(PQD5) Avatar-directed Treatment for Ovarian Cancer

(PQD5) 卵巢癌的阿凡达定向治疗

• 批准号: 8848362
• 负责人: Saravut Weroha
• 金额: $ 64.27万
• 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/8848362
• 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; Health; 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 marker; predictive modeling; response; statistics; tumor; tumor microenvironment

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.

描述（由申请人提供）：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。这些统计数据强调了需要更好地了解这种癌症的生物学和改进的治疗方法。为了解决这个问题，我们已经开发了治疗初治，腹腔内移植，患者来源的异种移植物在SCID小鼠从卵巢癌，原发性腹膜癌和输卵管癌的连续患者的发展新的治疗和OC生物学的理解。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，移植率非常高（约70 - 75%）。这些模型在组织学和分子学上准确地概括了源患者的肿瘤。最重要的是，Avatar模型对细胞毒性化疗的反应与患者结局一致。具体而言，铂类耐药OC（PR-OC）患者的Avatars对铂类化疗无反应。相反，Avatar对铂类敏感OC患者的铂类化疗反应消退。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）开发Avatar模型：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、聚乙二醇化脂质体多柔比星）的MTD。患者的个体Avatar模型将在存在基于铂的化疗的情况下扩展，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时间的干预措施。为了适应生成用于指导其他机构患者化疗的Avatar模型，我们将评估从马约诊所-亚利桑那州和马约诊所-佛罗里达州运送到马约诊所-罗切斯特的肿瘤以高速率生成模型的可行性。2)阿凡达最佳化疗药物的确定。我们将确定单个铂类耐药Avatar模型对四种补救化疗药物的敏感性，并在每位患者发生PR-OC时为她推荐一种“获胜”治疗（或多种治疗）。将进行阵列CGH、SNP和转录组分析，以识别对单个药物的应答特征，通过比较单个药物以去除全身化疗应答特征组分，将增强对单个药物的应答特征。3)Avatar导向治疗的临床试验。使用个体Avatar反应数据，治疗将针对II期临床试验中患者的一种补救化疗药物。Avatar反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特征。未来的研究将旨在验证签名。