(PQD5) Avatar-directed Treatment for Ovarian Cancer

项目摘要 2012年，估计有22，300名美国妇女将患上卵巢癌（OC），15，500人将死于此 疾病这些统计数据强调了需要更好地了解这种癌症的生物学， 改善治疗方法。为了解决这个问题，我们开发了一种未经治疗的腹腔内治疗方法， 在来自连续卵巢癌、原发性腹膜癌、 和输卵管癌，用于开发新的治疗方法和了解OC生物学。到 迄今为止，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， 其以非常高的速率（~70-75%）移植。这些模型准确地概括了源患者的肿瘤 从组织学和分子学角度来看最重要的是，Avatar模型对细胞毒性化疗的反应是 与患者结局一致。具体来说，铂类耐药OC（PR-OC）患者的Avatars 对含铂化疗无反应。相反，Avatar回归以响应基于白金的 化疗源自铂敏感型OC患者。我们现在建议使用Avatar模型 PR-OC患者的直接治疗。为了实现这些目标，我们建议：1）开发Avatar 模型：我们将确定PR-OC患者的四种标准挽救剂的MTD（托泊替康， 紫杉醇、吉西他滨、聚乙二醇化脂质体阿霉素）。患者的个人头像模型将扩大 在存在铂类化疗的情况下，为了概括肿瘤化疗反应性， PR-OC患者为了优化我们的方法，我们将评估几种干预措施， 提高植入率和植入时间。为了适应《阿凡达》这一代 在其他机构的患者中指导化疗的模型，我们将评估产生 从亚利桑那州马约诊所和佛罗里达州马约诊所运送到马约诊所的肿瘤模型的高比率， 罗切斯特。2)Avatars最佳化疗药物的确定。我们将确定敏感性 的个体铂耐药Avatar模型对四种补救化疗药物的耐受性，并推荐 在患者发展PR-OC时，为每位患者提供“获胜”治疗（或治疗）。阵列CGH、SNP和 将进行转录组分析，以鉴定对单个药物的应答特征， 通过比较单个药物来增强，以消除全身化疗反应性 签名组件。3)Avatar导向治疗的临床试验。使用个体化身响应数据， 在II期临床试验中，治疗将针对患者的一种补救化疗剂。 Avatar响应和患者结局之间的一致性将用于进一步丰富 对四种化疗药物的反应。未来的研究将旨在验证签名。

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.