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) 是成人中最常见的恶性原发性脑癌，平均生存期为 1 治疗包括最大程度的安全切除，然后进行放化疗和替莫唑胺辅助治疗。 (TMZ)，后者仅使中位生存期增加了 2.5 个月，而且大多数靶向治疗试验都显示。 由于酪氨酸激酶受体和相关血脑屏障（BBB）的激活而未成功 因此，迫切需要找到一种更有效的治疗方法。 使用连接地图（CMap）生成的数据，该地图由远大研究所开发，用于识别药物 通过分析 4 个样本中的 99 个 GBM 和 38 个相邻正常样本，根据癌症的遗传图谱重新调整用途。 通过数据库分析，CMap 将组蛋白脱乙酰酶 (HDAC) 抑制剂确定为最佳候选药物。 GEPIA 将 HDAC1 和 HDAC2 确定为上调程度最高的 HDAC，将 HDAC11 确定为下调程度最高的 HDAC。 因此，我们选择了 BBB 渗透性 PCI-24781/abexinostat，因为它对 GBM 基因特征具有特异性 - 特定 HDAC（抑制 HDAC1 和 HDAC2，但不抑制 HDAC11 或 IIa 类 HDAC）进行初步评估。 研究表明，与其他泛 HDAC 抑制剂相比，PCI-24781 诱导显着更大的细胞凋亡和 在体外 GBM 细胞系中下调 DNA 修复机制（CHK1、RAD51 和 MGMT）此外，PCI-24781。 与 TMZ 联合使用，可有效降低原位小鼠模型中的肿瘤负荷 伏立诺他联合 TMZ 并提高生存率，我们认为通过 PCI 可以抑制 1 类 HDAC。 24781 将通过靶向 DNA 修复机制来增强 TMZ 在 GBM 中的功效。为了检验这一假设，我们。 我们提出了两个具体目标：在目标 1 中，我们将评估 PCI-24781 与 TMZ 在体内 GBM 模型中的功效。 将使用小鼠 GBM 类器官、基因工程 GBM 小鼠模型和患者来源的异种移植物 评估 BBB 通透性并测量毒性，并记录每项的治疗效果和存活率。 我们将分析单独和联合使用 PCI-24781 和 TMZ 治疗的小鼠组的效果。 通过 IHC 对切除肿瘤中的 DNA 修复机制蛋白进行联合治疗，还将进行 RNA- seq 和 Omni-ATAC-seq 分析分别确定其他途径和染色质可及性， 受 PCI-24781 的影响 在目标 2 中，1 期临床试验将评估毒性并确定 PCI-24781 的 MTD。 24781 用 TMZ 治疗复发性高级别神经胶质瘤患者 我们将分析患者的外泌体以证明。 这些目标将共同阐明蛋白质乙酰化和 BBB 通透性之间的协同机制。 PCI-24781与TMZ在GBM中的耐受性将PCI-24781与TMZ结合将成功克服TMZ。 抵抗，对肿瘤生长和复发产生负面影响，有效提高GBM的生存率 患者。

项目成果

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

成人胶质瘤年龄调整县发病率空间分布的探索性分析，内布拉斯加州医学，2009-2019 年。

• 发表时间: 2024-02
• 作者: Ratnapradipa, Kendra L;Yellala, Amulya;Shonka, Nicole
• 通讯作者: Shonka, Nicole