Aerosolized Epigenetic Therapy for Metastatic Lung Cancer

项目摘要 肺癌(LC)在全球每年超过200万例，仍然是癌症的主要原因。 美国和欧洲的相关死亡事件。治疗LC仍然具有挑战性，因为约60%的患者表现为 IV期疾病，肿瘤相对于改变的遗传和表观遗传机制的异质性 基因表达，与治疗相关的耐药性。把化疗和免疫治疗结合起来作为第一个 晚期LC的治疗方案显著提高了应答率和存活率；然而，中位数 无进展生存期(PFS)仍为8.8个月，IV期LC患者为4.9个月 化疗/免疫与化疗相比，一年存活率分别为69%和49%。二线药物 复发后提供最低限度的益处。表观遗传去调控涉及启动子中的胞嘧啶甲基化 数百个基因的区域，阻碍转录，导致表达丧失。因此，一种可以 逆转甲基化和唤醒这些基因可以产生持久和持续的肿瘤消退。这个 胞嘧啶核苷类似物5-氮杂胞苷(5AZA)和5-氮杂-2‘-脱氧胞苷(DAC)抑制酶 负责胞嘧啶甲基化导致通过胞嘧啶启动子沉默的基因的重新表达 高甲基化。这些FDA批准的药物是治疗血源性癌症的有效药物， 骨髓发育不良和急性白血病。包括LC在内的实体肿瘤的表观遗传治疗受到 5AZA和DAC水溶液稳定性差及肝脏和肝脏胞苷脱氨酶的分解代谢 大兵。Lovelace Biomedical与Bend Research/Lonza合作，通过开发一种 5AZA(5AZA-DP)稳定干粉(DP)配方。新型干粉雾化器(DryNeb)的研制 由Nob Hill Treateutics为局部肺递送产生最佳气雾剂颗粒大小-活动性和最佳 促进患者无强迫“轻松”潮气呼吸时的全身吸收特性 肺功能动作。在给潮汐呼吸大鼠注射5AZA-DP的研究中，优胜者 药代动力学在肝脏中实现，最令人印象深刻的是在大脑中，半衰期为4小时 与注射用5-AZA水溶液比较。用灌注法建立的大鼠肺肿瘤模型 从人肺肿瘤中获得的细胞，潮汐吸入5AZA-DP后，肿瘤负荷减少了70%-95% 评估了不同的非小细胞肺肿瘤，远远超过全身注射 5AZA。一项概念验证临床研究显示，在接受I期治疗的8名患者中，有3名患者出现了稳定的局限性肺癌 用雾化5AZA水溶液。第二阶段SBIR通过三个具体目标建立在这些令人兴奋的数据的基础上，通过 专注于5AZA-DP的配方放大和稳定性优化，气雾剂在 DryNeb和GLP毒理学研究。完成这些目标将支持申请研究药物 向FDA申请(IND)允许在I期剂量递增安全性中使用DryNeb对5AZA-DP进行评估 随后对接受标准护理治疗的LC患者进行IB期研究。

Project Summary Lung cancer (LC) with over 2 million cases/year worldwide also remains the leading cause of cancer- related death in the US and Europe. Treating LC remains challenging due to ~60% of patients presenting with Stage IV disease, the heterogeneity of tumors with respect to genetic and epigenetic mechanisms that alter gene expression, and treatment-related resistance. Combining chemotherapy with immunotherapy as the first treatment option for advanced LC has significantly improved response rates and survival; however, median duration for progression free survival (PFS) was still 8.8 versus 4.9 months for Stage IV LC patients receiving chemo/immune versus chemotherapy with 69% and 49% alive at one year, respectively. Second line drugs after relapse provide minimal benefit. Epigenetic deregulation involves cytosine methylation in the promoter region of hundreds of genes to impede transcription leading to loss of expression. Thus, a therapy that could reverse methylation and awaken these genes could produce durable and sustained tumor regression. The cytosine nucleoside analogs 5-azacytidine (5AZA) and 5-aza-2’-deoxycytidine (DAC) inhibit the enzyme responsible for cytosine methylation resulting in re-expression of genes silenced through cytosine promoter hypermethylation. These FDA approved drugs are serving as potent therapy for blood-borne cancers, myelodysplasia and acute leukemia. Epigenetic therapy for solid tumors including LC has been impacted by the poor stability in an aqueous solution of 5AZA and DAC and catabolism by cytidine deaminase in liver and GI. Lovelace Biomedical working with Bend Research/Lonza have overcome these barriers by developing a stable dry powder (DP) formulation of 5AZA (5AZA-DP). The novel dry powder nebulizer (DryNeb) developed by Nob Hill Therapeutics generates optimal aerosol particle sizes for local lung delivery-activity and optimal systemic absorption characteristics while facilitating patients’ “easy” tidal breathing inhalation with no forced pulmonary function maneuvers. In studies in which 5AZA-DP was delivered to tidally breathing rats, superior pharmacokinetics were achieved in the liver, and most impressively to the brain with a half-life of 4 hours when compared with injected aqueous solutions of 5AZA. Using a rat lung tumor model developed from instilling cells obtained from human lung tumors, tidally inhaled 5AZA-DP reduced tumor burden by 70–95% for the 4 different non-small cell lung tumors evaluated, far exceeding the 32% reduction seen with systemic injection of 5AZA. A proof-of-concept clinical study showed stable localized lung cancer in 3 of 8 Phase I patients treated with nebulized aqueous 5AZA. This Phase II SBIR through three specific aims builds on these exciting data by focusing on performing formulation scale up and stability optimization of 5AZA-DP, aerosol performance in the DryNeb, and GLP toxicology studies. Completion of these aims will support filing an investigational drug application (IND) to the FDA to allow evaluation of 5AZA-DP using DryNeb in a Phase I dose escalation safety study followed by a Phase IB study in LC patients who have relapsed on standard-of-care therapy.