Design, Develop, Validate, and Implement Biomarkers for Clinical Investigations

设计、开发、验证和实施用于临床研究的生物标志物

• 批准号: 8763741
• 负责人: Liang Cao
• 金额: $ 33.56万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8763741
• 关键词: 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; Adult; Angiogenic Factor; Apoptotic; BAY 54-9085; Biological; Biological Assay; Biological Markers; CCR; Cell Surface Receptors; Cells; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Correlative Study; Data; Development; EGF gene; Enrollment; Evaluation; Fibrinogen; Future; Genetic Markers; Goals; Growth Factor; Immunoassay; Insulin; Insulin-Like-Growth Factor I Receptor; International; Investigation; Journals; KRAS2 gene; Laboratories; Lymphoma; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Manuscripts; Mesothelioma; Modeling; Monoclonal Antibodies; Mutation; Neoplasm Circulating Cells; Non-Small-Cell Lung Carcinoma; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphoproteins; Preparation; Proteins; Recurrence; Refractory; Sampling; Signal Transduction Pathway; Site; Solid Neoplasm; Specimen; Technology; Therapeutic; Thymus Epithelial Neoplasm; Validation; Vascular Endothelial Growth Factors; base; bevacizumab; cancer genetics; cytokine; design; flexibility; genetic analysis; new technology; novel; phase 1 study; phase 2 study; receptor; response; tumor

I. Biomarker Assay Design, Development, and Validation We develop, validate, and implement assays for clinical specimens using electrochemiluminescence (ECL)-based immunoassays. This is the most sensitive and quantitative immunoassay technology platform today. The ECL platform is well suited for this ongoing task because it offers a high degree of flexibility, stability and reliability. It is capable of multiplex analysis to determine the levels of total and phospho-proteins in a single assay well using a limited amount of clinical specimens. Because clinical samples may vary dramatically, the ability to normalize these samples beyond total protein concentration is critical in generating statistically significant data with patient specimens. At the present, we developed, validated and utilized a wide range of biomarker assays, including angiogenic factors, cytokines, cell surface receptors, intracellular phosphoproteins and apoptotic biomarkers. II. Recently Completed Biomarker Studies Currently, we are engaged with 16 clinical protocols at NCI-CCR. For many of these clinical trials, we helped to design, develop, validate, and implement customized biomarker assays for correlative analytical studies. The evaluation of these biomarkers often constitutes a pivotal part of the clinical study for investigational agents. The following are some examples in the studies that we contributed with biomarker analysis at NCI. Several manuscripts are in preparation. 1. Kalra N, Zhang J, Yu Y, Ho M, Merino M, Cao L, Hassan R. Efficacy of anti-insulin-like growth factor I receptor monoclonal antibody cixutumumab in mesothelioma is highly correlated with insulin growth factor-I receptor sites/cell. International journal of cancer. 2012. 2. Speranza G, Gutierrez ME, Kummar S, Strong JM, Parker RJ, Collins J, Yu Y, Cao L, Murgo AJ, Doroshow JH, Chen A. Phase I study of the synthetic triterpenoid, 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO), in advanced solid tumors. Cancer Chemother. Pharmacol. 69: 431-8, 2012. 3. Giaccone G, Rajan A, Berman A, Kelly RJ, Szabo E, Lopez-Chavez A, Trepel J, Lee MJ, Cao L, Espinoza-Delgado I, Spittler J, Loehrer PJ. Phase II Study of Belinostat in Patients With Recurrent or Refractory Advanced Thymic Epithelial Tumors. J. Clin. Oncol. 29: 2052-9, 2011. 4. Kelly RJ, Rajan A, Force J, Lopez-Chavez A, Keen C, Cao L, Yu Y, Choyke P, Turkbey B, Raffeld M, Xi L, Steinberg SM, Wright JJ, Kummar S, Gutierrez M, Giaccone G. Evaluation of KRAS Mutations, Angiogenic Biomarkers, and DCE-MRI in Patients with Advanced Non-Small-Cell Lung Cancer Receiving Sorafenib. Clin. Cancer Res. 17: 1190-9, 2011. 5. Kummar S, Gutierrez ME, Chen A, Turkbey IB, Allen D, Horneffer YR, Juwara L, Cao L, Yu Y, Kim YS, Trepel J, Chen H, Choyke P, Melillo G, Murgo AJ, Collins J, Doroshow JH. Phase I trial of vandetanib and bevacizumab evaluating the VEGF and EGF signal transduction pathways in adults with solid tumours and lymphomas. Eur. J. Cancer. 47: 997-1005, 2011. III. Development of novel technology and applications with circulating tumor cells The ability of use circulating tumor cells (CTC) for cancer genetic and biomarker analysis offer the potential to transform clinical trials and patient management. Substantial effort was made towards CTC purification and subsequently genetic analysis of the CTC cells which results highly promising advances in this field. We have initiated 4 clinical trials in the past year with our CTC technologies, including two prove-of-concept trials with lung and prostate cancer; as well as two drug trials with a goal to provide first-of-the-kind novel enablement for using CTC to guide patient treatment. We expect to double down our effort and to have some significant advances in the near future. Two manuscripts are in preparation.

