Inhibition of lysosomal flux in carcinogen-induced head and neck cancer

抑制致癌物诱发的头颈癌中的溶酶体通量

基本信息

批准号：
10306375
负责人：
UMAMAHESWAR DUVVURI
金额：
$ 36.8万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10306375
关键词：
11q13 Adjuvant Therapy Alcohols Antimalarials Antineoplastic Agents Apoptosis Biochemical Biogenesis Biological Assay Calcium Carcinogens Cell Survival Cells Cessation of life Chimeric Proteins Chloride Channels Chlorides Chromosomal Duplication Cisplatin Clinical Trials Coupled Cytotoxic Chemotherapy Cytotoxic agent Data Development Disease Drug resistance Epithelial Excision Excretory function Exocytosis Exposure to FDA approved Genes Genetic Head and Neck Cancer Head and Neck Neoplasms Head and Neck Squamous Cell Carcinoma Human Imaging Techniques Immune Ion Channel Knock-out Libraries Link Lysosomes MAP Kinase Gene MAPK Signaling Pathway Pathway Malignant Neoplasms Mass Spectrum Analysis Measurement Measures Mediating Membrane Fusion Methods Modeling Molecular Mus National Institute of Dental and Craniofacial Research Oncogenic Operative Surgical Procedures Oral cavity Outcome Pathology Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Play Process Prognosis Proteomics Protocols documentation Radiation Reporting Resistance Role Sampling Signal Transduction TFE3 gene Testing Therapeutic Therapeutic Intervention Tissues Tobacco Toxin Translating Up-Regulation base cancer cell cancer drug resistance cancer therapy cancer type cell type chemoradiation chemotherapy clinical investigation confocal imaging driving force effective therapy experimental study genetic analysis genetic manipulation genomic data human model human tissue improved improved outcome inhibitor knock-down mortality mouse model mutant neoplastic cell new therapeutic target novel novel drug combination novel strategies overexpression patient derived xenograft model prevent public health relevance synaptotagmin VII synergism targeted agent tool trafficking transcription factor treatment strategy tumor tumor growth tumor xenograft tumorigenesis

项目摘要

Squamous cell carcinoma of the head and neck (SCCHN) is a devastating disease that has a dismal prognosis, despite aggressive surgical and adjuvant therapy. The average estimated overall survival for patients is approximately 50% at 5 years (NIDCR.GOV). The high mortality rate demonstrates that current therapeutic strategies are not adequate. In an effort to improve the outcomes for these patients, genetic analysis of SCCHN has been used to identify potential novel therapeutic targets. One of the most commonly altered genes in this malignancy is the calcium activated chloride channel TMEM16A/ANO1. TMEM16A is amplified in 30% of SCCHN, and overexpression is correlated with poor oncologic outcomes in several cancer types. Our recent data demonstrates that TMEM16A expression abrogates cisplatin-induced apoptosis. It is therefore likely that TMEM16A plays a cytoprotective role in cancer cells. How TMEM16A improves the survival and resistance of cancer cells to therapeutic interventions is unknown. Sequestration of the cancer drugs and other toxins by the lysosomes followed by their expulsion through the process of lysosomal exocytosis has emerged as a mechanism that enhances drug resistance of cancer cells. We find that TMEM16A expression is associated with increased lysosomal acidification, biogenesis and exocytosis. We propose that TMEM16A over-expressing cells are more efficient in the expulsion of cytotoxic drugs than wild-type cells. We also postulate that TMEM16A overexpressing tumors are more likely to upregulate lysosomal flux, and therefore contribute to oncogenesis and resistance to cytotoxic chemotherapy. This is a groundbreaking concept, since it identifies a new function of a novel ion channel and a new paradigm in cancer pathology and suggests a new approach to cancer treatment. During this project, we will identify the mechanism of the TMEM16A-dependent cytoprotective upregulation of the lysosomal throughput and sequestration/expulsion of cytotoxic drugs. We will test this hypothesis using human tissues and patient-derived xenograft models. Finally we will test our concepts using the mouse model of human head and neck tumors and the new approaches specifically aimed at suppressing lysosomal biogenesis and exocytosis using repurposed antimalarial drugs. The results for these studies can be directly translated to clinical investigations, by combining anti-lysosomal drugs with conventional cytotoxic agents, noth of which are FDA-approved agents.

头颈鳞状细胞癌 (SCCHN) 是一种毁灭性的疾病，预后不佳，尽管进行了积极的手术和辅助治疗。患者的平均估计总生存期为 5 年时约为 50% (NIDCR.GOV)。高死亡率表明目前的治疗策略不够充分。为了改善这些患者的治疗结果，对 SCCHN 进行基因分析已被用于识别潜在的新治疗靶点。该基因中最常改变的基因之一恶性肿瘤是钙激活的氯离子通道 TMEM16A/ANO1。 TMEM16A 的 30% 被扩增 SCCHN 和过度表达与多种癌症类型的不良肿瘤结果相关。我们最近的数据表明 TMEM16A 表达消除顺铂诱导的细胞凋亡。因此很可能 TMEM16A 在癌细胞中发挥细胞保护作用。 TMEM16A 如何提高癌细胞的存活率和对治疗干预的抵抗力尚不清楚。溶酶体隔离癌症药物和其他毒素，然后通过溶酶体排出溶酶体胞吐作用过程已成为增强癌细胞耐药性的机制。我们发现 TMEM16A 表达与溶酶体酸化、生物合成和胞吐作用。我们认为TMEM16A过表达细胞在排出细胞毒性物质方面更有效药物优于野生型细胞。我们还假设 TMEM16A 过表达的肿瘤更有可能上调溶酶体通量，因此有助于肿瘤发生和对细胞毒性化疗的抵抗。这是一个开创性的概念，因为它确定了新型离子通道的新功能和癌症的新范例病理学并提出了一种新的癌症治疗方法。在这个项目中，我们将确定 TMEM16A 依赖性细胞保护上调的机制溶酶体吞吐量和细胞毒性药物的隔离/排出。我们将使用以下方法来检验这个假设人体组织和患者来源的异种移植模型。最后我们将使用鼠标模型测试我们的概念人类头颈部肿瘤的研究以及专门针对抑制溶酶体的新方法使用重新利用的抗疟药物进行生物发生和胞吐作用。这些研究的结果可以直接通过将抗溶酶体药物与常规细胞毒药物相结合转化为临床研究，其中是 FDA 批准的制剂。