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

项目摘要 抗血管生成剂贝伐单抗（BEV）是生物治疗中最有效的形式之一 宫颈癌（Cervical Cancer，CC）然而，反应是可变的，BEV是昂贵的，并且显著的毒性可能会导致 发生.考虑到全球癌症负担的预计增加和有限的卫生保健资源， 必须进行研究，以确定真正受益于昂贵疗法的患者。的 开发一种血管生成生物标志物来指导BEV的使用，可以最大限度地提高获益， 毒性和成本。我的合作者安德鲁尼克松博士和他在杜克大学的团队开发了一种基于蛋白质的 血浆多重阵列（血管瘤），由26种参与血管生成的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，白细胞介素-6（IL-6）， 在晚期转移性CC女性患者中，证实了BEV在其他实体瘤中的预测疗效 在妇科肿瘤组（GOG）注册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。关键的III期GOG-0240，一种2x2双因子安慰剂， 基于紫杉烷的化疗与BEV的对照试验是评估生物标志物的理想平台。 我们的具体目标是确定（a）基线IL-6是否可预测基于生存结局的BEV获益，（B） 其他血管组生物标志物可预测和/或预后晚期CC妇女的生存结局 和c）血管组生物标志物变化与结果和反应相关。基线血浆样本和 将在尼克松博士的实验室中使用多个多重系统分析GOG-0240的前循环2 包括来自Quanterix公司、MesoScaleDiscovery和Protein Simple（R&D Systems）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曲线和 对数秩检验将比较治疗组。我们的最终目标是改善女性CC患者的结局 通过合理指导BEV治疗;最大限度地减少毒性和成本;并确定新的靶点以开发未来 抗血管生成疗法。我们预计，我们的研究将有助于协调其他国家的分析。 恶性肿瘤，这对于理解IL-6和其他候选生物标志物是否预测BEV至关重要 功效是或不是疾病特异性。

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.