(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（由适用提供）：2012年，估计有22,300名美国妇女将发展卵巢癌（OC），而15,500名将死于这种疾病。这些统计数据凸显了需要改善对这种癌症生物学的理解和改进治疗方法的必要性。为了解决这个问题，我们已经在保守的卵巢，原发性腹膜和输卵管癌的SCID小鼠的SCID小鼠中开发了治疗，腹膜内的，患者衍生的异种移植，以开发新的治疗和对OC生物学的了解。迄今为止，我们已经成功地从所有亚型的OC患者那里雕刻了160多个单独的模型，这些模型以非常高的速度植入（约70-75％）。这些模型可以准确地从组织学和分子上概括源患者的肿瘤。最重要的是，阿凡达模型对细胞毒性化疗的反应与患者结局一致。具体而言，抗铂OC（PR-OC）的患者的头像对基于铂的化学疗法反应不反应。相反，阿凡达（Avatar）响应基于铂的化学疗法而响应铂敏感OC患者的化学疗法。现在，我们建议使用AVATAR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）开发阿凡达模型：我们将确定PR-OC患者（拓扑替克，紫杉醇，吉西他滨，pegypy脂肪体脂质体阿霉素）患者的四种标准打捞剂的MTD。患者的单个头像模型将在存在基于铂的化学疗法的情况下扩展，以概括PR-OC患者的肿瘤化学疗法反应性。为了优化我们的方法论，我们将评估旨在提高植入率和时间的几种干预措施。预计会在其他机构的患者中发电用于指导化疗的产生，我们将评估从Mayo诊所 - 阿里桑那和梅奥临床纤维化的肿瘤运送到梅奥临床诊所的可行性。 2）确定化身的最佳化学疗法。我们将确定单个耐铂的化身模型对四种打捞化疗剂的敏感性，并在她开发PR-OC时为每个患者建议对每个患者进行“胜利”治疗（或治疗）。将执行阵列CGH，SNP和转录组分析，以确定对单个药物的响应的签名，通过在各个药物之间进行比较，可以增强其去除广义化学疗法响应能力签名成分。 3）阿凡达指导治疗的临床试验。使用单独的头像响应数据，将在II期临床试验中针对患者的挽救化疗剂之一进行治疗。化身反应与患者结局之间的一致性将用于进一步丰富对四种化学疗法剂的反应的签名。然后，未来的研究将旨在验证签名。