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.

项目总结 肾细胞癌(RCC)是世界上最常见的十大癌症之一，由多个 不同的组织结构。肾细胞癌的一种特别侵袭性的亚型是易位肾细胞癌(TRCC)， 破坏性和侵袭性肿瘤，由涉及转录因子的基因融合所定义。 MIT/TFE基因家族，最常见的是TFE3。目前，还没有批准的治疗剂是 专门针对tRCC的生物学。此外，我们对TFE3是如何 融合导致了这种癌症，这是一个重大的未得到满足的医疗需求。我们最近将基因组发现应用于 识别可能代表tRCC新治疗靶点的基因和/或途径的方法。这些 研究发现核因子红系相关因子2(NRF2)途径激活--一个主调节因子 细胞对氧化应激的反应--这是tRCC的一个定义特征。有趣的是，在tRCC中，NRF2激活 在没有激活这一途径中的体细胞变化的情况下发生的，这些变化通常在其他癌症中发现，例如 扩增NFE2L2(编码NRF2的基因)或失活Keap1(NRF2的负调控因子)， 提示了TRCC中NRF2调控的一种新模式。在这个项目中，我们将探索分子机制。 通过这种方式，NRF2信号在tRCC中被激活，并将建立靶向 Nrf2通路在该肿瘤中的表达。在目标1中，我们将剖析TFE3融合调控的分子机制 TRCC中的NRF2信号转导。我们将检验TFE3融合和NRF2协调调节 关键抗氧化剂基因的表达和功能。我们还将使用无偏见的功能基因和化学物质 蛋白质组学方法识别tRCC中TFE3融合的关键氧化还原敏感效应因子。在目标2中，我们将测试 抑制NRF2通路在tRCC中的功能后果和治疗潜力。我们将评估 肾细胞癌组织中NRF2途径激活的蛋白标记物然后我们将同时使用基因和小分子 确定NRF2抑制是否代表体外培养的tRCC细胞的依赖性的分子方法 在活体内。该项目利用创新的生化和功能遗传学方法来阐明基本的 TFE3融合调控NRF2信号的机制。更广泛地说，这些研究可能有 对理解NRF2通路在其他癌症中是如何调控的启示。该项目还寻求 将NRF2通路作为tRCC的治疗靶点，从而推进机制驱动的 治疗假说有可能改善癌症的预后，代表了一种未得到满足的医学 没有既定的护理标准的需要。