Rational design of drug combinations to target chemotherapy resistance in high-grade serous ovarian cancer via metabolomic profiling of patient-derived organoids

项目 摘要/摘要 这 耐药 疾病 费率 女人, 代谢组学 抵抗， 的 演算法 至 监管部门 的 有机化合物。 已确定 治疗方法 该项目旨在为药物的设计重新编程开发一个新的、跨学科的框架-- 肿瘤向反应状态发展。这项试点将专注于高级别浆液性卵巢癌， 高达20%的患者对卡铂初次治疗无效，80%的患者复发 一开始有反应的病人。我们将从12个难治性和12个响应性肿瘤组织中获得原发肿瘤组织 种植患者衍生的有机化合物作为患者肿瘤的个性化体外模型，并执行 对组织样本和有机体进行分析。这将使我们能够识别新陈代谢状态 这将精确定位耐药肿瘤用来逃避作用的分子逃逸机制 化疗药物。在项目的第二阶段，我们将开发一种新的计算方法，L 这预测了哪种其他药物最有可能将肿瘤重新编程为对卡铂敏感的状态。 为此，我们将把抗性的代谢图谱映射到一个整合的代谢、信号和 绘制路径图，然后识别目标位于预期效果上游的药物。在最后一部分 这个项目，我们将选择得分最高的预测，并在 具体地说，我们希望通过用 毒品。如果成功，该项目将为组合的合理设计建立一个新的范式 治疗难治性肿瘤。 F F

Project Summary/Abstract This resistant disease rates women, metabolomics resistance, of algorithm To regulatory of organoids. identified therapies project aims to develop a novel, interdisciplinary framework for the designed reprogramming of drug- tumors towards a responsive state. This pilot will focus on high-grade serous ovarian cancer, a with up to 20% o patients being refractory to primary treatment with carboplatin, and 80% relapse of initially responsive patients. We will obtain primary tumor tissue rom 12 refractory and 12 responsive grow patient-derived organoids as a personalized in vitro model of the patients' tumors, and perform profiling on both tissue samples and organoids. This will allow us to identify metabolic states of which will pinpoint the molecular escape mechanisms resistant tumors employ to evade the action the chemotherapeutic agent. In the second phase of the project, we wil l develop a novel computational that predicts which other drug is most likely to reprogram the tumor into a carboplatin-sensitive state. this end, we will map the metabolic profiles of resistance onto an integrated metabolic, signaling and pathway map to then identify drugs whose targets are upstream of the desired effect. In the last part the project, we will choose the highest-scoring predictions and validate them experimentally on the Specifically, we expect to render resistant organoids responsive by pretreating them with the drugs. If successful, this project will establish a new paradigm for the rational design of combination in refractory tumors. f f