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

BCCMA：克服卵巢癌的化疗耐药性：铂类耐药的生物标志物和靶向驱动因素的识别和验证

• 批准号: 10585641
• 负责人: SANDRA ORSULIC
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585641
• 关键词: ASF1A gene; Address; Apoptosis; Architecture; Area; Autophagocytosis; Award; Biological Assay; Biological Markers; Biological Models; Cancer Patient; Cancer cell line; Catalytic Domain; Cause of Death; Cell Line; Cells; Cellular biology; Cessation of life; Characteristics; Chemoresistance; Chromatin; Chromosome Mapping; Clinical; Clinical Data; Clinical Management; Coculture Techniques; Collaborations; DNA Repair Pathway; Data; Data Set; Databases; Dependence; Development; Diagnosis; Disease Resistance; Drug Addiction; Drug Compounding; Drug Screening; Drug Targeting; Evaluation; Event; Experimental Models; Fatal Outcome; Fibroblasts; Gene Expression; Genes; Glycolysis; Goals; Histologic; Histopathology; Hypoxia; Image; Image Analysis; Imaging Device; Immunocompetent; Knowledge; Link; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Membrane Lipids; Membrane Transport Proteins; Metabolic; Metabolism; Methods; Modeling; Molecular; Molecular Analysis; Molecular Profiling; Morphology; Multiomic Data; Mus; Mutate; NUAK1 gene; Nature; Necrosis; Neuroendocrine Cell; Neurosecretory Systems; Nuclear; Organoids; Ovarian Serous Adenocarcinoma; Pathologist; Pathology; Pathway interactions; Patient Care; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Platinum; Population; Predisposition; Primary Neoplasm; Proteome; Quality of life; Recurrence; Recurrent disease; Research; Research Personnel; Resistance; Resource Sharing; Resources; Role; Sampling; Serous; Slide; Systems Biology; Technology; Testing; Therapeutic; Tissues; Treatment Efficacy; Tumor Debulking; Validation; Veterans; Woman; Xenograft Model; bioinformatics tool; biomarker development; biomarker driven; biomarker identification; biomarker validation; cancer cell; cancer therapy; chemotherapy; chromatin remodeling; clinically relevant; data integration; data modeling; digital; drug sensitivity; druggable target; efficacy testing; fatty acid oxidation; genetic signature; improved; inhibitor; metabolic abnormality assessment; metabolic imaging; mouse model; multidisciplinary; multiple omics; neoplastic cell; neuroendocrine differentiation; neuroendocrine phenotype; new therapeutic target; novel; novel strategies; novel therapeutic intervention; ovarian neoplasm; oxidized lipid; patient derived xenograft model; personalized medicine; pre-clinical; pressure; prevent; protein expression; refractory cancer; resistance mechanism; spectroscopic imaging; standard care; stem cell biomarkers; stemness; targeted agent; targeted treatment; therapeutic biomarker; therapeutic target; therapy resistant; transcriptome; treatment strategy; tumor; tumor microenvironment

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.

该协作优异奖申请 (CMA) 由三个项目 (CMA1-3) 组成，解决了一个关键问题 卵巢癌（OC）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 的标准治疗结合了手术 以铂类为基础的化疗进行细胞减灭术。诊断为 HGSOC 的患者通常患有疾病 复发与化疗耐药的出现有关。临床上必要的关键是增加 HGSOC 的生存是为了防止铂电阻 (PtR) 的发展或找到替代方法 靶向 PtR 肿瘤。这个跨学科合作项目的主要目标是确定新目标 以及 HGSOC 治疗效果的生物标志物。这需要更好地理解其机制 导致 HGSOC 细胞转化为侵袭性、抗治疗表型。越来越多的证据 支持以下假设：PtR 的一个关键贡献者是将癌细胞重新编程为较少的细胞。 分化和代谢适应状态。这项由三位知名 OC 研究人员共同提出的提案 将利用他们的跨学科专业知识和丰富的资源来定义新的抵抗机制 OC。 CMA1 将使用数字空间分析和系统生物学来提供对 PtR 的整体理解 优先考虑细胞内在和微环境临床相关的潜在分子途径。独特的 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 PtR 中的微环境。 CMA2 将研究与 PtR 聚焦出现相关的代谢适应 PtR HGSOC 肿瘤中脂肪酸氧化的转变。 CMA2 将使用与 CMA1&3 共享的资源，并且 细胞生物学和新颖的单细胞代谢成像来定义 PtR HGSOC 独特的代谢依赖性。 由于 PtR 肿瘤极易受到氧化脂质膜诱导的死亡，因此铁死亡的机制 将在用新型代谢靶向剂治疗的 PtR 模型中进行检查，并将对其进行测试 与 CMA1。 CMA3将探索将复发的HGSOC细胞重编程为更多去分化的肿瘤 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 类似 NE 的状态会导致治疗抵抗——这是一个在 OC 中尚待探索的概念。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情况 模型系统将针对化疗压力下 NE 样细胞的出现进行评估。 将挖掘现有的药物依赖性数据库来识别 NE 样细胞中的可药物靶点。药品 将单独或联合测试对这些细胞的有效性，作为 PtR OC 的靶向治疗 患者衍生的类器官和异种移植模型。 NE 样细胞的标志包括代谢适应和 将分别用 CMA2 和 CMA1 探讨组织学特征。 CMA1 基本原理：组织病理学切片的评估是建立 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得到证实。 充分利用以了解 PtR 的根本原因并制定个性化治疗策略。事先的 PtR的研究主要使用癌细胞系并集中于细胞内在事件。然而，来自临床的数据 样本表明组织微环境 (TME) 是 PtR 的主要驱动因素。具体来说，癌症—— 研究显示相关成纤维细胞 (CAF) 可在邻近癌细胞中诱导 PtR。我们假设更高- 从病理幻灯片图像中提取的顺序特征与不同的分子特征相关联，例如 特定基因和蛋白质的表达、代谢以及对特定药物的敏感性。我们将结合空间 通过小鼠模型和 CAF/癌细胞共培养物的分析进行图像分析，以机械方式剖析 TME 在 PtR 中的作用。患者载玻片图像数据与其他组学数据的整合将增加一个关键 信息层，用于优先考虑 PtR 的生物学和临床相关生物标志物和驱动因素。