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: 7969993
• 负责人: Liang Cao
• 金额: $ 18.14万
• 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/7969993
• 关键词: Angiogenic Factor; Antibodies; Antineoplastic Agents; BAY 54-9085; Biological; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Bone marrow biopsy; CCR; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Collaborations; Correlative Study; Data; Development; Enrollment; Evaluation; Feasibility Studies; Goals; Head and Neck Cancer; Immunoassay; Interleukin-6; Interleukin-8; Investigation; Laboratories; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of thymus; Manuscripts; Marker Discovery; Measures; Mitogen-Activated Protein Kinases; Modeling; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Phase II Clinical Trials; Plasma; Proteins; Proto-Oncogene Proteins c-akt; Radiation; Relative (related person); Rhabdomyosarcoma; Sampling; Services; Signal Transduction; Sirolimus; Specimen; Staging; Technology; Therapeutic; Tissues; Validation; Variant; Vascular Endothelial Growth Factors; androgen independent prostate cancer; assay development; base; cancer therapy; cytokine; design; drug development; flexibility; inhibitor/antagonist; mTOR inhibition; meetings; osteosarcoma; pre-clinical; response; tumor

Background: The development of targeted anti-cancer therapies requires the demonstration of the effects of the investigation agents on the intended target and pathway and the discovery of the markers that can be associated with the response. Thus, we are engaged in detecting the effects of agents on pathway-specific biomarkers and in discovering response biomarkers to be implemented in correlative studies. I. Technology, 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. We have successfully utilized the technology for immunoassays that detect changes in ERK, AKT pathways, mTOR inhibition, angiogenic factors, as well as a variety of cytokines in clinical protocols at NCI. We are currently the only lab at NCI provides services and collaboration with assays on these platform. We are constantly pushing the envelope to come up with new assays capable of meeting the unmet needs in clinical trials. II. Current and Recently Completed Biomarker Studies. Currently, we are engaged with 10 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 following are some examples: 1) For a phase II clinical trial of sorafenib in androgen-independent prostate cancer (PI, William Dahut), our laboratory performed assay validation with the investigational agent sorafenib and implemented assays with bone marrow biopsy specimens to determine its effects on the targeted MAP kinase pathway (Dahut WL, et al. Clin. Cancer Res. 14: 209-14, 2008). 2) For another clinical trial that investigated a combination targeted therapy against ovarian cancer (PI, Elise Kohn), our group developed assays and performed the analysis of angiogenic factor vascular endothelial growth factor (VEGF) and cytokines, including interleukin-6 (IL6) and interleukin-8 (IL8) from plasma obtained from the patients throughout the drug trial period (Azad NS, et al. J. Clin. Oncol. 26: 3709-14, 2008). 3) In another rapamycin trial (PI, Chand Khanna), we measured the changes in the relative changes of S6RP signaling from both osteosarcoma biopsies and peripheral blood mononuclear cells (PBMC) following the administration of rapamycin. Our data showed a highly statistically significant reduction of p-S6RP in PBMC. The p/t-S6RP ratio changed from 25% pre-drug to 0.5% post-drug with p<0.001, with samples obtained from day 2 to the end of the study. Our results further showed that there is a high degree of variation in tumor biopsies. The statistically significant effect of rapamycin on the S6RP pathway can only be demonstrated as p/t-S6RP ratio using our duplex assay capable of quantitatively measuring both p-S6RP and t-S6RP in the same assay well (manuscript submitted). III. Preclinical investigations in support of drug development. We are engaged with a wide range of preclinical investigations in support of clinical studies at NCI. Some examples are: 1) Discovering the predictive biomarker for anti-IGF1R antibodies against rhabdomyosarcoma in collaboration with Dr. Lee Helman. 2) Feasibility studies for anti-IGF1R therapy in thymic cancers with Dr. Giuseppe Giaccone. 3) Evaluation of TORC1/2 inhibitor Palomid 529 in combination with radiation against head and neck cancers in collaboration with Dr. Stephen Yoo of DCTD. 4) Development and evaluation of highly sensitive assay HIF1a assay as a biomarker for HIF1a inhibitors. In summary, biomarker analysis for pharmacodynamic biomarkers and predictive biomarkers is an essential part of early stage cancer drug development. We have unique capabilities in assay development, validation and implementation, and we actively engage clinical trials at NCI.

