Inhaled Delivery of Vidaza for Targeted Epigenetic Lung Cancer Therapy

 产品说明：LC的新型靶向和化学疗法的发展已经在晚期LC的中位生存期方面取得了适度的改善，但它们没有提供明确的治疗途径，可以使其成为慢性而不是致命的疾病。此外，对于美国每年诊断的超过220，000例新肺癌病例中的大多数，大多数靶向治疗不是一种选择，化疗的持久反应是罕见的，复发后的中位生存期仅为6.5个月。这提出了一个艰巨的挑战，以开发一个不同的“盒子外”的方法，具有低全身毒性，这反过来将允许长期给药，以实现和维持治疗反应。癌症基因组图谱已经询问了600多个非小细胞肺癌（NSCLC），并发现几乎所有的肿瘤都含有数百个基因，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。表观遗传疗法通过其唤醒这些基因的能力提供了一种策略，最终可以产生持久和持续的肿瘤消退。一项II期试验将非细胞毒性剂量的去甲基化剂维达扎（5-氮杂胞苷）与组蛋白去乙酰化酶（HDAC）抑制剂恩替司他（MS 275）相结合，在难治性晚期NSCLC患者中显示出有希望的结果。所需的连续每日皮下给药方案可能会限制表观遗传治疗在III期试验或辅助治疗中的扩展，而口服制剂由于水解而存在问题;两种给药途径都受到胞苷脱氨酶的催化作用，大大缩短了维达扎的半衰期。这些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，雾化给药将Vidaza直接输送到肺部。气雾剂吸收到肺血管中也避免了肝脏首过，从而消除了胞苷脱氨基作用的初始灭活，同时提供全身剂量以治疗隐匿性转移。我们开发的原位肺癌模型，其中人肺癌衍生细胞系的异种移植物被移植到裸大鼠的整个肺中，允许测试组合疗法和不同的给药途径。我们的第一项研究表明，以类似于II期临床试验的剂量和时间表全身递送维达扎和恩替司他在抑制肿瘤生长60%方面具有协同作用，并诱导表观基因组的重编程，如通过基因去甲基化和重表达所检测到的。最近的研究表明，以气雾剂形式给药的Vidaza水性制剂可以有效降低肺肿瘤负荷，并以相当于有效全身剂量的三分之一诱导300个基因的常见整体去甲基化。本申请的主要目标是开发Vidaza的最佳气雾剂制剂，并开发与恩替司他和组蛋白甲基化抑制剂组合的给药策略，其使用我们的原位模型最大限度地影响NSCLC中的肿瘤负荷和表观基因组的重编程。这项工作的成果将使未来的创新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.