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

头颈部鳞状细胞癌(SCCHN)是一种毁灭性的疾病，预后很差， 尽管进行了积极的手术和辅助治疗。患者的平均总存活率估计为 5年时约50%(NIDCR.GOV)。高死亡率表明，目前的治疗方法 战略是不够的。为了改善这些患者的预后，对SCCHN的基因分析 已被用于确定潜在的新治疗靶点。其中最常见的改变基因之一 恶性肿瘤是钙激活的氯离子通道TMEM16A/ANO1。TMEM16A在30%的人中扩增 在几种癌症类型中，SCCHN的过度表达与不良的肿瘤预后相关。我们最近 数据表明，TMEM16A的表达可以抑制顺铂诱导的细胞凋亡。因此，很可能是 TMEM16A对癌细胞具有细胞保护作用。 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。 通过溶酶体隔离抗癌药物和其他毒素，然后通过 溶酶体胞吐过程已成为增强癌细胞耐药性的一种机制。 我们发现TMEM16A的表达与溶酶体酸化、生物发生和 胞吐。我们认为TMEM16A过表达细胞在排出细胞毒物方面更有效 药物比野生型细胞多。我们还假设TMEM16A过表达的肿瘤更有可能上调 溶酶体通量，因此有助于肿瘤的发生和对细胞毒化疗的耐药性。这是一个 突破性的概念，因为它确定了一种新的离子通道的新功能和癌症的新范式 并提出了一种治疗癌症的新方法。 在这个项目中，我们将确定TMEM16A依赖的细胞保护性上调的机制 溶酶体的吞吐能力和细胞毒药物的隔离/排出。我们将使用以下工具验证这一假设 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 以及专门针对抑制溶酶体的新方法 使用重新调整用途的抗疟疾药物的生物发生和胞吐作用。这些研究的结果可以直接 转化为临床研究，通过将抗溶酶体药物与传统细胞毒剂相结合，没有 其中包括FDA批准的药物。

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.