背景：有针对性的抗癌疗法的发展需要证明调查剂对预期目标和途径的影响以及可以与反应相关的标记物的发现。因此，我们参与检测药物对途径特异性生物标志物的影响，并发现在相关研究中实施的反应生物标志物。 I.技术，测定设计，开发和验证。我们使用电化学发光（ECL）的免疫测定法开发，验证和实施临床标本的测定法。这是当今最敏感和定量的免疫测定技术平台。 ECL平台非常适合这项正在进行的任务，因为它具有高度的灵活性，稳定性和可靠性。它能够使用有限量的临床标本来确定单个测定中的总磷酸蛋白水平和磷酸蛋白质的水平。由于临床样品可能会发生巨大变化，因此将这些样品归一化的能力超出了总蛋白质浓度，对于用患者标本生成统计学上重要的数据至关重要。我们已经成功地利用了该技术来检测ERK，AKT途径，MTOR抑制作用，血管生成因子以及NCI临床方案中各种细胞因子的变化。我们目前是NCI的唯一实验室提供服务和与这些平台上测定法的协作。我们一直在推动信封提出能够满足临床试验中未满足需求的新测定。 ii。当前和最近完成的生物标志物研究。目前，我们在NCI-CCR上使用了10种临床方案。 对于许多临床试验，我们帮助设计，开发，验证和实施定制的生物标志物测定法进行相关分析研究。以下是一些例子：1）对于索拉非尼在雄激素独立的前列腺癌（PI，William Dahut）中的II期临床试验中，我们的实验室对研究剂索拉非尼进行了测定验证，并使用骨髓活检进行了测定，以确定其对靶标MAP KINase Pathway的作用，以确定其对靶标的MAP Kinase Pathway的影响（DAHUT cancer and canci cancion and canci cancy and cancy。 2) For another clinical trial that investigated a combination targeted therapy against ovarian cancer (PI, Elise Kohn), our group developed assays and performed the analysis of angiogenic factor vascular endothelial growth factor (VEGF) and cytokines, including interleukin-6 (IL6) and interleukin-8 (IL8) from plasma obtained from the patients throughout the drug trial period (Azad NS, et al. J. Clin。 3）在另一项雷帕霉素试验（PI，Chand Khanna）中，我们测量了帕帕霉素后，S6RP信号传导的相对变化和外周血单核细胞（PBMC）的相对变化。我们的数据显示，PBMC中P-S6RP的统计学上显着降低。 P/T-S6RP的比率从25％的预药物变为0.5％的药物，p <0.001，从第2天获得的样品到研究结束。我们的结果进一步表明，肿瘤活检有很高的变化。雷帕霉素对S6RP途径的统计显着作用只能证明是使用我们的双链分析的P/T-S6RP比，能够在同一测定法中定量测量P-S6RP和T-S6RP（手稿）。 iii。临床前研究支持药物开发。我们参与了广泛的临床前研究，以支持NCI的临床研究。一些例子是：1）与李·赫尔曼（Lee Helman）博士合作，发现针对横纹肌肉瘤的抗IGF1R抗体的预测生物标志物。 2）与Giuseppe Giaccone博士在胸腺癌中进行抗IGF1R治疗的可行性研究。 3）与DCTD的Stephen Yoo博士合作，评估Torc1/2抑制剂Palomid 529与头颈癌的辐射结合使用。 4）对高度敏感测定HIF1A分析作为HIF1A抑制剂的生物标志物的开发和评估。总之，用于药效生物标志物和预测生物标志物的生物标志物分析是早期癌症药物开发的重要组成部分。我们在测定开发，验证和实施方面具有独特的功能，并且我们在NCI中积极参与临床试验。