BCCMA: Overcoming chemoresistance in ovarian cancer: Targeting Unique Vulnerabilities in Neuroendocrine-like Ovarian Cancer Cells

BCCMA：克服卵巢癌的化疗耐药性：针对神经内分泌样卵巢癌细胞的独特弱点

• 批准号: 10701594
• 负责人: Sanaz Memarzadeh
• 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: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701594
• 关键词: Address; Award; Bioinformatics; Biological Assay; Biological Availability; Biological Markers; Biological Models; Cancer Patient; Cancer cell line; Carboplatin; Carcinoma; Caring; Cause of Death; Cell Death; Cells; Cellular biology; Cessation of life; Characteristics; Chemoresistance; Cholesterol; Clinical; Clinical Management; Clinical Trials; Clinical Trials Design; Coculture Techniques; DNA Repair Pathway; Data; Data Set; Databases; Dependence; Designer Drugs; Development; Diagnosis; Disease; Disease Resistance; Dose; Drug Addiction; Drug Screening; Drug Targeting; Fatal Outcome; Future; Gene Expression Profile; Genes; Genetic; Goals; Harvest; Histologic; Human; Immunocompetent; In Vitro; Knowledge; Link; Lipids; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of ovary; Membrane Lipids; Membrane Transport Proteins; Metabolic; Metabolism; Modeling; Molecular; Mus; Neuroendocrine Therapy; Neurosecretory Systems; Oncogenic; Organoids; Ovarian; Ovarian Serous Adenocarcinoma; PLK1 gene; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Platinum; Population; Predisposition; Proteome; Proteomics; Publishing; Recurrence; Recurrent disease; Research Personnel; Resistance; Resource Sharing; Resources; Robotics; Role; Sampling; Serous; Systems Biology; TXN gene; Technology; Testing; Therapeutic; Translations; Treatment Efficacy; Tumor Debulking; Woman; Work; biomarker driven; cancer cell; chemotherapy; cholesterol biosynthesis; clinically relevant; drug candidate; drug sensitivity; drug testing; druggable target; efficacy testing; fatty acid oxidation; improved; in vivo; in vivo evaluation; inhibitor; innovation; intraperitoneal; kinase inhibitor; metabolic abnormality assessment; metabolic imaging; metabolic profile; mouse model; multidisciplinary; neoplastic cell; neuroendocrine phenotype; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; ovarian neoplasm; oxidized lipid; patient derived xenograft model; pharmacologic; pre-clinical; precision medicine; pressure; prevent; refractory cancer; resistance mechanism; spectroscopic imaging; standard care; targeted agent; targeted treatment; therapeutic biomarker; therapy resistant; transcriptome; transcriptome sequencing; transcriptomic profiling; transcriptomics; translational potential; treatment strategy; tumor; tumor microenvironment; tumor progression

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 needed key to increasing survival in HGSOC is to prevent the development of platinum resistance or identify alternative means of targeting platinum resistant (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 results in transformation of HGSOC cells to an aggressive, therapy-resistant phenotype. Increasing evidence support the hypothesis that a key contributor to platinum resistance 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 resources to define new mechanisms of resistance in OC. CMA1 will use 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. 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 single cell metabolic imaging to define unique metabolic dependencies of PtR HGSOC. As PtR tumors are 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 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 emergence of NE-like cells under chemotherapeutic pressures. Data emerging from the analysis of patient tumor samples in this proposal in addition to 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 with carboplatin in targeting PtR OCs. Hallmarks of NE-like cells including metabolic adaptations and histologic characteristics will be explored with CMA2 & CMA1 respectively. Rationale: Recent work demonstrates that many epithelial cancers converge to more aggressive state with genetic hallmarks and characteristics of NE-like cells. Histologic analysis, the original standard for defining neuroendocrine phenotypes, of recurrent ovarian tumors supports emergence of NE-like cells. Our preliminary bulk RNA sequencing data from longitudinally collected ovarian tumor samples, further supports chemo-induced progression to an NE-like state based on our previously published NE gene expression signatures. Pan cancer data has revealed that NE-like cells are more aggressive and resistant to chemotherapy. This is why understanding the molecular underpinnings of NE-like cells in ovarian cancers is critical. We hypothesize that eradication of PtR disease, requires additional therapeutic approaches that are directed to target NE-like cells in ovarian tumors. CMA3 plans to mechanistically define vital pathways for survival of PtR NE-like tumor cells and test drugs that can eliminate this tumor subpopulation. We envision our work will result in immediate clinical trial designs that can test new approaches for treating OC patients.

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。临床上需要增加的关键 HGSOC中的生存是防止铂耐药性的发展或识别靶向的替代方法 抗铂（PTR）肿瘤。这个跨学科和协作项目的主要目标是确定 HGSOC治疗功效的新型靶标和生物标志物。这需要更好地理解 导致HGSOC细胞转化为侵略性治疗的表型的机制。 越来越多的证据支持以下假设：铂耐药性的关键因素是重新编程 癌细胞的分化较不分化和代谢适应状态。三个协作提案 既定的OC研究人员将利用其跨学科专业知识和资源来定义新的 OC中的抗性机制。 CMA1将使用空间分析和系统生物学来提供整体 了解PTR以及优先考虑细胞内部和微环境临床相关的基础 分子途径。临床前免疫能力的小鼠模型和共培养模型将用于研究 肿瘤微环境在PTR中的作用。 CMA2将研究与 PTR的出现重点是在PTR HGSOC肿瘤中转向脂肪酸氧化CMA2将使用资源 与CMA1和3共享，以及细胞生物学以及单细胞代谢成像，以定义独特的代谢 PTR HGSOC的依赖性。由于PTR肿瘤易受氧化脂质膜诱导的死亡，因此 在用新的代谢靶向剂治疗的PTR模型中，将检查铁凋亡的机制，这些机制将 将用CMA1进行测试。 CMA3将探索重复的HGSOC细胞重编程为更多的肿瘤 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出现NE样细胞的出现。数据 除了现有药物依赖性外，还从对患者肿瘤样本的分析中出现 数据库将被开采以鉴定NE样细胞中的可毒靶标。对这些细胞有效的药物 将在靶向PTR OC中单独测试或与卡铂结合进行测试。 Ne样细胞的标志包括 将分别用CMA2和CMA1探索代谢适应和组织学特征。 理由：最近的工作表明，许多上皮癌与更具侵略性的状态 NE样细胞的遗传标志和特征。组织学分析，定义的原始标准 复发性卵巢肿瘤的神经内分泌表型支持NE样细胞的出现。我们的初步 来自纵向收集的卵巢肿瘤样品的大量RNA测序数据进一步支持化学诱导的 基于我们先前发表的NE基因表达特征的NE样状态。 PAN癌 数据表明，NE样细胞更具侵略性和对化学疗法的抗性。这就是原因 了解卵巢癌中NE样细胞的分子基础至关重要。我们假设这一点 根除PTR疾病需要其他治疗方法，这些方法针对靶向NE样细胞 卵巢肿瘤。 CMA3计划机械地定义了PTR状肿瘤细胞存活的重要途径和 测试可以消除这种肿瘤亚群的药物。我们设想我们的工作将立即进行临床试验 可以测试用于治疗OC患者的新方法的设计。