Aerosolized Epigenetic Therapy for Metastatic Lung Cancer

雾化表观遗传疗法治疗转移性肺癌

• 批准号: 10760630
• 负责人: Steven A Belinsky
• 金额: $ 86.11万
• 依托单位: NOB HILL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10760630
• 关键词: Acute leukemia; Aerosols; Air; Air Movements; Azacitidine; Brain; Breathing; Cancer Etiology; Cancer Model; Cancer Patient; Catabolism; Cells; Cessation of life; Characteristics; Chemicals; Chronic Obstructive Pulmonary Disease; Clinic; Clinical Research; Combination Drug Therapy; Cytidine Deaminase; Cytosine; Data; Deoxycytidine; Devices; Diagnosis; Disease; Documentation; Dose; Drug Kinetics; Dryness; Dysmyelopoietic Syndromes; Emulsions; Enzyme Inhibition; Epigenetic Process; Europe; Evaluation; FDA approved; Forced expiratory volume function; Formulation; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Transcription; Half-Life; Hour; Human; Hypermethylation; Immune; Immunotherapy; Inhalation; Inhalation Toxicology; Inhalators; Injections; Investigational Drugs; Label; Legal patent; Liver; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Methylation; Modeling; Nebulizer; Particle Size; Patients; Performance; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Powder dose form; Practice Guidelines; Progression-Free Survivals; Promoter Regions; Rattus; Regulatory Pathway; Relapse; Reporting; Research; Resistance; Rodent; Rodent Model; Safety; Signal Pathway; Small Business Innovation Research Grant; Solid Neoplasm; Stream; Technology; Testing; Therapeutic; Tissues; Toxicology; Tumor Burden; Work; absorption; aerosolized; aqueous; chemotherapy; epigenetic therapy; first-in-human; good laboratory practice; immune activation; improved; in vivo; innovation; manufacture; novel; nucleoside analog; phase III trial; pre-clinical; pressure; programs; promoter; pulmonary function; quality assurance; research clinical testing; response; safety study; scale up; standard of care; success; transcriptome; transcriptome sequencing; tumor; tumor heterogeneity

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.

项目摘要 肺癌（LC）在全球每年有超过200万例病例，仍然是癌症的主要原因- 在美国和欧洲的相关死亡。LC治疗仍然具有挑战性，因为约60%的患者表现为 IV期疾病，肿瘤在遗传和表观遗传机制方面的异质性， 基因表达和治疗相关的耐药性。以化疗和免疫治疗相结合为先 晚期LC的治疗选择显著提高了缓解率和生存率;然而， 无进展生存期（PFS）的持续时间仍然为8.8个月，而接受化疗的IV期LC患者为4.9个月。 化疗/免疫与化疗相比，分别有69%和49%的患者在一年内存活。二线药物 在复发后提供最小的益处。表观遗传失调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 逆转甲基化并唤醒这些基因可以产生持久和持续的肿瘤消退。的 胞嘧啶核苷类似物5-氮杂胞苷（5AZA）和5-氮杂-2 '-脱氧胞苷（DAC）抑制该酶 负责胞嘧啶甲基化，导致通过胞嘧啶启动子沉默的基因重新表达 超甲基化。这些FDA批准的药物是作为血液传播的癌症的有效治疗， 骨髓增生异常和急性白血病。包括LC在内的实体瘤的表观遗传治疗受到以下因素的影响： 在5AZA和DAC的水溶液中的稳定性差，并且在肝脏中被胞苷脱氨酶催化， 美国大兵Lovelace Biomedical与弯曲研究/龙沙合作，通过开发一种 5AZA稳定干粉（DP）制剂（5AZA-DP）。新型干粉雾化器（DryNeb）开发 由诺布希尔治疗产生最佳的气雾剂颗粒大小的局部肺输送活性和最佳的 全身吸收特性，同时促进患者“容易”的潮式呼吸吸入， 肺功能检查在将5AZA-DP递送至潮式呼吸大鼠的研究中上级 在肝脏中实现了药代动力学，最令人印象深刻的是在大脑中，半衰期为4小时， 与注射的5AZA水溶液相比。使用大鼠肺肿瘤模型， 从人肺肿瘤中获得的细胞，潮汐吸入5AZA-DP使4例患者的肿瘤负荷降低了70-95%。 不同的非小细胞肺肿瘤的评估，远远超过了32%的减少与全身注射 5AZA。一项概念验证临床研究显示，8例I期治疗患者中有3例出现稳定的局部肺癌 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基础上， 专注于进行5AZA-DP的处方放大和稳定性优化， DryNeb和GLP毒理学研究。完成这些目标将支持研究药物的备案 向FDA提交IND申请，允许在I期剂量递增安全性研究中使用DryNeb评价5AZA-DP 在标准治疗后复发的LC患者中进行的IB期研究。