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.

项目概要 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 卵巢癌临床治疗面临的挑战。最常见和最致命的卵巢亚型 癌症是高级别浆液性卵巢癌（HGSOC）。 HGSOC 的标准治疗结合了手术 含铂化疗的细胞减灭术。治疗最初成功地实现了缓解。 然而，大多数女性癌症都会复发。患有复发性疾病的患者可能会继续对额外的药物产生反应 但最终会形成铂电阻 (PtR)。此时，肿瘤通常是 对其他治疗策略有抵抗力。 HGSOC 增加生存的关键是防止发展 PtR 或确定靶向耐药肿瘤的替代方法。这一跨学科的主要目标 合作项目旨在确定 HGSOC 治疗功效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、抗治疗的表型。虽然之前关于 PtR 的研究主要集中在 DNA 修复上 途径或改变的膜转运蛋白，新概念支持以下假设：PtR 的关键贡献者 是将癌细胞重新编程为分化程度较低且代谢适应性强的状态。这 三位成熟的卵巢癌研究人员的合作提案将利用他们的跨学科优势 专业知识和丰富的资源来定义卵巢癌中 PtR 的新分子机制。 CMA1 将利用 深度成像定义 PtR 的临床相关生物标志物，同时数字空间分析和系统生物学 将用于识别 PtR 背后的分子途径。临床前免疫活性小鼠模型将 用于测试 CMA1、2&3 中发现的潜在靶向疗法。 CMA2将研究代谢适应 与 PtR 的出现相关，重点关注耐药 HGSOC 细胞中脂肪酸氧化的转变，以及 肿瘤。 CMA2 将使用与 CMA1 和 3 以及细胞生物学和新型单细胞代谢共享的资源 成像来定义 PtR HGSOC 独特的代谢依赖性。由于耐药肿瘤极易受到 氧化脂质膜诱导死亡，将在治疗的 PtR 模型中检查铁死亡的机制 新型代谢靶向药物，将与 CMA1 一起进行测试。 CMA3 将定义新兴的 通过对收集的患者肿瘤进行转录组分析，发现复发性 HGSOC 的去分化表型 疾病进展的各个阶段。通过定义导致细胞去分化的分子途径， 我们将揭示可以使用小分子、激酶抑制剂进行治疗的新漏洞， 多组学数据、患者来源的类器官和 PDX 模型将 为CMA1&2的协作项目提供宝贵的共享资源。 CMA2 的总体假设是代谢重编程是代谢重编程的关键且必要的步骤。 PtR 的开发。我们推测这种转变是通过癌细胞氧化状态的改变而引发的，因为 铂造成的 DNA 损伤。为了检验这一假设，我们将确定 Pt-R 癌细胞和 由于活性氧产生增加，肿瘤发生代谢转变为脂肪酸氧化 物种（ROS）。我们将测量细胞内 ROS、葡萄糖和脂质消耗并量化表达和 关键脂质转运蛋白和调节脂肪生成的限速酶的功能。分子研究结果将是 通过使用高内涵受激拉曼散射 (SRS) 代谢成像和多模态 SRS 进行验证/ 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耐药状态以及这些抑制剂是否诱导 PtR 细胞通过铁死亡而死亡。对这一过程的机制理解将带来新的治疗方法 致命的 PtR HGSOC 和其他癌症的机会。