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.

由三个项目（CMA1-3）组成的合作功绩奖申请（CMA）解决了关键 卵巢癌临床管理（OC）的挑战。 OC的最常见和致命的亚型是 高级浆液卵巢癌（HGSOC）。 HGSOC的标准治疗方法结合了手术 基于铂的化学疗法的细胞来减少。被诊断为HGSOC的患者经常患有疾病 与化学疗法抗性的出现有关的复发。临床上增加的关键 HGSOC中的生存是为了防止铂耐药性（PTR）的发展或确定的替代方法 靶向PTR肿瘤。这个跨学科和协作项目的主要目标是确定新颖的目标 和HGSOC治疗功效的生物标志物。这需要更好地理解 导致HGSOC细胞转化为侵略性，抗治疗的表型。越来越多的证据 支持以下假设：PTR的关键因素是将癌细胞重编程为较少的 差异化和代谢适应性状态。三名成熟的OC研究人员的合作提议 将利用其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的整体了解 优先考虑细胞中的和微环境临床相关的基本分子途径。独特的 临床前免疫能力的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聚焦的出现相关的代谢适应 在PTR HGSOC肿瘤中转向脂肪酸氧化时。 CMA2将使用与CMA1和3共享的资源，并且 细胞生物学和新型的单细胞代谢成像，以定义PTR HGSOC的独特代谢依赖性。 由于PTR肿瘤非常容易受到氧化脂质膜诱导的死亡的影响 将在用新的代谢靶向剂处理的PTR模型中检查，该模型将进行测试 与CMA1。 CMA3将探索重复的HGSOC细胞重编程为更脱落的肿瘤 神经内分泌（NE）样特征的亚群。其他肿瘤中的越来越多的证据表明进展 对于NE样状态导致抗治疗性 - OC中尚待探讨的概念。鉴定在 OC，转录组，蛋白质组，基因脆弱性和匹配患者肿瘤的药物敏感性景观 将评估模型系统在化学治疗压力下的NE样细胞的出现。 现有的药物依赖数据库将被开采以鉴定NE样细胞中的可药物靶标。毒品 对这些细胞有效的有效测试或组合作为使用PTR OC的靶向疗法 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 组织学特征将分别用CMA2和CMA1探索。 CMA1理由：组织病理学幻灯片的评估是建立HGSOC诊断的主要方法 和指导治疗决策。但是，嵌入在组织病理学幻灯片中的丰富数据尚未 充分利用以了解PTR的根本原因并制定个性化的治疗策略。事先的 对PTR的研究主要使用了癌细胞系，并专注于细胞中性事件。但是，来自临床的数据 样品表明组织微环境（TME）是PTR的主要驱动力。具体而言，癌症 - 显示相关的成纤维细胞（CAF）在相邻的癌细胞中诱导PTR。我们假设这更高 从病理幻灯片图像中提取的顺序特征与不同的分子曲线有关，例如 特定的基因和蛋白质表达，代谢以及对特定药物的敏感性。我们将结合空间 在小鼠模型和CAF/癌细胞共培养中进行测定的图像分析，以机械剖析 TME在PTR中的作用。来自患者幻灯片与其他 - 元数据数据的图像数据的集成将添加一个键 信息层以优先于生物学和临床上的生物标志物以及PTR的驱动因素。