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.

抽象的 肾癌的患病率正在上升，是全球十大最常见癌症之一。透明细胞 肾细胞癌（ccRCC）是最常见和最具侵袭性的肾癌类型。而原发性 ccRCC 经过手术治疗后，30%的患者被诊断患有区域晚期或转移性疾病， 需要全身治疗。尽管目前的治疗方法针对肿瘤微环境，但 5 年生存率 晚期 ccRCC 的比率仍为 11%。 HIF-2 在 ccRCC 中发挥重要的致癌作用，这导致 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性 大多数患者的反应。因此，需要确定直接治疗的额外治疗靶点 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。标志特征 VHL 缺陷型 ccRCC 的机制包括缺氧 (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 敲除可减少 ccRCC 的生长和存活，且与 HIF-2 无关。然而， 对 1) FTO 如何促进 VHL 缺陷的 ccRCC 生长和存活以及 2) 的可操作机制见解 基于 FTO 的疗法在 ccRCC 中的治疗潜力是本文所解决的知识中的关键差距 应用。我们的中心假设是 m6A 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，支持 Belzutifan 敏感和 耐药ccRCC。我们的具体目标将检验以下假设：（目标 1）FTO 促进 VHL 缺陷 通过 m6A 增加谷氨酰胺转运蛋白 SLC1A5 的表达来进行 ccRCC 谷氨酰胺重编程 去甲基化； （目标 2）FTO 抑制剂在 VHL 缺陷的 ccRCC 中造成代谢脆弱性，可通过 治疗上用于治疗 Belzutifan 敏感和耐药肿瘤。得出结论后我们就会明白 m6A 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。 这一贡献意义重大，因为它将确立 SLC1A5，一种可操作的预后癌症疗法 目标，由 FTO 通过 m6A 修饰进行调节。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性的快速转化非常重要 FTO 抑制剂等医学方法目前正在临床开发中。