BCCMA: Overcoming chemoresistance in ovarian cancer: Identification and validation of biomarkers and targetable drivers of platinum resistance

这个合作优异奖申请（CMA），包括三个项目（CMA 1 -3），解决了一个关键的 卵巢癌（OC）的临床治疗面临的挑战。OC最常见和致命的亚型是 高级别浆液性卵巢癌（HGSOC）。HGSOC的标准治疗结合了外科手术 以铂为基础的化疗进行细胞减灭。诊断为HGSOC的患者通常患有疾病 复发与化疗耐药性的出现有关。临床上必要的关键是增加 HGSOC的生存是为了防止铂耐药（PtR）的发展或确定替代方法， 靶向PtR肿瘤。这个跨学科的合作项目的主要目标是确定新的目标 和HGSOC治疗效果的生物标志物。这就需要更好地理解 导致HGSOC细胞转化为侵袭性、治疗抗性表型。越来越多的证据 支持PtR的一个关键贡献者是癌细胞重新编程为一个更小的细胞的假设。 分化和代谢适应状态。这份由三位知名OC研究人员提出的合作提案 将利用他们的跨学科专业知识和丰富的资源来定义新的耐药机制， OC. CMA 1将使用数字空间分析和系统生物学来提供对PtR的全面理解 优先考虑细胞内在和微环境临床相关的潜在分子途径。独特 临床前免疫活性小鼠模型和共培养模型将用于研究肿瘤的作用 微环境在PtR CMA 2将研究与PtR聚焦出现相关的代谢适应 在PtR HGSOC肿瘤中向脂肪酸氧化的转变。CMA 2将使用与CMA 1&3共享的资源， 细胞生物学和新的单细胞代谢成像来定义PtR HGSOC的独特代谢依赖性。 由于PtR肿瘤对氧化脂质膜诱导的死亡高度敏感，因此铁凋亡的机制 将在用新型代谢靶向剂治疗的PtR模型中进行检查， 在CMA 1。CMA 3将探索复发性HGSOC细胞重编程为更去分化的肿瘤 具有神经内分泌（NE）样特征的亚群。其他肿瘤中越来越多的证据表明进展 到NE样状态导致治疗抗性-这一概念在OC中尚待探索。为了鉴定NE样细胞， OC，匹配患者肿瘤的转录组、蛋白质组、基因脆弱性和药物敏感性 并将评价模型系统在化疗压力下NE样细胞的出现。 现有的药物依赖性数据库将被挖掘，以识别NE样细胞中的药物靶点。药物 将单独或组合作为PtR OC的靶向治疗进行测试， 患者来源的类器官和异种移植模型。NE样细胞的特征包括代谢适应和 将分别用CMA 2和CMA 1探索组织学特征。 CMA 1原理：组织病理学切片评价是确定HGSOC诊断的主要方法 并指导治疗决策。然而，组织病理学载玻片中嵌入的丰富数据尚未被 充分利用这一点来了解PtR的根本原因，并制定个性化的治疗策略。之前 对PtR的研究主要使用癌细胞系，并且集中于细胞内在事件。然而，临床数据 样本表明，组织微环境（TME）是PtR的主要驱动因素。尤其是癌症- 相关的成纤维细胞（CAF）显示在相邻癌细胞中诱导PtR。我们假设- 从病理切片图像中提取的顺序特征与不同的分子谱相关联，例如 特定基因和蛋白质表达、代谢和对特定药物敏感性。我们将联合收割机 在小鼠模型和CAF/癌细胞共培养物中使用测定进行图像分析，以机械地解剖 TME在PtR中的作用。将来自患者载玻片的图像数据与其他组学数据整合将增加一个关键点， 优先考虑生物学和临床相关生物标志物和PtR驱动因素的信息层。

This Collaborative Merit Award application (CMA), consisting of three projects (CMA1-3), addresses a critical challenge in the clinical management of ovarian cancer (OC). The most common and lethal subtype of OC is high-grade serous ovarian carcinoma (HGSOC). Standard treatment for HGSOC combines surgical cytoreduction with platinum-based chemotherapy. Patients diagnosed with HGSOC often suffer from disease relapse associated with the emergence of chemotherapy resistance. The clinically necessary key to increasing survival in HGSOC is to prevent the development of platinum resistance (PtR) or identify alternative means of targeting PtR tumors. The main goal of this interdisciplinary and collaborative project is to identify novel targets and biomarkers of therapeutic efficacy for HGSOC. This requires a better understanding of the mechanisms that result in transformation of HGSOC cells to an aggressive, therapy-resistant phenotype. Increasing evidence supports the hypothesis that a key contributor to PtR is the reprogramming of cancer cells into a less differentiated and metabolically adaptable state. This collaborative proposal by three established OC researchers will leverage their interdisciplinary expertise and rich resources to define new mechanisms of resistance in OC. CMA1 will use digital spatial profiling and systems biology to provide a holistic understanding of PtR as well as prioritize cell-intrinsic and microenvironmental clinically relevant underlying molecular pathways. Unique preclinical immunocompetent mouse models and co-culture models will be used to study the role of the tumor microenvironment in PtR. CMA2 will study metabolic adaptation associated with the emergence of PtR focusing on a shift to fatty acid oxidation in PtR HGSOC tumors. CMA2 will use resources shared with CMA1&3 and cellular biology and novel single cell metabolic imaging to define unique metabolic dependencies of PtR HGSOC. As PtR tumors are highly susceptible to death induced by oxidized lipid membranes, mechanisms of ferroptosis will be examined in PtR models treated with novel metabolism targeting agents, which will be tested with CMA1. CMA3 will explore the reprogramming of recurrent HGSOC cells into more dedifferentiated tumor subpopulations with neuroendocrine (NE)-like features. Mounting evidence in other tumors suggest progression to a NE-like state results in therapy resistance - a concept yet to be explored in OC. To identify NE-like cells in OC, the transcriptome, proteome, gene vulnerability, and drug sensitivity landscape of matched patient tumors and model systems will be evaluated for the emergence of NE-like cells under chemotherapeutic pressures. Existing drug dependency databases will be mined for identification of druggable targets in NE-like cells. Drugs effective against these cells will be tested alone or in combination as targeted therapy for PtR OCs utilizing patient derived organoid and xenograft models. Hallmarks of NE-like cells including metabolic adaptations and histologic characteristics will be explored with CMA2 & CMA1 respectively. CMA1 rationale: The evaluation of histopathology slides is the main method to establish a HGSOC diagnosis and guide treatment decisions. However, the rich data embedded within histopathology slides have not been fully exploited to understand the underlying causes of PtR and develop personalized treatment strategies. Prior research on PtR mostly used cancer cell lines and focused on cell-intrinsic events. However, data from clinical samples suggest that the tissue microenvironment (TME) is a major driver of PtR. Specifically, cancer- associated fibroblasts (CAFs) were shown to induce PtR in adjacent cancer cells. We hypothesize that higher- order features extracted from pathology slide images are associated with distinct molecular profiles, such as specific gene and protein expression, metabolism, and sensitivity to specific drugs. We will combine spatial image profiling with assays in mouse models and CAF/cancer cell co-cultures to mechanistically dissect the role of the TME in PtR. The integration of image data from patient slides with other -omics data will add a key layer of information to prioritize biologically- and clinically-relevant biomarkers and drivers of PtR.