 与 线粒体！和核凋亡相关蛋白，并表明 IGFBP-3 的作用需要快速 内化、磷酸化以及与多室核受体 RXRa 和的关联 Nur77 导致两种快速诱导细胞凋亡的途径。特别是，我们描述了核 Nur77 响应 IGFBP-3 治疗的线粒体易位是 IGFBP-3 中的关键事件 级联反应并可作为 IGFBP-3 反应性的生物标志物。重要的是，我们还表明 对带有异种移植物的小鼠体内施用 IGFBP-3 可显着抑制肿瘤， 抑制血管生成，并且当单独给予 IGFBP-3 时可以观察到其体内作用 治疗，并与其他药物联合使用可增强疗效。我们的工作有助于推动 这个领域到目前的状态，在这次 SPORE 更新中，我们建议进一步研究 IGFBP 的作用- 3 作为男性前列腺癌的治疗方法。我们的具体目标是 (1) 开发组织病理学检测 前列腺癌中的 IGFBP-3 通路分子及其在确定疾病预后中的作用评估 以及它们作为 IGFBP-3 体内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）；并使用 SPORE 组织阵列资源确定基线是否处于内部 IGFBP-3、Nur77 和 RXRa 的肿瘤染色水平可预测前列腺患者的临床结果 癌症。 (2) 在患有 CaP 的男性中进行 IGFBP-3 的 1 b 期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分子定义的活性剂量 使用目标 1 中开发的检测方法诱导细胞凋亡。次要目标是使用 基因组和蛋白质组分析以确定其他治疗替代标记。 (3) 优化IGFBP-3 在开始更大规模的二期研究之前，在体内小鼠模型中治疗前列腺癌。这个目标是一个 反向翻译将建立在先前的临床研究的基础上。我们的目标是确定药物 与 IGFBP-3 协同作用，如 IGF 受体抑制剂、EGF 受体拮抗剂和营养剂 包括Pom X。这些努力共同将有助于促进合理的IGFBP-3相关的发展 评估其对前列腺癌疗效的疗法和工具。作为第一个针对其他疾病的临床试验 IGF轴的组成部分已经在进行中，我们相信IGFBP-3将产生额外的肿瘤 鉴于其 IGF 依赖性和非依赖性细胞凋亡促进特性，具有抑制作用。如果 如果成功的话，我们的研究结果可能会为治疗这种疾病提供新途径并铺平道路 致力于涉及 IGFBP-3 的更大规模的临床研究。