(PQD5) Avatar-directed Treatment for Ovarian Cancer

(PQD5) 卵巢癌的阿凡达定向治疗

• 批准号: 8682446
• 负责人: PAUL HALUSKA
• 金额: $ 62.16万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-13 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8682446
• 关键词: Address; American; Arizona; Back; Biology; Cancer Biology; Cell Line; Characteristics; Clear Cell; Clinic; Clinical; Clinical Trials; Collection; Cytotoxic Chemotherapy; Data; Development; Disease; Endometrial; Engraftment; Florida; Funding; Future; Gene Expression Profile; Generations; Goals; Histologic; Individual; Institution; Intervention; Malignant neoplasm of fallopian tube; Malignant neoplasm of ovary; Methodology; Modeling; Mucinous; Nature; Outcome; Ovarian; Ovarian Carcinoma; Paclitaxel; Papillary; Pathway interactions; Patient Agents; Patients; Peritoneal; Phase II Clinical Trials; Physicians; Platinum; Positioning Attribute; Proteins; Recurrence; Research; Resistance; SCID Mice; Serous; Shipping; Ships; Source; Sterically Stabilized Liposome; Time; Topotecan; Translating; Woman; Work; Xenograft procedure; base; cancer cell; chemotherapeutic agent; chemotherapy; falls; gemcitabine; improved; novel; novel therapeutics; predictive modeling; public health relevance; response; response marker; statistics; tumor; tumor microenvironment

Project Summary In 2012, an estimated 22,300 American women will develop ovarian carcinoma (OC) and 15,500 will die of this disease. These statistics highlight the need for improved understanding of the biology of this cancer and improved approaches to therapy. To address this, we have developed treatment-na¿ve, intraperitoneally- engrafted, patient-derived xenografts in SCID mice from consecutive patients with ovarian, primary peritoneal, and fallopian tube cancers for the development of novel therapeutics and understanding of OC biology. To date, we have been successful in engrafting over 160 individual models from OC patients of all subtypes, which engraft at a very high rate (~70-75%). These models accurately recapitulate the source patients' tumor histologically and molecularly. Most importantly, the response of Avatar models to cytotoxic chemotherapy is concordant with patient outcomes. Specifically, patients with platinum-resistant OC (PR-OC) have Avatars that do not respond to platinum-based chemotherapy. Conversely, Avatar regress in response to platinum-based chemotherapy originating from patients with platinum-sensitive OC. We now propose to use Avatar models to direct therapy in patients with PR-OC. To reach these goals, we propose to: 1) Development of Avatar models: We will determine the MTD of the four standard salvage agents for patients with PR-OC (topotecan, paclitaxel, gemcitabine, pegylated liposomal doxorubicin). Patients' individual Avatar models will be expanded in the presence of platinum-based chemotherapy, to recapitulate the tumors chemotherapy responsiveness in the patient with PR-OC. To optimize our methodology we will evaluate several interventions aimed at improving the rate of and time to engraftment. In anticipation of accommodating the generation of Avatar models for directing chemotherapy in patients from other institutions, we will assess the feasibility of generating models at a high rate with tumor shipped from the Mayo Clinic-Arizona and Mayo Clinic-Florida to Mayo Clinic- Rochester. 2) Determination of optimal chemotherapy agent for Avatars. We will determine the sensitivity of the individual platinum-resistant Avatar models to the four salvage chemotherapy agents and recommend a 'winning' treatment (or treatments) for each patient at the time she develops PR-OC. Array CGH, SNP and transcriptome profiling will be performed to identify the signature of response to individual agents, which will be enhanced by comparisons among the individual agents to remove generalized chemotherapy responsiveness signature components. 3) Clinical trial of Avatar-directed therapy. Using the individual Avatar response data, treatment will be directed to one of the salvage chemotherapy agents in patients on a phase II clinical trial. Concordance between the Avatar response and patient outcomes will be used to further enrich the signature of response to the four chemotherapy agents. Future studies will then aim to validate the signature.

项目摘要 2012年，估计有22,300名美国妇女将患上卵巢癌，其中15,500人将死于卵巢癌 疾病。这些统计数据突显了需要更好地了解这种癌症和 改进了治疗方法。为了解决这个问题，我们开发了一种治疗方法--不，通过腹膜内-- 在SCID小鼠体内植入患者来源的异种移植物，这些移植物来自连续的卵巢，原发腹膜， 和输卵管癌，为发展新的治疗方法和了解OC生物学提供帮助。至 到目前为止，我们已经成功地从所有亚型的OC患者中移植了160多个个体模型， 嫁接率很高(~70%~75%)。这些模型准确地概括了原始患者的肿瘤。 从组织学和分子水平上讲。最重要的是，阿凡达模型对细胞毒化疗的反应是 与患者的结果相一致。具体地说，耐铂卵巢癌(PR-OC)患者的化身 对以铂为基础的化疗没有反应。相反，阿凡达对白金的反应是倒退 化疗来源于对铂敏感的卵巢癌患者。我们现在建议使用阿凡达模型来 PR-OC患者的直接治疗。为了实现这些目标，我们建议：1)开发阿凡达 模型：我们将测定PR-OC患者四种标准抢救剂的MTD(拓扑替康， 紫杉醇、吉西他滨、聚乙二醇化阿霉素脂质体)。患者的个人阿凡达模型将被扩展 在以铂为基础的化疗存在的情况下，概述肿瘤的化疗反应性 PR-OC患者。为了优化我们的方法，我们将评估几种旨在 提高植入率和植入率。在期待适应阿凡达一代的情况下 指导其他机构患者化疗的模式，我们将评估生成 有肿瘤的模特从亚利桑那州的梅奥诊所和佛罗里达州的梅奥诊所运往梅奥诊所- 罗切斯特。2)阿凡达最佳化疗药物的确定。我们将确定敏感度 对四种挽救化疗药物的个人抗铂阿凡达模型，并建议 在患者出现PR-OC时为每个患者提供“获胜”治疗(或多个治疗)。数组CGH、SNP和 将进行转录组分析，以确定对个别试剂的响应签名，这将是 通过单个药物之间的比较来增强消除全身化疗反应的能力 签名组件。3)阿凡达定向治疗的临床试验。使用个人化身响应数据， 治疗将针对正在进行第二阶段临床试验的患者使用其中一种抢救化疗药物。 阿凡达反应和患者结果之间的一致性将被用来进一步丰富 对四种化疗药物的反应。未来的研究将致力于验证签名。