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概述