I. 生物标志物检测设计、开发和验证 我们使用基于电化学发光 (ECL) 的免疫检测来开发、验证和实施临床样本检测。这是当今最灵敏、最定量的免疫分析技术平台。 ECL 平台非常适合这项持续的任务，因为它提供了高度的灵活性、稳定性和可靠性。它能够使用有限数量的临床样本进行多重分析，以确定单次测定孔中的总蛋白和磷酸化蛋白的水平。由于临床样本可能差异很大，因此将这些样本标准化至总蛋白浓度之外的能力对于生成患者样本的统计显着数据至关重要。目前，我们开发、验证和利用了广泛的生物标志物检测，包括血管生成因子、细胞因子、细胞表面受体、细胞内磷蛋白和凋亡生物标志物。二.最近完成的生物标志物研究 目前，我们正在 NCI-CCR 开展 16 项临床方案。对于其中许多临床试验，我们帮助设计、开发、验证和实施用于相关分析研究的定制生物标志物测定。这些生物标志物的评估通常构成研究药物临床研究的关键部分。以下是我们在 NCI 进行的生物标志物分析研究中的一些示例。几份手稿正在准备中。 1. Kalra N，Zhang J，Yu Y，Ho M，Merino M，Cao L，Hassan R。抗胰岛素样生长因子 I 受体单克隆抗体 cixutumumab 在间皮瘤中的疗效与胰岛素生长因子-I 受体位点/细胞高度相关。国际癌症杂志。 2012. 2. Speranza G, Gutierrez ME, Kummar S, Strong JM, Parker RJ, Collins J, Yu Y, Cao L, Murgo AJ, Doroshow JH, Chen A. 合成三萜类化合物 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic 酸 (CDDO) 在晚期实体瘤中的 I 期研究。癌症化疗者。药理学。 69：431-8，2012。 3. Giaccone G、Rajan A、Berman A、Kelly RJ、Szabo E、Lopez-Chavez A、Trepel J、Lee MJ、Cao L、Espinoza-Delgado I、Spittler J、Loehrer PJ。 Belinostat 在复发性或难治性晚期胸腺上皮肿瘤患者中的 II 期研究。 J.克林。安科尔。 29: 2052-9, 2011. 4. Kelly RJ, Rajan A, Force J, Lopez-Chavez A, Keen C, Cao L, Yu Y, Choyke P, Turkbey B, Raffeld M, Xi L, Steinberg SM, Wright JJ, Kummar S, Gutierrez M, Giaccone G. KRAS 突变、血管生成生物标志物和 接受索拉非尼治疗的晚期非小细胞肺癌患者的 DCE-MRI。临床。癌症研究中心。 17: 1190-9, 2011。 5. Kummar S、Gutierrez ME、Chen A、Turkbey IB、Allen D、Horneffer YR、Juwara L、Cao L、Yu Y、Kim YS、Trepel J、Chen H、Choyke P、Melillo G、Murgo AJ、Collins J、Doroshow JH。 vandetanib 和 bevacizumab 的 I 期试验评估成人实体瘤和淋巴瘤中的 VEGF 和 EGF 信号转导途径。欧元。 J.癌症。 47：997-1005，2011 年。利用循环肿瘤细胞开发新技术和应用利用循环肿瘤细胞 (CTC) 进行癌症遗传和生物标志物分析的能力为改变临床试验和患者管理提供了潜力。我们在 CTC 纯化和随后的 CTC 细胞遗传分析方面做出了大量努力，这在该领域取得了非常有前途的进展。去年，我们利用 CTC 技术启动了 4 项临床试验，其中包括两项针对肺癌和前列腺癌的概念验证试验；以及两项药物试验，旨在为使用 CTC 指导患者治疗提供首创的新颖支持。我们期望加倍努力，并在不久的将来取得一些重大进展。两份手稿正在准备中。