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

基本信息

项目摘要

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.
摘要 胶质母细胞瘤(GBM)是成人中最常见的恶性原发性脑癌, 年治疗包括最大限度的安全切除,其次是放化疗和辅助替莫唑胺 (TMZ)后者仅使中位生存期延长2.5个月。此外,大多数靶向治疗试验 由于酪氨酸激酶受体的激活和相对的血脑屏障(BBB)而未成功 不渗透性因此,迫切需要找到更有效的治疗方法。这项研究建立在初步的 使用连接图(CMap)生成的数据,由BROAD研究所开发,用于识别 根据癌症的基因图谱进行再利用本文分析了4个地区99例GBM和38例邻近正常组织标本, 数据集,CMap确定组蛋白脱乙酰酶(HDAC)抑制剂为首选。数据库分析使用 GEPIA将HDAC 1和HDAC 2鉴定为上调最多的HDAC,将HDAC 11鉴定为下调最多的HDAC。 因此,我们选择了BBB渗透性PCI-24781/阿贝司他,这是由于其对GBM基因标签的特异性。 特异性HDAC(抑制HDAC 1和HDAC 2,但不抑制HDAC 11或IIa类HDAC)进行评估。初步 研究表明,与其他泛HDAC抑制剂相比,PCI-24781诱导的细胞凋亡显著增加, 在体外GBM细胞系中下调DNA修复机制(CHK 1、RAD 51和MGMT)。此外,PCI-24781 有效地降低了原位鼠模型中的肿瘤负荷,与TMZ组合, vorinostat与TMZ和提高生存率。由此,我们假设用PCI抑制1类HDAC- 24781将通过靶向DNA修复机制增强TMZ在GBM中的功效。为了验证这个假设,我们 提出两个具体目标: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 以评估BBB渗透性并测量毒性。将记录每种药物的疗效和生存期 用PCI-24781和TMZ单独和组合处理的小鼠组。我们将分析 通过IHC在切除的肿瘤中对DNA修复机器蛋白进行联合治疗,还将进行RNA- seq和Omni-ATAC-seq分析,以分别鉴定其他途径和染色质可及性, 受PCI-24781影响。在目标2中,1期临床试验将评估毒性并确定PCI的MTD。 24781例复发性高级别胶质瘤患者接受TMZ治疗。我们将分析患者的外泌体, 蛋白质乙酰化和血脑屏障通透性。这些目标将共同阐明以下方面的协同机制: 和PCI-24781与TMZ在GBM中的耐受性。PCI-24781与TMZ联合应用可成功克服TMZ 耐药性,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

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Surinder K. Batra其他文献

Functions of tumorigenic and migrating cancer progenitor cells in cancer progression and metastasis and their therapeutic implications
  • DOI:
    10.1007/s10555-007-9052-4
  • 发表时间:
    2007-02-02
  • 期刊:
  • 影响因子:
    8.700
  • 作者:
    Murielle Mimeault;Surinder K. Batra
  • 通讯作者:
    Surinder K. Batra
Wolfram 症候群の実態調査
关于 Wolfram 综合征的事实调查
  • DOI:
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Yukihiro Tamura;Michiyo Higashi;Sho Kitamoto;Seiya Yokoyama;Masahiko Osako;Michiko Horinouchi;Takeshi Shimizu;Mineo Tabata;Surinder K. Batra;Masamichi Goto;Suguru Yonezawa;松永仁恵,田部勝也,太田康晴,奥屋 茂,和田安彦,山田祐一郎,雨宮 伸,杉原茂孝,岡 芳知,谷澤幸生
  • 通讯作者:
    松永仁恵,田部勝也,太田康晴,奥屋 茂,和田安彦,山田祐一郎,雨宮 伸,杉原茂孝,岡 芳知,谷澤幸生
PP01.05 Targeting MUC16-Mediated KRASi Resistance in NSCLC
PP01.05 针对非小细胞肺癌中 MUC16 介导的 KRASi 耐药性
  • DOI:
    10.1016/j.jtho.2025.03.013
  • 发表时间:
    2025-04-01
  • 期刊:
  • 影响因子:
    20.800
  • 作者:
    Ashu Shah;Shamema Salam;Sanjib Chaudhary;Iniyan A. Muthamil;Imayavaramban Lakshmanan;Surinder K. Batra;Apar K. Ganti
  • 通讯作者:
    Apar K. Ganti
Mo1138 COMPARATIVE PROTEOMICS REVEALS TRANSLATIONAL POTENTIAL OF TARGETS FOR PANCREATIC DUCTAL ADENOCARCINOMA
  • DOI:
    10.1016/s0016-5085(23)02780-4
  • 发表时间:
    2023-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Mathilde Resell;Hanne-Line Rabben;Manoj Amrutkar;Lars Hagen;Surinder K. Batra;Caroline S. Verbeke;Timothy C. Wang;Duan Chen;Chun-Mei Zhao
  • 通讯作者:
    Chun-Mei Zhao
MUC5AC in stromal heterogeneity and the Progression of Pancreatic Cancer
  • DOI:
    10.1016/j.canlet.2023.216541
  • 发表时间:
    2024-01-28
  • 期刊:
  • 影响因子:
  • 作者:
    Surinder K. Batra
  • 通讯作者:
    Surinder K. Batra

