Validation of a genomic signature that predicts for sub-optimal debulking of epithelial ovarian cancer

验证预测上皮性卵巢癌次优减灭的基因组特征

• 批准号: 10150186
• 负责人: Michael Birrer
• 金额: $ 9.6万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10150186
• 关键词: Validation; genomic; signature; predicts; sub

Project Summary Epithelial ovarian cancer (EOC) affects approximally 21,000 women a year in the USA resulting in 13,000 deaths. Standard treatment includes debulking surgery followed by adjuvant chemotherapy. For 80% of women this treatment is effective and prolongs survival. However, in 20% of women the cancer is extensively disseminated through the peritoneum at time of surgery which complicates the surgical procedure and does not allow optimal tumor debulking. For these women, tumor debulking is not effective and they experience complicated and prolonged postoperative recovery. A recent randomized phase III trial demonstrated that neoadjuvant chemotherapy with interval debulking surgery is an effective alternative treatment for ovarian cancer patients and may be the ideal approach for patients who cannot undergo optimal up front debulking. Thus there is a need to identify and stratify patients based on their response to debulking surgery and develop more effective surgical and chemotherapeutic approaches targeting sub-optimally debulked tumors To address this need, we performed a meta-analysis of gene expression data using publicly available profiles of 1,525 ovarian cancers and identified 198 genes that were highly expressed in tumors that were not optimally debulked. We refer to these genes as “debulking signature. Ontologic pathway analysis of the debulking signature showed hyper-activation of a specific oncogenic signaling responsible for malignant cancer behaviors such as dissemination resistance to chemotherapy, i.e. the TGF- pathway. Thus, the signature may serve as a predictive biomarker for patients who would benefit from up-front surgery and provide a biological rationale for novel targeted therapies of tumors that cannot be optimally debulked. The goal of this project is to develop a validated genomic signature which can be developed into clinical diagnosis, and test in ovarian cancer mouse models whether targeting one of the most enriched pathways of this signature, TGF-β, is effective. We will validate the 198 genes identified as highly expressed in EOC that are not optimally debulked using two independent tissue arrays and establish an optimal genomic signature that can be used for pre-operative diagnosis of these tumors (aim 1). We will then perform preclinical studies testing whether inhibitors of the TGF- pathway currently being used in clinical trials for other cancers, improve management of disseminated ovarian cancer models in mice (aim 2). Altogether, we will establish a predictive biomarker that assists the surgeon and patient to choose the best surgical procedure to be applied to an EOC patient, as well as identify a new adjuvant chemotherapeutic option that improves therapeutic outcome. If successful, these studies will spare women from therapeutic suffering and prolong their lives.

项目摘要 上皮卵巢癌（EOC）每年在美国影响约21,000名女性，导致13,000 死亡人数。标准治疗包括脱身手术，然后进行调整化疗。为80％ 妇女这种治疗是有效的，可以延长生存。但是，在20％的女性中，癌症是广泛的 手术时通过腹膜传播，这使手术过程复杂化并做 不允许最佳的肿瘤缓解。对于这些妇女，肿瘤的缓解无效，她们经历了 术后复杂和延长的恢复。 最近的一项随机III期试验表明，新辅助化学疗法随着间隔的延伸 手术是卵巢癌患者的有效替代治疗方法，可能是 无法获得最佳前端的患者。有必要识别和分层患者 基于他们对延展手术的反应，并发展出更有效的手术和化学治疗性 针对亚次优肿瘤的方法 为了满足这种需求，我们使用公开可用的配置文件对基因表达数据进行了荟萃分析 在1,525种卵巢癌中，并鉴定出198个基因，这些基因在肿瘤中高度表达的基因 淘汰。我们将这些基因称为“延迟签名。 签名显示了负责恶性癌的特定致癌信号的过度激活 诸如对化学疗法的耐药性，即TGF-途径等行为。那，签名可能 作为将受益于前期手术并提供生物学的患者的预测生物标志物 无法最佳地延伸的新型靶向疗法的基本原理。 该项目的目的是开发一个经过验证的基因组签名，可以将其发展为 临床诊断和在卵巢癌小鼠模型中测试是否针对最多 该特征的富集途径TGF-β是有效的。我们将验证198个鉴定为高度的基因 在EOC中表达的，该EOC未使用两个独立组织阵列最佳地延伸并建立一个 最佳基因组特征可用于这些肿瘤的术前诊断（AIM 1）。然后我们会 进行临床前研究测试目前在临床试验中使用的TGF-途径的抑制剂是否 对于其他癌症，可以改善小鼠散布卵巢癌模型的管理（AIM 2）。 总之，我们将建立一个预测性生物标志物，以帮助外科医生和患者选择最佳 要应用于EOC患者的手术程序，并确定了新的调整化学治疗选择 这改善了治疗结果。如果成功，这些研究将使女性免于治疗 并延长他们的寿命。