(PQD5) Avatar-directed Treatment for Ovarian Cancer

描述(申请人提供)：2012年，估计有22,300名美国妇女将患上卵巢癌(OC)，15,500人将死于这种疾病。这些统计数据突出表明，需要更好地了解这种癌症的生物学原理，并改进治疗方法。为了解决这一问题，我们从连续的卵巢癌、原发腹膜癌和输卵管癌患者身上开发了治疗SCID小鼠的治疗方法--原始的、腹膜内植入的、患者来源的异种移植，用于开发新的治疗方法和了解OC生物学。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，植入率很高(~70-75%)。这些模型从组织学和分子学上准确地概括了来源患者的肿瘤。最重要的是，阿凡达模型对细胞毒性化疗的反应与患者的预后一致。具体地说，铂耐药卵巢癌(PR-OC)患者的化身对以铂为基础的化疗没有反应。相反，阿凡达对铂类敏感OC患者的铂类化疗反应减退。我们现在建议使用阿凡达模型来指导PR-OC患者的治疗。为了实现这些目标，我们建议：1)阿凡达模型的建立：我们将测定PR-OC患者四种标准救助剂(拓扑替康、紫杉醇、吉西他滨、聚乙二醇脂质体阿霉素)的MTD。患者的个体化身模型将在基于铂的化疗存在的情况下进行扩展，以概括PR-OC患者的肿瘤化疗反应性。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的干预措施。为了适应阿凡达模型的生成以指导来自其他机构的患者的化疗，我们将评估从亚利桑那州的梅奥诊所和佛罗里达州的梅奥诊所向梅奥诊所-罗切斯特运送肿瘤的高速率生成模型的可行性。2)阿凡达最佳化疗药物的确定。我们将确定个体抗铂阿凡达模型对四种挽救化疗药物的敏感性，并在患者出现PR-OC时为其推荐一种(或多种)获胜的治疗方法。将进行阵列CGH、SNP和转录组分析，以确定对个别药物的应答签名，并将通过单个药物之间的比较来增强，以消除普遍的化疗应答签名成分。3)阿凡达定向治疗的临床试验。使用阿凡达个体反应数据，治疗将针对第二阶段临床试验中患者的一种挽救化疗药物。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签名。未来的研究将致力于验证签名。

DESCRIPTION (provided by applicant): 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.