Angiogenic biomarker discovery to direct bevacizumab therapy in cervical cancer - Blood-based Angiome Profiling: An ancillary analysis of GOG-0240

血管生成生物标志物的发现可指导宫颈癌贝伐单抗治疗 - 基于血液的血管瘤分析：GOG-0240 的辅助分析

• 批准号: 10112674
• 负责人: ANDREW B. NIXON
• 金额: $ 26.8万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112674
• 关键词: Address; Angiogenesis Inhibitors; Biological Markers; Biological Response Modifier Therapy; Blood; Cancer Burden; Cancer Patient; Cessation of life; Clinical; Combination immunotherapy; Development; Disease; Enrollment; Event; Foundations; Future; Goals; Growth Factor; Gynecologic Oncology Group; Healthcare; Hemangioma; Hypertension; Immune response; Immunotherapy; Inflammation; Inflammatory Response; Interleukin-6; Laboratories; Maintenance; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Measures; Outcome; Paclitaxel; Participant; Patients; Phase; Plasma; Predictive Factor; Progression-Free Survivals; Proteins; Randomized; Recurrence; Research; Resources; Role; Sampling; Signal Pathway; Solid Neoplasm; Specimen; Statistical Data Interpretation; System; Technology; Testing; Toxic effect; Tumor Angiogenesis; United States Food and Drug Administration; Woman; angiogenesis; base; bevacizumab; biomarker discovery; cancer therapy; candidate marker; chemotherapy; cost; cost effective; cytokine; design; improved; improved outcome; interest; kidney cell; novel; open label; phase III trial; placebo controlled trial; predict clinical outcome; predictive marker; prognostic; prognostic of survival; research and development; response; survival outcome; taxane; therapy development; thrombotic; treatment comparison; treatment group; tumor microenvironment

Project Summary The anti-angiogenic agent bevacizumab (BEV) is one of the most effective forms of biologic therapy developed thus far for cervical cancer (CC). However, response is variable, BEV is expensive, and significant toxicity may occur. Given the projected increase in the global burden of cancer and limited health care resources, it is imperative that research be conducted to define patients that will truly benefit from expensive therapies. The development of an angiogenic biomarker to direct the use of BEV could maximize benefit, as well as minimize toxicity and cost. My collaborator, Dr. Andrew Nixon, and his team at Duke have developed a protein-based plasma multiplex array (angioma) that consists of 26 growth factors and cytokines involved in angiogenesis and inflammation. We propose to evaluate our most promising biomarker, interleukin-6 (IL-6), which has demonstrated predictive efficacy for BEV in other solid tumors, in women with advanced metastatic CC enrolled on the Gynecologic Oncology Group (GOG) 240. Our primary aim is to determine if IL-6 levels can be utilized to direct BEV therapy for women with CC. The pivotal phase III GOG-0240, a 2x2 bifactorial placebo- controlled trial of taxane-based chemotherapy with and without BEV is the ideal platform to assess biomarkers. Our specific aims will determine if (a) baseline IL-6 is predictive of BEV benefit based on survival outcomes, (b) other angiome biomarkers are predictive and/or prognostic of survival outcomes in women with advanced CC and c) angiome biomarker change is associated with outcome and response. Plasma samples at baseline and pre-cycle 2 from GOG-0240 will be analyzed in Dr. Nixon’s laboratory using several multiplex systems including technology from Quanterix Corporation, MesoScaleDiscovery, and Protein Simple (R&D Systems). Statistical analyses will be performed to identify and validate biomarkers of interest. Kaplan-Meier plots and log-rank tests will compare treatment groups. Our ultimate goal is to improve the outcome for women with CC by rationally directing BEV therapy; minimizing toxicity and cost; and identifying novel targets to develop future anti-angiogenic therapies. We anticipate that our research will help to harmonize analyses across other malignancies, which will be critical for understanding if IL-6 and other candidate biomarkers predictive of BEV efficacy are, or are not, disease specific.

项目摘要 抗血管生成剂贝伐单抗（BEV）是开发的最有效的生物治疗形式之一 对于宫颈癌（CC）而言。但是，响应是可变的，BEV很昂贵，并且很大的毒性可能 发生。考虑到全球癌症燃烧和有限的医疗保健资源的预计增加，这是 必须进行研究以定义将真正受益于昂贵疗法的患者。 开发用于指导BEV使用的血管生成生物标志物可以最大程度地提高益处，并且最小 毒性和成本。我的合作者安德鲁·尼克松（Andrew Nixon）和他在杜克大学的团队开发了一个基于蛋白质的 血浆多重阵列（血管瘤）由26种生长因子和细胞因子组成 和炎症。我们建议评估我们最有前途的生物标志物Interleukin-6（IL-6），它具有 在其他实体瘤中证明了BEV的预测效率 注册妇科肿瘤学组（GOG）240。我们的主要目的是确定IL-6水平是否可以 用于指导CC女性的BEV治疗。关键阶段III GOG-0240，2x2双分配安慰剂 - 有或没有BEV的基于紫杉烷的化学疗法的对照试验是评估生物标志物的理想平台。 我们的具体目的将确定（a）基线IL-6是否基于生存结果预测BEV益处，（b） 其他血管群生物标志物是晚期CC女性生存结果的预测性和/或预后 c）血管组生物标志物变化与结果和反应有关。基线和 GOG-0240的前循环2将在尼克松博士的实验室中使用多个多重系统进行分析 包括来自Quanterix Corporation，介质甲发现和蛋白质简单（R＆D系统）的技术。 将进行统计分析以识别和验证感兴趣的生物标志物。 Kaplan-Meier情节和 对数秩检验将比较治疗组。我们的最终目标是改善CC女性的结果 通过合理指导BEV治疗；最小化毒性和成本；并确定新的目标以发展未来 抗血管生成疗法。我们预计我们的研究将有助于协调其他人的分析 恶性肿瘤，这对于理解IL-6和其他候选生物标志物是否可以预测BEV至关重要 疗效是或不具体疾病。