Surinder K. Batra的其他文献

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{{ truncateString('Surinder K. Batra', 18)}}的其他基金

Truncated O-glycan-dependent mechanisms inducing metastatic dissemination in pancreatic cancer
截短的O-聚糖依赖性机制诱导胰腺癌转移扩散
  • 批准号:
    10683305
  • 财政年份:
    2022
  • 资助金额:
    $ 43.7万
  • 项目类别:
Molecular Imaging Probe(s) for Optical Surgical Navigation of Pancreatic Cancer
用于胰腺癌光学手术导航的分子成像探针
  • 批准号:
    10557180
  • 财政年份:
    2022
  • 资助金额:
    $ 43.7万
  • 项目类别:
Novel Therapy to Inhibit IPMN Progression
抑制 IPMN 进展的新疗法
  • 批准号:
    10446455
  • 财政年份:
    2022
  • 资助金额:
    $ 43.7万
  • 项目类别:
Molecular Imaging Probe(s) for Optical Surgical Navigation of Pancreatic Cancer
用于胰腺癌光学手术导航的分子成像探针
  • 批准号:
    10367553
  • 财政年份:
    2022
  • 资助金额:
    $ 43.7万
  • 项目类别:
Novel Therapy to Inhibit IPMN Progression
抑制 IPMN 进展的新疗法
  • 批准号:
    10640955
  • 财政年份:
    2022
  • 资助金额:
    $ 43.7万
  • 项目类别:
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:
    10504826
  • 财政年份:
    2022
  • 资助金额:
    $ 43.7万
  • 项目类别:
Truncated O-glycan-dependent mechanisms inducing metastatic dissemination in pancreatic cancer
截短的O-聚糖依赖性机制诱导胰腺癌转移扩散
  • 批准号:
    10503433
  • 财政年份:
    2022
  • 资助金额:
    $ 43.7万
  • 项目类别:
Urine and serum biomarkers for early diagnosis and risk assessment of pancreatic cancer
用于胰腺癌早期诊断和风险评估的尿液和血清生物标志物
  • 批准号:
    10156494
  • 财政年份:
    2021
  • 资助金额:
    $ 43.7万
  • 项目类别:
Urine and serum biomarkers for early diagnosis and risk assessment of pancreatic cancer
用于胰腺癌早期诊断和风险评估的尿液和血清生物标志物
  • 批准号:
    10339431
  • 财政年份:
    2021
  • 资助金额:
    $ 43.7万
  • 项目类别:
Urine and serum biomarkers for early diagnosis and risk assessment of pancreatic cancer
用于胰腺癌早期诊断和风险评估的尿液和血清生物标志物
  • 批准号:
    10551280
  • 财政年份:
    2021
  • 资助金额:
    $ 43.7万
  • 项目类别:

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