Connectivity mapping identified novel combination therapy for glioblastoma

连接映射确定了胶质母细胞瘤的新型联合疗法

• 批准号: 10686268
• 负责人: Surinder K. Batra
• 金额: $ 43.7万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686268
• 关键词: ATAC-seq; Acetylation; Adjuvant; Adult; Aftercare; Apoptosis; Archives; Blood - brain barrier anatomy; Brain Neoplasms; CHEK1 gene; Cell Line; Cells; Chromatin; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Communities; Correlative Study; DNA Repair; DNA Repair Pathway; Data; Data Set; Databases; Dose; Dose Limiting; Drug resistance; Enzymes; Excision; FDA approved; Gene Expression Profiling; Genetic; Genetic Engineering; Glial Fibrillary Acidic Protein; Glioblastoma; Glioma; HDAC1 gene; HDAC11 gene; HDAC2 gene; Heat-Shock Proteins 90; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; In Vitro; Interruption; LoxP-flanked allele; MGMT gene; Malignant - descriptor; Malignant neoplasm of brain; Maps; Measures; Modality; Modeling; Mus; Operative Surgical Procedures; Organoids; PTEN gene; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase I Clinical Trials; Protein Acetylation; Proteins; Radiation therapy; Receptor Protein-Tyrosine Kinases; Recurrence; Resected; Resistance; Sampling; Signal Transduction; Specificity; Survival Rate; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Tumor Burden; Vorinostat; Xenograft procedure; bioinformatics tool; blood-brain barrier permeabilization; cancer genetics; candidate identification; chemoradiation; cohort; design; drug candidate; drug repurposing; effective therapy; efficacy evaluation; epidermal growth factor receptor VIII; exosome; genetic signature; improved; in vivo; inhibitor; mouse model; neuro-oncology; novel; patient derived xenograft model; pharmacologic; phase 1 study; pre-clinical; preclinical study; response; response biomarker; success; synergism; targeted therapy trials; temozolomide; tool; transcriptome sequencing; tumor; tumor growth

Abstract Glioblastoma (GBM), the most common malignant primary brain cancer in adults, has an average survival of one year. Treatment includes maximal safe resection, followed by chemoradiation and adjuvant temozolomide (TMZ), the latter only increasing median survival by 2.5 months. Moreover, most targeted therapy trials have been unsuccessful due to activation of tyrosine kinase receptors and relative blood-brain barrier (BBB) impermeability. Thus, a pressing need remains to find a more effective therapy. This study builds on preliminary data generated using Connectivity Map (CMap), developed by the BROAD institute to identify drugs for repurposing based on cancer’s genetic profile. By analyzing 99 GBM and 38 adjacent normal samples from 4 datasets, CMap identified histone deacetylase (HDAC) inhibitors as top candidates. Database analysis using GEPIA identified HDAC1 and HDAC2 as the most upregulated and HDAC11 as the most downregulated HDACs. Thus, we selected the BBB permeant PCI-24781/abexinostat due to its specificity for GBM gene signature- specific HDACs (inhibiting HDAC1 and HDAC2, but not HDAC11, or class IIa HDACs) to evaluate. In preliminary studies, as compared to other pan HDAC inhibitors, PCI-24781 induced significantly greater apoptosis and downregulated DNA repair machinery (CHK1, RAD51, and MGMT) in GBM cell lines in vitro. Further, PCI-24781 efficiently decreased the tumor burden in orthotopic murine models in combination with TMZ compared to vorinostat with TMZ and enhanced survival. From this, we hypothesize that inhibiting class 1 HDACs with PCI- 24781 will enhance the efficacy of TMZ in GBM by targeting DNA repair machinery. To test this hypothesis, we propose two specific aims: In Aim 1, we will evaluate the efficacy of PCI-24781 with TMZ in in vivo GBM models. Murine GBM organoids, genetically engineered GBM mouse models, and patient-derived xenografts will be used to evaluate BBB permeability and to measure toxicity. Therapeutic efficacy and survival will be recorded for each group of mice treated with PCI-24781 and TMZ singly and in combination. We will analyze the effect of combination therapy on DNA repair machinery proteins by IHC in resected tumors and will also perform RNA- seq and Omni-ATAC-seq analyses to identify additional pathways and chromatin accessibility, respectively, impacted by PCI-24781. In Aim 2, a phase 1 clinical trial will evaluate toxicity and determine the MTD of PCI- 24781 with TMZ in recurrent high-grade glioma patients. We will analyze patient exosomes to demonstrate protein acetylation and BBB permeability. Together, these aims will elucidate mechanisms for synergy between and tolerance of PCI-24781 with TMZ in GBM. Combining PCI-24781 with TMZ will successfully overcome TMZ resistance, negatively impacting tumor growth and recurrence and effectively improving the survival of GBM patients.

