Inhaled Delivery of Vidaza for Targeted Epigenetic Lung Cancer Therapy

吸入 Vidaza 用于靶向表观遗传肺癌治疗

• 批准号: 10208793
• 负责人: Steven A Belinsky
• 金额: $ 47.58万
• 依托单位: LOVELACE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208793
• 关键词: Adjuvant; Adjuvant Therapy; Aerosols; Affect; Amino Acids; Apoptosis; Azacitidine; Cancer Etiology; Cancer Model; Catabolism; Cell Line; Cell Proliferation; Cell Survival; Chromatin Remodeling Factor; Chronic; Combined Modality Therapy; Coupled; Cytidine; Cytidine Deaminase; Cytosine; Deacetylation; Deamination; Diagnosis; Diffusion; Disease; Dose; Drug Kinetics; EZH2 gene; Epigenetic Process; Evolution; Formulation; Functional disorder; Future; Gene Silencing; Genes; Genetic Transcription; Goals; Gravitation; Growth; Half-Life; Hepatic; Heterogeneity; Histology; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Human; Hydrolysis; Hypermethylation; In Vitro; Inhalation; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Methylation; Modeling; Modification; Molecular; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Nude Rats; Oral; Particle Size; Pathogenesis; Pathway interactions; Patients; Performance; Peripheral; Pharmaceutical Preparations; Pharmacology; Phase; Phase I/II Clinical Trial; Phase II Clinical Trials; Powder dose form; Progression-Free Survivals; Promoter Regions; Rattus; Refractory; Relapse; Route; Schedule; Secondary Prevention; Sedimentation process; Squamous Cell; Testing; The Cancer Genome Atlas; Translating; Tumor Burden; Tumor Suppressor Genes; Tumor-Derived; Vidaza; Work; Xenograft procedure; absorption; aerosolized; aqueous; base; cancer cell; cancer clinical trial; cancer therapy; cell growth; chemotherapy; comparative efficacy; demethylation; epigenetic therapy; epigenome; gene panel; histone methylation; histone methyltransferase; improved; in vivo; inhibitor/antagonist; innovation; novel; partial response; phase II trial; phase III trial; promoter; public health relevance; response; small molecule inhibitor; subcutaneous; systemic toxicity; targeted treatment; treatment response; tumor; tumor growth; tumor heterogeneity; virtual

 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.

 描述：新型靶向和化学治疗的LC的演变已在晚期LC的中位生存率方面取得了适度的改善，但它们没有提供明确的治疗方法，可以使这种治疗可能导致这种慢性，而不是致命的疾病。此外，在美国每年被诊断出的22万多个新的肺癌病例中，大多数靶向疗法都不是一种选择，化学疗法的持久反应并不常见，退休后的中位生存期为6.5个月。这提出了一个艰巨的挑战，即以低系统性毒性开发出不同的“盒子外”方法，进而将使长期的剂量能够实现和持续的治疗反应。癌症基因组图集已经询问了600多种非小细胞肺癌（NSCLC），并揭示了几乎所有肿瘤都包含数百个基因，这些基因具有巨大的胞质甲基化启动子区域，导致转录减少。通过唤醒这些基因的能力，表观遗传疗法提供了一种策略，最终可以产生持久且持续的肿瘤回归。脱甲基剂vidaza（5-苯乙他）与组蛋白脱乙酰基酶（HDAC）抑制剂肠球菌（MS275）相结合的II期试验，将脱甲基化剂vidaza（5-苯乙他）（5-Azacytidine）与耐火剂，晚期NSCLC患者产生了希望。所需的每日连续下给药时间表可能会限制在III期试验或调整治疗中表观遗传疗法的扩展，而口服配方由于水解而有问题。两种剂量途径都被胞丁死亡酶的分解代谢，从而大大降低了维达扎半衰期。这些障碍可以通过雾化的给药来缓解使用和改善对表观遗传疗法的反应，从而将Vidaza直接传递到肺部。气溶胶吸收到肺脉管系统中也避免了肝炎的第一次过去，从而消除了胞苷死亡的初始失活，同时提供了系统性剂量来治疗转移酶。我们开发的原始肺癌模型在裸鼠的整个肺部植入了人类肺癌衍生细胞系的异种移植，允许对联合疗法和不同的给药途径进行测试。我们的第一项研究表明，以剂量的剂量和安排类似于II期临床试验的剂量的全身递送在抑制肿瘤生长60％的抑制和诱导的表观基因组的重新编码方面是协同作用的。最近的研究现在表明，作为气溶胶给药的维达扎的水性公式可以有效地减少肺部肿瘤燃烧，并诱导300个基因的共同全球脱甲基化，三分之一是可比有效的全身剂量。该应用的主要目标是开发Vidaza的最佳气溶胶公式，并与组蛋白甲基化的Entinostat和抑制剂共同开发出剂量策略，该抗体蛋白甲基化的抑制剂最大程度地影响NSCLC中表观基因组的肿瘤燃烧和重编程。这项工作的高潮将使未来的创新阶段I/II肺癌临床试验。