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：
10517124
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/10517124
关键词：
ABCB1 gene Adult Affect Antihypertensive Agents Biological Response Modifier Therapy 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 of activation protein Mibefradil Mismatch Repair Mismatch Repair Deficiency Modeling Mus Mutate Mutation Oxidative Stress PMS2 gene Patients Pharmaceutical Preparations Phenotype Plant Roots 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，对所有脑癌都具有固有或适应性抵抗力 GBM 对替莫唑胺产生耐药性的一个重要机制是其治疗中使用的一线化疗源于 MSH6 和 MSH2 等关键基因的突变 DNA 错配修复 (MMR)——这种机制也存在于结肠癌和其他 MMR 缺陷的癌症中。 GBM 变得高度突变，特别具有攻击性，并且对许多化疗具有抵抗力，并且尽管最近的一份报告描述了这种情况，但迫切需要找到有效的治疗方法。两例儿童 MMR 缺陷、超突变 GBM 对免疫治疗检查点有反应抑制剂，我们自己和其他人的临床经验一致表明成年患者缺乏反应该提案测试了用这些药物治疗的 MMR 缺陷、高度突变的 GBM。我们的初步研究是针对 MMR 缺陷、超突变 GBM 的方法，并使用独特的工具来实现这一目标。扩展先前的报告，表明钙通道抑制可能对 MMR 缺陷具有活性癌症首次表明结合不同钙通道抑制剂——羧酰胺三唑 (CAI)、米贝拉地尔和维拉帕米——对 MMR 缺陷的 GBM 系具有优先和协同活性此外，我们的初步结果进一步表明 TGF-β 是这方面的潜在靶点。化疗药物伊立替康和抗胆固醇他汀类药物可以重新用作 TGF- 对 MMR 缺陷的 GBM 具有优先活性的 β 抑制剂正在测试这些治疗策略。对照匹配的 GBM 系组，每个组包括亲本系和源自其的 MMR 缺陷系，以及自发产生 MMR 缺陷的 GBM 系和对照 GBM 系。缺陷系均具有源自体内继发突变的 MSH6 或 MSH2 不足替莫唑胺治疗或shRNA的稳定表达本提案将使用这些匹配的。亲本/错配修复缺陷 GBM 系，用于测试钙通道阻断组合和 TGF-β 的效果此外，考虑到 MMR 缺陷和过度突变以及两者的治疗作用。方法可能会影响抗 GBM 免疫反应，我们还将开发一种具有免疫功能的 MMR 缺陷 GBM 小鼠模型来测试这些影响的机制的有针对性和公正的研究。将进行，包括评估两种治疗策略之间的联系和磷酸蛋白质组学和 RNA-seq 分析将产生新的生物学和治疗学成果。这些见解可能会迅速影响 MMR 缺陷、高度突变的 GBM 和其他癌症的治疗。