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

• 批准号: 10542340
• 负责人: UMAMAHESWAR DUVVURI
• 金额: $ 12.42万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542340
• 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; Cytoprotection; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Development; Disease; Drug resistance; Epithelium; 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; Induction of Apoptosis; 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; Play; Process; Prognosis; Proliferating; Proteomics; Protocols documentation; Radiation; Reporting; Resistance; Role; Sampling; Signal Transduction; TFE3 gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tobacco; Toxin; Translating; Tumor Promotion; Up-Regulation; 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; new therapeutic target; novel; novel drug combination; novel strategies; overexpression; patient derived xenograft model; pharmacologic; prevent; public health relevance; synaptotagmin VII; synergism; targeted agent; tool; trafficking; transcription factor; treatment strategy; tumor; tumor growth; tumor xenograft; tumorigenesis

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.

头颈部鳞状细胞癌（SCCHN）是一种预后不佳的毁灭性疾病，