Inhaled Delivery of Vidaza for Targeted Epigenetic Lung Cancer Therapy

 描述：针对LC的新的靶向和化疗疗法的发展已经使晚期LC的中位生存期有了适度的改善，但它们没有提供明确的治疗途径，可能使这种疾病成为一种慢性而不是致命的疾病。此外，在美国每年确诊的22万多例新肺癌病例中，大多数人都不能选择大多数靶向治疗，化疗的持久反应并不常见，复发后的中位生存期仅为6.5个月。这就提出了一项艰巨的挑战，即要开发一种不同的、具有低系统毒性的“开箱即用”方法，从而使慢性给药能够实现并维持治疗反应。癌症基因组图谱询问了600多例非小细胞肺癌(NSCLC)，发现几乎所有肿瘤都包含数百个基因，这些基因具有密集的胞嘧啶甲基化启动子区域，导致转录减少。表观遗传疗法通过唤醒这些基因的能力，提供了一种最终可能产生持久和持续的肿瘤消退的策略。一项将非细胞毒性剂量的脱甲基维达扎(5-azacytidine)与组蛋白脱乙酰酶(HDAC)抑制剂Eninostat(MS275)相结合的II期试验显示，在难治性晚期NSCLC患者中取得了有希望的结果。所需的连续每日皮下给药时间表可能会限制表观遗传疗法在第三阶段试验或辅助治疗中的扩展，而口服制剂因水解而出现问题；这两种给药途径都受到胞苷脱氨酶的分解代谢，从而大大缩短了Vidaza的半衰期。这些阻碍扩大使用和改善对表观遗传疗法的反应的障碍可以通过雾化给药来缓解，这种雾化给药将把Vidaza直接输送到肺部。气雾剂被肺血管吸收也避免了肝脏首次通过，从而消除了胞苷脱氨所致的初始失活，同时提供了全身剂量来治疗隐匿性转移瘤。我们开发的原位肺癌模型，其中人肺癌来源的细胞系异种移植到整个裸鼠的肺部，允许测试联合治疗和不同的给药途径。我们的第一个研究表明，与II期临床试验相似的剂量和时间表的全身给药，在抑制肿瘤生长方面具有协同作用，并通过基因去甲基化和重新表达检测到诱导表观基因组的重新编程。最近的研究表明，以雾化吸入的形式给予维达扎的水性制剂可以有效地减轻肺癌的负担，并以可比有效全身剂量的三分之一诱导300个基因的共同全局去甲基化。这项应用的主要目标是开发Vidaza的最佳气雾剂配方，并利用我们的原位模型开发与内抑素和组蛋白甲基化抑制剂相结合的剂量策略，以最大限度地影响NSCLC的肿瘤负担和表观基因组的重新编程。这项工作的最终结果将使未来创新的I/II期肺癌临床试验成为可能。

 DESCRIPTION: The evolution of novel targeted- and chemo-therapies for LC has achieved modest improvement in median survival for advanced LC, but they offer no clear path to treatments that could make this a chronic, rather than fatal disease. Furthermore, for the majority of the more than 220,000 new lung cancer cases diagnosed annually in the US for which most targeted therapy is not an option, durable responses with chemotherapy are uncommon and median survival after relapse is only 6.5 months. This presents a daunting challenge to develop a different "outside of the box" approach with low systemic toxicity that in turn will allow chronic dosing to achieve and sustain therapeutic responses. The Cancer Genome Atlas has interrogated over 600 non-small cell lung cancers (NSCLCs) and revealed that virtually all tumors contain hundreds of genes that have densely cytosine methylated promoter regions leading to reduced transcription. Epigenetic therapy through its ability to awaken these genes offers a strategy that could ultimately produce durable and sustained tumor regression. A Phase II trial combining non-cytotoxic doses of the demethylating agent Vidaza (5- azacytidine) with the histone deacetylase (HDAC) inhibitor entinostat (MS275) showed promising results in patients with refractory, advanced NSCLC. The required continuous daily subcutaneous dosing schedule may constrain the expansion of epigenetic therapy in Phase III trials or in adjuvant therapy, while oral formulations are problematic due to hydrolysis; both dosing routes are subjected to catabolism by cytidine deaminase that greatly reduces Vidaza half-life. These barriers to expanding use and improving the response to epigenetic therapy could be mitigated by aerosolized administration that would deliver Vidaza directly to the lungs. The absorption of the aerosol into the pulmonary vasculature also avoids hepatic first pass, thus eliminating initial inactivation by cytidine deamination, while providing systemic dose to treat occult metastases. The orthotopic lung cancer model we developed in which xenografts of human lung cancer-derived cell lines are engrafted throughout the lungs of the nude rat allows testing of combination therapies and different routes of administration. Our first studies demonstrated that systemic delivery of Vidaza and entinostat at doses and schedule similar to the Phase II clinical trial were synergistic in suppressing tumor growth by 60% and induced reprogramming of the epigenome as detected by gene demethylation and re-expression. Recent studies now show that an aqueous formulation of Vidaza administered as an aerosol can effectively reduce lung tumor burden and induce common global demethylation of 300 genes at one-third the comparable effective systemic dose. The major goals of this application are to develop an optimal aerosol formulation of Vidaza, and to develop dosing strategies in combination with entinostat and inhibitors of histone methylation that maximally affect tumor burden and reprogramming of the epigenome in NSCLC using our orthotopic model. The culmination of this work will enable future innovative Phase I/II lung cancer clinical trials.