The role of the RNA demethylase FTO in metabolic reprogramming of renal cell carcinoma

RNA去甲基化酶FTO在肾细胞癌代谢重编程中的作用

• 批准号: 10659085
• 负责人: Erinn B. Rankin
• 金额: $ 47.79万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-10 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659085
• 关键词: 3-Dimensional; Address; Amino Acid Transporter; Angiogenesis Inhibitors; Apoptosis; Automobile Driving; Biological Assay; Biological Markers; Cell Line; Cell Survival; Cells; Clear cell renal cell carcinoma; Clinic; Combined Modality Therapy; Compensation; Consumption; Data; Development; Diagnosis; Disease; Foundations; Glutamine; Growth; Hypoxia; Immunocompetent; Immunotherapy; Knowledge; Magnetic Resonance Imaging; Malignant Epithelial Cell; Malignant Neoplasms; Maps; Mediating; Messenger RNA; Metabolic; Metabolism; Methylation; Mission; Modeling; Modification; Molecular; Monitor; Oncogenic; Operative Surgical Procedures; PET/CT scan; Patients; Phenocopy; Play; Prevalence; Proliferating; Proteins; Public Health; RNA; RNA methylation; Reader; Renal Cell Carcinoma; Renal carcinoma; Research; Resistance; Role; Safety; Signal Transduction; Site; Survival Rate; Systemic Therapy; Testing; Therapeutic; Therapeutic Agents; Time; Translating; Translations; Tumor Suppressor Proteins; Tumor Weights; United States National Institutes of Health; VHL gene; Von Hippel-Lindau Syndrome; Woman; Work; X-Ray Computed Tomography; advanced disease; angiogenesis; cancer cell; carboxylate; carboxylation; cell growth; clinical development; demethylation; efficacy evaluation; epitranscriptomics; fat mass and obesity-associated protein; human model; inhibitor; innovation; insight; knock-down; loss of function; mRNA Decay; men; metabolomics; molecular imaging; mouse model; multidisciplinary; novel; obesity treatment; objective response rate; patient derived xenograft model; precision medicine; prognostic; response; stable isotope; synthetic lethal interaction; targeted cancer therapy; therapeutic target; time use; tumor; tumor growth; tumor metabolism; tumor microenvironment; uptake

Abstract Kidney cancer is increasing in prevalence and is one of the top 10 most common cancers world-wide. Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of kidney cancer. While primary ccRCC is treated with surgery, 30% of patients are diagnosed with regionally advanced or metastatic disease that requires systemic therapy. Despite current treatments that target the tumor microenvironment, the 5-year survival rate for advanced ccRCC remains 11%. HIF-2 plays an important oncogenic role in ccRCC, which has led to the recent development of the HIF-2 inhibitor belzutifan. However, innate and acquired resistance limits durable responses in the majority of patients. Thus, there is a need to identify additional therapeutic targets that directly inhibit the growth and survival of ccRCC cancer cells. The von Hippel Lindau (VHL) tumor suppressor gene is lost in ccRCC tumors associated with the VHL disease and in 90% of sporadic ccRCC tumors. Hallmark features of VHL deficient ccRCC include constitutive activation of hypoxic (HIF) signaling, angiogenesis and metabolic reprogramming. We recently discovered a synthetic lethal interaction between the RNA demethylase FTO and VHL in ccRCC. Importantly, FTO knockdown reduces ccRCC growth and survival independent of HIF-2. Yet, actionable mechanistic insights into 1) how FTO promotes VHL deficient ccRCC growth and survival and 2) the therapeutic potential of FTO-based therapy in ccRCC are critical gaps in knowledge addressed in this application. Our central hypothesis is that the m6A RNA demethylase, fat-mass and obesity-associated protein (FTO), promotes glutamine reprogramming to support the growth of belzutifan sensitive and resistant ccRCC. Our specific aims will test the following hypotheses: (Aim1) FTO promotes VHL deficient ccRCC glutamine reprogramming by increasing the expression of the glutamine transporter SLC1A5 via m6A demethylation; (Aim 2) FTO inhibitors create a metabolic vulnerability in VHL deficient ccRCC that can be exploited therapeutically to treat belzutifan sensitive and resistant tumors. Upon conclusion, we will understand the role of m6A RNA methylation and FTO as epitranscriptomic regulators of glutamine reprogramming in ccRCC. This contribution is significant since it will establish that SLC1A5, an actionable and prognostic cancer therapy target, is regulated by FTO through m6A modifications. Additionally, insight into the mechanisms of FTO- mediated growth, survival and glutamine reprogramming is important for the rapid translation of precision medicine approaches as FTO inhibitors are currently in clinical development.

摘要 肾癌的患病率正在增加，并且是全球十大最常见的癌症之一。透明细胞 肾细胞癌（ccRCC）是最常见和侵袭性的肾癌类型。虽然原发性ccRCC 接受手术治疗，30%的患者被诊断患有区域性晚期或转移性疾病， 需要系统治疗尽管目前的治疗靶向肿瘤微环境， 晚期ccRCC的发生率仍为11%。HIF-2在ccRCC中起重要的致癌作用，这导致了 HIF-2抑制剂Belzutifan的最新进展。然而，先天和后天的抵抗力限制了持久的 大多数患者的反应。因此，需要鉴定另外的治疗靶标，其直接 抑制ccRCC癌细胞的生长和存活。von Hippel Lindau（VHL）肿瘤抑制基因是 在与VHL疾病相关的ccRCC肿瘤和90%的散发性ccRCC肿瘤中丢失。标志性特征 VHL缺陷型ccRCC的病理改变包括缺氧（HIF）信号传导、血管生成和代谢的组成性激活。 重新编程我们最近发现了RNA去甲基化酶FTO和 ccRCC中的VHL。重要的是，FTO敲低降低了不依赖于HIF-2的ccRCC生长和存活。然而， 关于1）FTO如何促进VHL缺陷型ccRCC生长和存活以及2） 基于FTO的治疗在ccRCC中的治疗潜力是本研究中解决的知识的关键差距。 应用程序.我们的中心假设是，m6 A RNA去甲基化酶，脂肪量和肥胖相关 蛋白（FTO），促进谷氨酰胺重编程，以支持贝珠单抗敏感和 耐药ccRCC。我们的具体目标将测试以下假设：（目的1）FTO促进VHL缺陷 通过m6 A增加谷氨酰胺转运蛋白SLC 1A 5的表达进行ccRCC谷氨酰胺重编程 （目的2）FTO抑制剂在VHL缺陷型ccRCC中产生代谢脆弱性， 在治疗上被用于治疗贝祖替凡敏感和耐药肿瘤。在结束时，我们会明白 m6 A RNA甲基化和FTO作为ccRCC中谷氨酰胺重编程的表观转录组调节剂的作用。 这一贡献是重要的，因为它将确定SLC 1A 5，一种可行的和预后的癌症治疗方法， 靶向，通过m6 A修饰由FTO调节。此外，深入了解FTO的机制- 介导的生长、存活和谷氨酰胺重编程对于精确的快速翻译是重要的。 作为FTO抑制剂的药物方法目前处于临床开发中。