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.

头部和颈部鳞状细胞癌（SCCHN）是一种毁灭性疾病，预后很沮丧，尽管有进取心的手术和辅助治疗。患者的平均估计总生存期为 5年时约50％（nidcr.gov）。高死亡率表明当前的治疗策略不足。为了改善这些患者的结果，SCCHN的遗传分析已被用来识别潜在的新型治疗靶标。其中最常见的基因之一恶性肿瘤是钙活化的氯化物通道TMEM16A/ANO1。 TMEM16A在30％的30％ SCCHN和过表达与几种癌症类型的肿瘤学结局不良相关。我们最近数据表明，TMEM16A表达消除了顺铂诱导的凋亡。因此很可能 TMEM16A在癌细胞中起细胞保护作用。 TMEM16A如何提高癌细胞对治疗干预措施的存活率和抵抗力尚不清楚。通过溶酶体隔离癌症药物和其他毒素，然后通过其驱逐溶酶体胞吐作用的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，生物发生和胞吞作用。我们建议TMEM16A过表达的细胞在驱逐细胞毒性方面更有效药物比野生型细胞。我们还假设TMEM16A过表达的肿瘤更有可能上调溶酶体通量，因此有助于造成细胞毒性化疗的肿瘤发生和抗性。这是一个突破性的概念，因为它确定了新型离子通道的新功能和癌症的新范式病理学并提出了一种新的癌症治疗方法。在此项目中，我们将确定TMEM16A依赖性细胞保护的机理溶酶体吞吐量和细胞毒性药物的隔离/驱动。我们将使用人体组织和患者衍生的异种移植模型。最后，我们将使用鼠标模型测试我们的概念人头和颈部肿瘤以及专门旨在抑制溶酶体的新方法使用再利用抗疟药的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性剂相结合，转化为临床研究其中是FDA批准的代理。