Understanding Metabolic Reprogramming in Platinum Resistant Ovarian Cancer

了解铂类耐药卵巢癌的代谢重编程

• 批准号: 10485428
• 负责人: Daniela E Matei
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10485428
• 关键词: Address; Award; Biological Assay; Biological Markers; Breast Cancer Cell; Cancer Patient; Carbon; Cause of Death; Cell Death; Cell Death Induction; Cell Line; Cells; Cellular biology; Cessation of life; Chemicals; Chemoresistance; Clinical; Clinical Management; Collaborations; Collecting Cell; Colorectal Cancer; Consumption; DNA Damage; DNA Repair Pathway; Data; Dependence; Development; Diagnosis; Disease Progression; Disease Resistance; Disease remission; Energy-Generating Resources; Enzymes; Fatal Outcome; Fatty Acids; Fatty-acid synthase; Fluorescence; Generations; Genetic; Glucose; Glutamine; Glutathione; Glycolysis; Goals; Human; Image; Imaging Device; Imaging Techniques; Immunocompetent; Immunotherapy; Induction of Apoptosis; Lipid Peroxidation; Lipids; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Measurement; Measures; Mediating; Membrane Lipids; Membrane Transport Proteins; Metabolic; Metabolism; Methods; Modeling; Molecular; Molecular and Cellular Biology; Monitor; Multiomic Data; Mus; Organoids; Ovarian; Ovarian Serous Adenocarcinoma; Oxidative Stress; Pathway interactions; Patients; Peroxides; Phenotype; Platinum; Pre-Clinical Model; Predisposition; Process; Reactive Oxygen Species; Recurrence; Recurrent Malignant Neoplasm; Recurrent disease; Reporting; Research Personnel; Resistance; Resource Sharing; Resources; Sampling; Serous; Systems Biology; Technology; Testing; Therapeutic; Treatment Efficacy; Tumor Debulking; Unsaturated Fatty Acids; Woman; Work; biomarker driven; cancer cell; cancer recurrence; cancer stem cell; chemotherapy; clinical development; clinically relevant; desaturase; digital; fatty acid oxidation; imaging modality; indexing; inhibitor; kinase inhibitor; lipid biosynthesis; lipidomics; metabolic abnormality assessment; metabolic imaging; molecular imaging; mouse model; multidisciplinary; multimodality; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutic intervention; ovarian neoplasm; oxaliplatin; oxidized lipid; patient derived xenograft model; pre-clinical; prevent; prognostic assays; refractory cancer; response; small molecule; spectroscopic imaging; standard care; targeted agent; targeted treatment; therapeutic biomarker; therapy resistant; transcriptomics; treatment strategy; tumor; two-photon

PROJECT SUMMARY This Collaborative Merit Award application (CMA), consisting of three projects (CMA1-3), addresses a critical challenge in the clinical management of ovarian cancer. The most common and most lethal subtype of ovarian cancer is high-grade serous ovarian carcinoma (HGSOC). Standard treatment for HGSOC combines surgical cytoreduction with platinum-based chemotherapy. The treatment is initially successful in achieving remission. However, cancer recurs in most women. Patients with recurrent disease may continue to respond to additional rounds of platinum but will ultimately develop platinum resistance (PtR). At that point, the tumor is typically resistant to other treatment strategies. The key to increasing survival in HGSOC is to prevent the development of PtR or identify alternative means of targeting resistant 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 either select for, or promote transformation of, HGSOC cells to an aggressive, therapy-resistant phenotype. While previous studies on PtR have focused on DNA repair pathways or altered membrane transporters, new concepts support 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 ovarian cancer researchers will leverage their interdisciplinary expertise and rich resources to define new molecular mechanisms of PtR in ovarian cancer. CMA1 will utilize deep imaging to define clinically-relevant biomarkers of PtR while digital spatial profiling and systems biology will be used to identify molecular pathways underlying PtR. Preclinical immunocompetent mouse models will be used to test potential targeted therapies discovered in CMA1,2&3. CMA2 will study metabolic adaptation associated with the emergence of PtR focusing on a shift to fatty acid oxidation in resistant HGSOC cells and 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 resistant 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 together with CMA1. CMA3 will define the emergent de-differentiated phenotype in recurrent HGSOC through transcriptomic analysis of patient tumors collected at various stages of disease progression. By defining molecular pathways that lead to cellular de-differentiation, we will reveal new vulnerabilities that can be therapeutically exploited using small molecules, kinase inhibitors, and cell-based immune therapy approaches Multi-omics data, patient derived organoids, and PDX models will provide valuable shared resource for collaborative projects in CMA1&2. The overarching hypothesis of CMA2 is that metabolic reprogramming is a key and necessary step in the development of PtR. We speculate that this shift is initiated through altered oxidative status in cancer cells, due to DNA injuries inflicted by platinum. To test the hypothesis, we will determine whether Pt-R cancer cells and tumors undergo a metabolic shift to fatty acid oxidation caused by increased generation of reactive oxygen species (ROS). We will measure intracellular ROS, glucose and lipid consumption and quantify expression and function of key lipid transporters and rate limiting enzymes regulating lipogenesis. Molecular findings will be validated by using high content stimulated Raman scattering (SRS) metabolic imaging and multimodal SRS / two-photon excitation fluorescence (TPEF). We will test whether by blockade of key enzymes or transporters involved in metabolic reprogramming can overcome the state of resistance and whether these inhibitors induce cell death in PtR cells through ferroptosis. Mechanistic understanding of this process will lead to new treatment opportunities for fatal PtR HGSOC and other cancers.

