Molecular mechanisms and therapeutic targeting of activated NRF2 signaling in MiT/TFE translocation renal cell carcinoma

MiT/TFE 易位肾细胞癌中激活的 NRF2 信号传导的分子机制和治疗靶向

• 批准号: 10633699
• 负责人: Srinivas Raghavan Viswanathan
• 金额: $ 50.89万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633699
• 关键词: 3-Dimensional; Antioxidants; Automobile Driving; Binding; Biochemical; Biology; Cause of Death; Cells; Chemicals; Chromatin; Collection; Complex; Credentialing; Data; Dependence; Disease; Gene Family; Gene Fusion; Genes; Genetic; Genetic Transcription; Genomics; Histologic; Histology; In Vitro; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Medical; Molecular; Neoplasms; Oncogenic; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patient-Focused Outcomes; Play; Prognosis; Proteomics; Regulation; Renal Cell Carcinoma; Renal carcinoma; Reporting; Role; Signal Transduction; TFE3 gene; Testing; Therapeutic; Therapeutic Agents; Tumor Tissue; United States; Work; Xenograft Model; cohort; effective therapy; efficacy evaluation; genetic approach; genomic data; improved outcome; in vivo; in vivo Model; innovation; insight; new therapeutic target; novel; novel therapeutic intervention; nuclear factor-erythroid 2; posttranscriptional; pre-clinical; prospective; protein biomarkers; response; small molecule; standard of care; targeted treatment; therapeutic target; transcription factor; two-dimensional

PROJECT SUMMARY Renal cell carcinoma (RCC) is one of the top ten most common cancers worldwide and is comprised of multiple distinct histologies. One particularly aggressive subtype of RCC is translocation renal cell carcinoma (tRCC), a devastating and aggressive neoplasm that is defined by a gene fusion involving a transcription factor in the MiT/TFE gene family, most commonly TFE3. Currently, there are no approved therapeutic agents that are specifically targeted to the biology of tRCC. In addition, we have an incomplete understanding of how TFE3 fusions drive this cancer, which represents a major unmet medical need. We recently applied genomic discovery approaches to identify genes and/or pathways that may represent novel therapeutic targets in tRCC. These studies revealed activation of the nuclear factor erythroid 2–related factor 2 (NRF2) pathway – a master regulator of a cell’s response to oxidative stress – to be a defining feature of tRCC. Interestingly, in tRCC, NRF2 activation occurs without the activating somatic alterations in this pathway that are usually found in other cancers, such as amplification of NFE2L2 (the gene encoding NRF2) or inactivation of KEAP1 (a negative regulator of NRF2), suggesting a novel mode of NRF2 regulation in tRCC. In this project, we will explore the molecular mechanisms by which NRF2 signaling is activated in tRCC and will also establish the therapeutic potential of targeting the NRF2 pathway in this cancer. In Aim 1, we will dissect the molecular mechanisms by which TFE3 fusions regulate NRF2 signaling in tRCC. We will test the hypothesis that TFE3 fusions and NRF2 coordinately regulate the expression and function of critical antioxidant genes. We will also use unbiased functional genetic and chemical proteomic approaches to identify critical redox-sensitive effectors of TFE3 fusions in tRCC. In Aim 2, we will test the functional consequences and therapeutic potential of NRF2 pathway inhibition in tRCC. We will assess protein markers of NRF2 pathway activation in tRCC tumor tissue. We will then use both genetic and small molecule approaches to determine whether NRF2 inhibition represents a dependency in tRCC cells both in vitro and in vivo. This project leverages innovative biochemical and functional genetic approaches to clarify the basic mechanisms by which NRF2 signaling is regulated by TFE3 fusions. More broadly, these studies may have implications for understanding how the NRF2 pathway is regulated in other cancers. This project also seeks to credential the NRF2 pathway as a therapeutic target in tRCC, thereby advancing a mechanism-driven therapeutic hypothesis with the potential to improve outcomes in a cancer that represents an unmet medical need with no established standard of care.

项目摘要 肾细胞癌（RCC）是全球十大最常见的癌症之一，由多个癌症组成 不同的组织学。 RCC的一种特别激进的亚型是易位肾细胞癌（TRCC），A 由涉及转录因子的基因融合定义的毁灭性和侵略性肿瘤 MIT/TFE基因家族，最常见的是TFE3。目前，没有批准的治疗剂 专门针对TRCC的生物学。此外，我们对TFE3的了解不完全了解 融合驱动了这种癌症，这代表了主要的未满足医疗需求。我们最近应用了基因组发现 识别可能代表TRCC中新型治疗靶标的基因和/或途径的方法。这些 研究揭示了核因子红系2相关因子2（NRF2）途径的激活 - 主调节剂 细胞对氧化应激的反应 - 是TRCC的定义特征。有趣的是，在TRCC中，NRF2激活 发生在该途径中通常在其他癌症中发现的无激活的体细胞改变的情况，例如 NFE2L2（编码NRF2的基因）的扩增或Keap1的灭活（NRF2的负调节剂）， 提出了TRCC中NRF2调节的新型模式。在这个项目中，我们将探索分子机制 通过在TRCC中激活NRF2信号，还将建立靶向靶向的治疗潜力 该癌症中的NRF2途径。在AIM 1中，我们将剖析TFE3融合的分子机制 TRCC中的NRF2信号传导。我们将测试TFE3融合和NRF2协调调节的假设 临界抗氧化基因的表达和功能。我们还将使用公正的功能遗传和化学 蛋白质组学方法鉴定TFE3融合在TRCC中的关键氧化还原敏感作用。在AIM 2中，我们将测试 NRF2途径在TRCC中抑制的功能后果和治疗潜力。我们将评估 TRCC肿瘤组织中NRF2途径激活的蛋白质标记。然后，我们将同时使用遗传和小 分子方法确定NRF2抑制是否代表TRCC细胞的依赖性 和体内。该项目利用创新的生化和功能遗传方法来阐明基本 NRF2信号传导受TFE3融合调节的机制。更广泛地，这些研究可能有 了解如何在其他癌症中调节NRF2途径的含义。这个项目也试图 在TRCC中，NRF2途径作为治疗目标，从而推进机构驱动 治疗假设，有可能改善代表未经医疗的癌症的预后 需要没有确定的护理标准。