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

项目摘要 抗血管生成药物贝伐单抗(bevizumab，bev)是生物治疗中最有效的形式之一。 到目前为止，对于宫颈癌(CC)。然而，反应是可变的，Bev是昂贵的，且显著的毒性可能 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，以确定哪些患者将真正从昂贵的治疗中受益。这个 开发一种血管生成生物标记物来指导BEV的使用可以使益处最大化，也可以将效益降到最低 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已经开发出一种基于蛋白质的 由26种生长因子和参与血管生成的细胞因子组成的血浆多重阵列(血管瘤) 和炎症。我们建议评估我们最有希望的生物标记物白介素6(IL-6)，它已经 BEV在其他实体肿瘤和晚期转移性CC患者中的预测效果 注册加入妇科肿瘤组(GOG)240。我们的主要目标是确定IL-6水平是否可以 用于指导女性CC患者的BEV治疗。关键阶段III GOG-0240，一种2x2双因素安慰剂- 以紫杉烷为基础的化疗在有无BEV的情况下的对照试验是评估生物标志物的理想平台。 我们的具体目标将决定(A)基线IL-6是否基于生存结果预测Bev益处，(B) 其他血管组生物标志物可预测和/或预测晚期CC患者的生存结果 C)血管组生物标记物的改变与预后和反应有关。基线的血浆样本和 来自GOG-0240的前周期2将在尼克松博士的实验室使用几个多路系统进行分析 包括Quanterix公司、MesoScaleDiscovery和Protein Simple(研发系统)的技术。 将进行统计分析，以确定和验证感兴趣的生物标志物。Kaplan-Meier图和 对数等级测试将比较处理组。我们的最终目标是改善女性CC患者的治疗结果 通过合理指导Bev疗法，将毒性和成本降至最低，并确定未来发展的新靶点 抗血管生成疗法。我们预计，我们的研究将有助于协调其他 恶性肿瘤，这将是理解IL-6和其他候选生物标记物是否预测Bev的关键 疗效取决于或不取决于疾病。

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.