抽象的 胶质母细胞瘤（GBM）是成年人中最常见的恶性原发性脑癌，平均存活率为一个 年。治疗包括最大的安全切除，然后进行化学放疗和调整替莫唑胺 （TMZ），后者仅增加中位生存期2.5个月。此外，大多数有针对性的治疗试验具有 由于酪氨酸激酶受体的激活和相对脑屏障（BBB）而失败 不理性。这是找到更有效的疗法的紧迫需求。这项研究以初步为基础 广泛研究所开发的连接图（CMAP）生成的数据，以识别用于 基于癌症的遗传特征重新利用。通过分析来自4个的99 GBM和38个相邻的正常样品 数据集CMAP鉴定出组蛋白脱乙酰基酶（HDAC）抑制剂是顶级候选者。数据库分析使用 GEPIA将HDAC1和HDAC2识别为最新的HDAC11，是最下调的HDAC。 这是，我们选择了BBB Pereant PCI-24781/Abexinostat，因为它对GBM基因签名的特异性 - 特定的HDAC（抑制HDAC1和HDAC2，而不是HDAC11或IIA级HDACS）来评估。在初步 研究，与其他PAN HDAC抑制剂相比，PCI-24781诱导的凋亡明显更大和 在体外GBM细胞系中的下调DNA修复机械（CHK1，RAD51和MGMT）。此外，PCI-24781 与TMZ相比 带有TMZ并增强生存的伏诺替托特。从中，我们假设抑制具有PCI的1类HDAC 24781将通过靶向DNA修复机械来提高TMZ在GBM中的效率。为了检验这一假设，我们 提案两个具体的目标：在AIM 1中，我们将使用TMZ在体内GBM模型中评估PCI-24781的效率。 将使用鼠GBM类器官，基因工程的GBM小鼠模型和患者衍生的Xenographicts 评估BBB渗透性并测量毒性。将记录每种治疗效率和生存 用PCI-24781和TMZ治疗的一组小鼠单独使用。我们将分析 IHC在切除的肿瘤中对DNA修复机械蛋白的联合疗法，还将进行RNA- SEQ和OMNI-ATAC-SEQ分析分别识别其他途径和染色质可及性 受PCI-24781的影响。在AIM 2中，1期临床试验将评估毒性并确定PCI的MTD 24781在复发性高度神经胶质瘤患者中具有TMZ。我们将分析患者外泌体以证明 蛋白质乙酰化和BBB渗透性。这些目标共同阐明了协同作用的机制 PCI-24781在GBM中使用TMZ的耐受性。将PCI-24781与TMZ相结合将成功克服TMZ 抗性，对肿瘤生长和复发产生负面影响，并有效提高GBM的存活率 患者。

项目成果

Exploratory analysis of the spatial distribution of adult glioma age-adjusted county incidence rates, Nebraska Medicine, 2009-2019.

• DOI: 10.1093/nop/npad050
• 发表时间: 2024-02
• 期刊: Neuro-oncology practice
• 影响因子: 2.7