(PQD5) Avatar-directed Treatment for Ovarian Cancer

描述（由申请人提供）：2012年，估计有22,300名美国女性将患上卵巢癌（OC）， 15,500人将死于这种疾病。这些统计数据突出表明，需要进一步了解这种癌症的生物学特性，并改进治疗方法。为了解决这个问题，我们在连续患有卵巢癌、原发性腹膜癌和输卵管癌的SCID小鼠中开发了治疗性的、腹腔内移植的、患者来源的异种移植物，以开发新的治疗方法和了解卵巢癌生物学。迄今为止，我们已经成功移植了来自所有亚型OC患者的160多个个体模型，其移植率非常高（~70-75%）。这些模型准确地概括了源患者的肿瘤的组织学和分子结构。最重要的是，Avatar模型对细胞毒性化疗的反应与患者的预后一致。具体来说，铂耐药OC （PR-OC）患者的avatar对铂基化疗没有反应。相反，对于铂敏感OC患者的铂基化疗，Avatar出现回归。我们现在建议使用Avatar模型来指导PR-OC患者的治疗。为了达到这些目标，我们建议：1)Avatar模型的开发：我们将确定PR-OC患者的四种标准挽救剂（拓扑替康、紫杉醇、吉西他滨、聚乙二醇脂质体阿霉素）的MTD。在铂类化疗的情况下，患者的个体Avatar模型将得到扩展，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时间的干预措施。为了适应阿凡达模型的生成以指导其他机构患者的化疗，我们将评估从亚利桑那州梅奥诊所和佛罗里达州梅奥诊所运送到罗切斯特梅奥诊所的肿瘤以高速率生成模型的可行性。我们将确定单个抗铂Avatar模型对四种补救性化疗药物的敏感性，并在每个患者出现PR-OC时为其推荐一种（或多种）“获胜”治疗。阵列CGH、SNP和转录组分析将用于确定对单个药物的反应特征，通过对单个药物的比较来消除普遍的化疗反应特征成分，这将得到加强。3)阿凡达导向疗法的临床试验。使用Avatar的个体应答数据，治疗将直接针对II期临床试验患者的一种补救性化疗药物。Avatar反应与患者预后之间的一致性将用于进一步丰富对四种化疗药物反应的特征。未来的研究将致力于验证这一特征。

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.