Vulnerabilities of MMR-deficient glioblastoma

MMR 缺陷的胶质母细胞瘤的脆弱性

基本信息

批准号：
10672360
负责人：
Benjamin W. Purow
金额：
$ 39.9万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672360
关键词：
ABCB1 gene Adult Affect Antihypertensive Agents Biological Brain Brain Neoplasms Calcium Calcium Channel Calcium Channel Blockers Calcium Channel Inhibition Cell Death Cell Survival Chelating Agents Childhood Cholesterol Clinic Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Colon Computer Models DNA DNA Damage DNA Repair Pathway Defect Development Devices Excision Genes Glioblastoma Hereditary Nonpolyposis Colorectal Neoplasms Hypertension Immune checkpoint inhibitor Immune response Immunocompetent Immunologics Immunotherapeutic agent In Vitro Knock-out L-Type Calcium Channels Least-Squares Analysis MADH3 gene MLH1 gene MSH2 gene MSH6 gene Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Mediator Mibefradil Mismatch Repair Mismatch Repair Deficiency Modeling Mus Mutate Mutation Oxidative Stress PMS2 gene Patients Pharmaceutical Preparations Phenotype Radiation Recurrence Reporting Resistance Resistance development Safety Secondary to Signal Transduction Simvastatin Small Interfering RNA T-Type Calcium Channels TGF Beta Signaling Pathway Testing Therapeutic Time Transforming Growth Factor beta Verapamil Work anti-PD-1 bevacizumab checkpoint therapy chemotherapy efficacy evaluation experience gene repair in vivo inhibitor insight irinotecan knock-down mouse model novel novel therapeutic intervention orotate pediatric patients phosphoproteomics pre-clinical resistance mechanism response small hairpin RNA standard care stem temozolomide tool transcriptome sequencing transcriptomics treatment strategy tumor voltage

项目摘要

Glioblastoma (GBM) is the most common and lethal brain cancer, with inherent or adaptive resistance to all existing treatments. One important mechanism by which GBM develops resistance to temozolomide, the frontline chemotherapy used in its treatment, stems from mutations in genes such as MSH6 and MSH2 critical in DNA mismatch repair (MMR)—a mechanism found in colon and other cancers as well. These MMR-deficient GBMs become hypermutated and particularly aggressive as well as resistant to many chemotherapies, and there is a pressing need to identify therapies that are effective against them. While a recent report describes two cases of pediatric MMR-deficient, hypermutated GBM that responded to immunotherapeutic checkpoint inhibitors, our own and others’ clinical experience has uniformly indicated a lack of responses in adult patients with MMR-deficient, hypermutated GBM treated with these agents. This proposal tests novel therapeutic approaches to MMR-deficient, hypermutated GBMs and uses unique tools to do so. Our preliminary studies expand on prior reports suggesting possible activity of calcium channel inhibition against MMR-deficient cancers to show for the first time that combining inhibitors of different calcium channels—carboxyamidotriazole (CAI), mibefradil, and verapamil—has preferential and synergistic activity against MMR-deficient GBM lines versus parental lines. In addition, our preliminary results further suggest TGF-β as a potential target in this setting, and that the chemotherapy drug irinotecan and the anti-cholesterol statins can be repurposed as TGF- β inhibitors with preferential activity against MMR-deficient GBM. These therapeutic strategies are being tested against matched sets of GBM lines that each include a parental line and an MMR-deficient line derived from it, as well as sets of GBM lines that spontaneously developed MMR deficiency and control GBM lines. The MMR- deficient lines each have MSH6 or MSH2 insufficiency derived either from mutations secondary to in vivo temozolomide treatment or from stable expression of shRNA. This proposal will use these matched parental/MMR-deficient GBM lines to test the effects of calcium channel blockade combinations and TGF-β inhibition in vitro and in vivo. In addition, given that MMR deficiency and hypermutation and both therapeutic approaches are likely to impact the anti-GBM immune response, we will also develop an immunocompetent mouse model of MMR-deficient GBM to test these effects. Both targeted and unbiased studies of mechanism will be performed, including assessing connections between the two therapeutic strategies and phosphoproteomic and RNA-seq analyses. The proposed studies will yield new biologic and therapeutic insights that could rapidly impact the treatment of MMR-deficient, hypermutated GBM and other cancers.

胶质母细胞瘤（GBM）是最常见和致命的脑癌，遗传或适应性抗性现有治疗方法。 GBM开发对替莫唑胺的抗性的一种重要机制，一线化学疗法用于治疗，源于MSH6和MSH2临界基因的突变在DNA不匹配修复（MMR）中 - 在结肠和其他癌症中发现的机制。这些MMR熟悉 GBM变得高度充满，尤其是侵略性，并且对许多化学疗法具有抗药性，并且迫切需要确定对它们有效的疗法。虽然最近的报告描述了两种儿科MMR缺陷率，超出的GBM，对免疫治疗点有反应抑制剂，我们自己和其他人的临床经验统一表明成年患者的反应不足使用这些药物处理的MMR缺陷，超重的GBM。该建议测试新疗法 MMR缺陷，超重的GBM的方法，并使用独特的工具来做到这一点。我们的初步研究扩展先前的报告，表明钙通道抑制对MMR缺陷的活性癌症首次结合不同钙通道的抑制剂 - 羧基二氮唑唑（CAI），Mibefradil和Verapamil-针对MMR缺陷型GBM线的优先和协同活性与父母线相对。此外，我们的初步结果进一步表明TGF-β是其中的潜在目标设置，并且可以将化学疗法药物伊立替康和抗胆固醇他汀类药物重新定义为TGF- 具有对MMR缺陷GBM的优先活性的β抑制剂。这些治疗策略正在测试相对于匹配的一组GBM线，各条线包括父母线和从中得出的MMR缺陷线，以及赞助MMR缺陷和控制GBM线的一组GBM线。 mmr- 缺乏线的每条线的MSH6或MSH2不足是从继发于体内突变的替莫唑胺处理或shRNA的稳定表达。该建议将使用这些匹配父母/MMR缺陷型GBM线，以测试钙通道阻滞组合和TGF-β的影响体外和体内抑制作用。另外，鉴于MMR缺乏症和超成名以及两种疗法方法可能会影响抗GBM免疫能力 MMR缺陷GBM的小鼠模型测试这些效果。针对机制的目标和公正研究将进行，包括评估两种治疗策略之间的联系磷蛋白质组学和RNA-seq分析。拟议的研究将产生新的生物学和治疗。可能会迅速影响MMR缺陷，高度沉积的GBM和其他癌症的见解。