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)是成人最常见的恶性原发脑癌,平均生存期为1 年。治疗包括最大限度的安全切除,然后是化疗和替莫唑胺辅助治疗。 (TMZ),后者仅使中位生存期增加2.5个月。此外,大多数靶向治疗试验都有 由于酪氨酸激酶受体和相对血脑屏障(BBB)的激活而失败 防渗性。因此,迫切需要找到一种更有效的治疗方法。这项研究建立在初步的基础上 使用连接图(Cmap)生成的数据,该图由布罗德研究所开发,用于识别 根据癌症的基因图谱进行再利用。通过分析来自4个国家的99个GBM和38个相邻的正常样本 数据集,Cmap将组蛋白脱乙酰酶(HDAC)抑制剂确定为首选候选药物。数据库分析使用 GEPIA发现HDAC1和HDAC2上调最严重,而HDAC11下调最严重。 因此,我们选择了血脑屏障pCI-24781/abexinostat,因为它对gbm基因签名具有特异性。 要评估的特定HDAC(禁止HDAC1和HDAC2,但不禁止HDAC11或IIa类HDAC)。在预赛中 研究表明,与其他PAN HDAC抑制剂相比,pCI-24781显著诱导更多的细胞凋亡和 GBM细胞系体外DNA修复机制(CHK1、RAD51和MGMT)下调。此外,pci-24781 与TMZ联合应用可有效降低小鼠原位移植模型的肿瘤负荷 带有TMZ的恒涡器和增强的存活率。由此,我们假设用PCI抑制1类HDAC- 24781将通过靶向脱氧核糖核酸修复机制来提高曲美他滨治疗基底膜的疗效。为了检验这一假设,我们 提出两个具体目标:在目标1中,我们将评估经皮细胞移植-24781联合曲美他滨在活体基底细胞瘤模型中的疗效。 将使用小鼠GBM有机化合物、基因工程GBM小鼠模型和患者来源的异种移植物 评价血脑屏障通透性和毒性。治疗效果和存活率将被记录下来。 PCI-24781和曲美他滨单独及联合用药组。我们将分析 IHC对切除肿瘤的DNA修复机制蛋白的联合治疗,并将执行RNA- SEQ和OMNI-ATAC-SEQ分析以分别识别附加途径和染色质可及性, 受pci-24781的影响。在目标2中,一期临床试验将评估毒性并确定经皮冠状动脉介入治疗的MTD。 24781在复发的高级别胶质瘤患者中使用三甲氧甲肼。我们将分析患者的外显子来证明 蛋白质乙酰化和血脑屏障通透性。这些目标将共同阐明两国之间的协同机制。 GB/TMZ对pci-24781的耐受性。将pci-24781与TMZ相结合将成功克服TMZ 耐药,对肿瘤生长和复发产生负面影响,有效提高GBM的存活率 病人。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

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

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:
    $ 44.59万
  • 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:
    $ 44.59万
  • 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:
    $ 44.59万
  • 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:
    $ 44.59万
  • 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:
    $ 44.59万
  • 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:
    10686268
  • 财政年份:
    2022
  • 资助金额:
    $ 44.59万
  • 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:
    $ 44.59万
  • 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:
    $ 44.59万
  • 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:
    $ 44.59万
  • 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:
    $ 44.59万
  • 项目类别:

相似海外基金

Metachronous synergistic effects of preoperative viral therapy and postoperative adjuvant immunotherapy via long-term antitumor immunity
术前病毒治疗和术后辅助免疫治疗通过长期抗肿瘤免疫产生异时协同效应
  • 批准号:
    23K08213
  • 财政年份:
    2023
  • 资助金额:
    $ 44.59万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Improving the therapeutic immunity of cancer vaccine with multi-adjuvant polymeric nanoparticles
多佐剂聚合物纳米粒子提高癌症疫苗的治疗免疫力
  • 批准号:
    2881726
  • 财政年份:
    2023
  • 资助金额:
    $ 44.59万
  • 项目类别:
    Studentship
Countering sympathetic vasoconstriction during skeletal muscle exercise as an adjuvant therapy for DMD
骨骼肌运动期间对抗交感血管收缩作为 DMD 的辅助治疗
  • 批准号:
    10735090
  • 财政年份:
    2023
  • 资助金额:
    $ 44.59万
  • 项目类别:
Evaluation of the Sensitivity to Endocrine Therapy (SET ER/PR) Assay to predict benefit from extended duration of adjuvant endocrine therapy in the NSABP B-42 trial
NSABP B-42 试验中内分泌治疗敏感性 (SET ER/PR) 测定的评估,用于预测延长辅助内分泌治疗持续时间的益处
  • 批准号:
    10722146
  • 财政年份:
    2023
  • 资助金额:
    $ 44.59万
  • 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
  • 批准号:
    10933287
  • 财政年份:
    2023
  • 资助金额:
    $ 44.59万
  • 项目类别:
DEVELOPMENT OF SAS A SYNTHETIC AS01-LIKE ADJUVANT SYSTEM FOR INFLUENZA VACCINES
流感疫苗类 AS01 合成佐剂系统 SAS 的开发
  • 批准号:
    10935776
  • 财政年份:
    2023
  • 资助金额:
    $ 44.59万
  • 项目类别:
DEVELOPMENT OF SMALL-MOLECULE DUAL ADJUVANT SYSTEM FOR INFLUENZA VIRUS VACCINE
流感病毒疫苗小分子双佐剂体系的研制
  • 批准号:
    10935796
  • 财政年份:
    2023
  • 资助金额:
    $ 44.59万
  • 项目类别:
A GLYCOLIPID ADJUVANT 7DW8-5 FOR MALARIA VACCINES
用于疟疾疫苗的糖脂佐剂 7DW8-5
  • 批准号:
    10935775
  • 财政年份:
    2023
  • 资助金额:
    $ 44.59万
  • 项目类别:
Adjuvant strategies for universal and multiseasonal influenza vaccine candidates in the context of pre-existing immunity
在已有免疫力的情况下通用和多季节流感候选疫苗的辅助策略
  • 批准号:
    10649041
  • 财政年份:
    2023
  • 资助金额:
    $ 44.59万
  • 项目类别:
Adjuvant Photodynamic Therapy to Reduce Bacterial Bioburden in High-Energy Contaminated Open Fractures
辅助光动力疗法可减少高能污染开放性骨折中的细菌生物负载
  • 批准号:
    10735964
  • 财政年份:
    2023
  • 资助金额:
    $ 44.59万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了