项目摘要 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 卵巢癌的临床治疗面临挑战。卵巢癌最常见和最致命的亚型 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。治疗最初成功地达到缓解。 然而，癌症在大多数女性中复发。复发性疾病的患者可能会继续对额外的 但最终会产生铂耐药（PtR）。在这一点上，肿瘤通常是 对其他治疗策略有抵抗力。提高HGSOC存活率的关键是防止HGSOC的发展， 或确定靶向耐药肿瘤的替代方法。这个跨学科的主要目标， 合作项目是确定HGSOC治疗效果的新靶点和生物标志物。这需要 更好地理解选择或促进HGSOC细胞转化的机制， 一种攻击性的耐药表型虽然以前对PtR的研究主要集中在DNA修复上， 通路或改变的膜转运蛋白，新的概念支持的假设，一个关键的贡献PtR 是将癌细胞重新编程为分化程度较低且代谢适应性较强的状态。这 三位卵巢癌研究人员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卵巢癌中PtR的新分子机制。CMA 1将利用 深度成像以定义PtR的临床相关生物标志物，而数字空间分析和系统生物学 将被用于识别PtR的分子通路。临床前免疫活性小鼠模型将 用于测试CMA 1，2&3中发现的潜在靶向治疗。CMA 2将研究代谢适应 与PtR的出现相关，PtR的重点是在抗性HGSOC细胞中向脂肪酸氧化的转变， 肿瘤的CMA 2将使用与CMA 1和3共享的资源以及细胞生物学和新的单细胞代谢 成像以定义PtR HGSOC的独特代谢依赖性。由于耐药肿瘤对 氧化脂质膜诱导的死亡，将在PtR处理的模型中检查铁凋亡的机制 新的代谢靶向药物，将与CMA 1一起进行测试。CMA 3将定义紧急 通过转录组学分析收集的患者肿瘤在复发性HGSOC中的去分化表型 疾病进展的不同阶段。通过定义导致细胞去分化的分子途径， 我们将揭示新的弱点，可以利用小分子，激酶抑制剂， 和基于细胞的免疫治疗方法多组学数据，患者衍生的类器官和PDX模型将 为CMA 1&2的合作项目提供宝贵的共享资源。 CMA 2的首要假设是代谢重编程是代谢过程中的关键和必要步骤。 发展PtR。我们推测，这种转变是通过改变癌细胞的氧化状态开始的， 铂金造成的DNA损伤为了验证这一假设，我们将确定Pt-R癌细胞和 由于活性氧的产生增加， 物种（ROS）。我们将测量细胞内ROS、葡萄糖和脂质消耗并定量表达， 关键脂质转运蛋白和限速酶调节脂肪生成的功能。分子研究结果将是 通过使用高含量受激拉曼散射（SRS）代谢成像和多模式SRS / 双光子激发荧光（TPEF）。我们将测试是否通过阻断关键酶或转运蛋白 参与代谢重编程可以克服抵抗状态，以及这些抑制剂是否诱导 PtR细胞通过铁凋亡而死亡。对这一过程的机理理解将导致新的治疗方法 致命的PtR HGSOC和其他癌症的机会。