Defining the role of KEAP/NRF2 signaling dysregulation and sensory nerve reprograming during acquisition of cisplatin resistance and metastasis in HNSCC

定义 KEAP/NRF2 信号失调和感觉神经重编程在 HNSCC 顺铂耐药和转移过程中的作用

• 批准号: 10707175
• 负责人: Abdullah Ali Osman
• 金额: $ 26.92万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707175
• 关键词: Adrenergic Agents; Afferent Neurons; Agreement; Biological Markers; CRISPR library; Cell Line; Cells; Chemoresistance; Cisplatin; Clinical; Clinical Data; Complex; DNA Sequence Alteration; Data; Data Correlations; Development; Disease; Distant Metastasis; Drug Targeting; Event; Fostering; Gene Expression; Genetic Transcription; Genomics; Glutaminase; Glutathione; Head and Neck Squamous Cell Carcinoma; Human; Human Papillomavirus; Immunotherapy; Incidence; Invaded; Knowledge; Laboratories; Link; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Metabolic; Metabolism; MicroRNAs; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Neoplasm Metastasis; Neurons; Normal tissue morphology; Paracrine Communication; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Prognosis; Publications; Recurrence; Reproducibility; Research; Resistance; Role; Signal Transduction; Solid Neoplasm; Somatic Mutation; TP53 gene; Testing; Therapeutic; Tongue Neoplasms; Toxic effect; Transcriptional Regulation; Treatment Failure; Upper aerodigestive tract cancer; afferent nerve; chemotherapy; clinical biomarkers; cohort; defined contribution; functional status; improved; in silico; inhibitor; knock-down; mortality; mutational status; neoplastic cell; neural; neurogenesis; novel; novel therapeutics; oral HPV-positive head and neck cancers; paracrine; perineural; permissiveness; pharmacologic; phase II trial; pre-clinical; prevent; response; tumor; tumor behavior; tumor microenvironment; tumor progression

Project 2 SUMMARY Cisplatin (CDDP) is frontline therapy for both Human Papilloma Virus (HPV) positive and negative head and neck squamous cell carcinomas (HNSCC). Unfortunately, there are no reproducible predictors of CDDP HNSCC response and patients develop acquired resistance and even distant metastasis following a course of this often toxic chemotherapy. To better understand and tackle the clinical problem of CDDP treatment failure, we developed multiple cell line models of acquired CDDP resistance in the laboratory using established HNSCC tumor lines with different genomic backgrounds and TP53 mutational and functional status. Surprisingly, nearly every CDDP resistant clone developed from these various genomic driver backgrounds had hyperactivation of the Nrf2 pathway either due to de novo somatic mutations in, or decreased RNA expression of, KEAP1 (negative regulator of Nrf2). Nrf2 activation has been linked to poor prognosis, lack of response to immune therapy, metastasis, and chemotherapy resistance. We demonstrated that Nrf2 hyperactivation was necessary to maintain acquired resistance, raising the possibility that the pathway could be clinically targeted to reverse or prevent acquired CDDP resistance in HNSCC. By targeting glutaminase 1 (GLS) with a novel drug, pools of glutathione needed for Nrf2 activity are depleted leading to a reversal of CDDP resistance. In parallel, we showed that paracrine signaling between sensory neurons that become reprogramed in the tumor microenvironment can foster CDDP resistance and that it may be possible to pharmacologically inhibit this signaling axis to boost CDDP sensitivity and tumor progression. Furthermore, data from our preclinical model suggest that Nrf2 activation accompanying CDDP resistance may also lead to more aggressive disease by increasing the rate of distant metastasis. While Nrf2 hyperactivation is likely a permissive and required step to acquired CDDP resistance, there may also be Nrf2 independent pathways contributing to resistance. Our central hypothesis is that Nrf2 hyperactivation either through somatic mutation for transcriptional control is a common and targetable event in development of acquired CDDP resistance across a range of genomic backgrounds. To bridge knowledge gaps in the pervasiveness of the Nrf2 pathway in development of CDDP resistance and tumor progression and ways to overcome treatment failure we propose the following Aims: 1) Define the contribution of Nrf2-dependent and-independent pathways to acquired CDDP resistance in HNSCC; 2) Delineate the functional and mechanistic interactions between acquired CDDP resistance, Nrf2 activation, neuronal reprograming in the tumor microenvironment, and DM; 3) Determine whether acquired CDDP resistance and tumor progression can be overcome by drugs targeting metabolism or stabilizing p53. Accomplishment of these Aims should yield translatable findings that will improve the treatment of patients with HNSCC and the related upper-aerodigestive tract cancers of the lung and esophagus and therefore have a major impact on cancer worldwide.

项目2摘要 顺铂（CDDP）是人乳头瘤病毒（HPV）阳性和负头的前线治疗 和颈部鳞状细胞癌（HNSCC）。不幸的是，CDDP没有可再现的预测指标 HNSCC反应和患者在经历了一段时间后会产生获得的抵抗，甚至遥远的转移 这种经常有毒化疗。为了更好地理解和解决CDDP治疗失败的临床问题， 我们使用已建立的HNSCC开发了实验室中获得的CDDP电阻的多个细胞系模型 具有不同基因组背景和TP53突变和功能状态的肿瘤线。令人惊讶的是，几乎 从这些各种基因组驱动器背景发展的每个CDDP克隆都有过度激活的 NRF2途径是由于从头躯体突变引起的，或降低了RNA的表达，Keap1（负 NRF2的调节器）。 NRF2激活与预后不良有关，对免疫治疗的反应不足， 转移和化学疗法抗性。我们证明了NRF2过度激活对于 保持获得后的抗性，从而提高了可以将途径临床瞄准或逆转的可能性 防止HNSCC中获得的CDDP抗性。通过用一种新药物靶向谷氨酰胺酶1（GLS）， NRF2活性所需的谷胱甘肽会耗尽，导致CDDP抗性的逆转。 同时，我们表明在重新编程的感觉神经元之间的旁分泌信号传导 肿瘤微环境可以促进CDDP的耐药性，并且有可能在药理上抑制 该信号轴可提高CDDP敏感性和肿瘤进展。此外，我们的临床前模型的数据 表明伴随CDDP耐药性的NRF2激活也可能导致更具侵略性的疾病 增加远处转移的速度。而NRF2过度激活可能是一个允许的，需要的步骤 获得的CDDP电阻，也可能有无独立的途径导致电阻。我们的中心 假设是通过躯体突变进行转录对照是NRF2过度激活是一种常见 以及在一系列基因组背景上开发获得的CDDP抗性的目标事件。到 在CDDP耐药性和肿瘤发展中，NRF2途径普遍存在的桥梁知识差距 进步和克服治疗失败的方法我们提出以下目的：1）定义贡献 HNSCC中获得的CDDP抗性的NRF2依赖性和独立的途径； 2）描述 获得的CDDP电阻，NRF2激活，神经元之间的功能和机械相互作用 在肿瘤微环境和DM中重新编程； 3）确定获得的CDDP电阻是否和 靶向代谢或稳定p53的药物可以克服肿瘤进展。完成这些 目标应产生可翻译的发现，以改善HNSCC和相关患者的治疗 肺和食道的上层大道消化道癌，因此对癌症产生了重大影响 全世界。