Molecular Pathogenesis of Neoplasia

肿瘤的分子发病机制

基本信息

批准号：
10684592
负责人：
John Heiss
金额：
$ 183.9万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684592
关键词：
AKT inhibition Animal Model Animals Anti-CD40 Antibodies Arginine Basic Science Bioinformatics Brain Brain Neoplasms CT26 Cell Line Cell Proliferation Cell Survival Cell membrane Cells Clinical Clinical Research Clinical Trials Collaborations Colon Carcinoma Conduct Clinical Trials Custom Defect Development ERBB3 gene Elements Endogenous Retroviruses Epigenetic Process Etiology Genetic Genetic Heterogeneity Glioblastoma Glioma Glomerular basement membrane antibody Growth HIV Heterogeneity Human Immune Immune checkpoint inhibitor Immune response Immunologic Surveillance Immunotherapy Inherited Injury Insulin Journals Laboratories Laboratory Study Ligands Literature Malignant Neoplasms Mannans Manuscripts Mediating Medical Medical Genetics Mesenchymal Stem Cells Methylation Modeling Molecular Morphology Mus Mutation National Institute of Neurological Disorders and Stroke Neoplasm Metastasis Neoplasms Neurology Oncogenic Operative Surgical Procedures PD-1 blockade Pathogenesis Pathologic Pathology Pathway interactions Patients Pharmacogenomics Pharmacology Phase I Clinical Trials Primary Neoplasm Protein Inhibition Protein phosphatase Protein-Arginine N-Methyltransferase Proto-Oncogene Proteins c-akt Publications Publishing Radiation Radiation therapy Radiation-Sensitizing Agents Rattus Reporting Research Research Personnel Role Site Solid Neoplasm Spinal Spinal Neoplasms Techniques Tendon structure Testing Therapeutic Time Tissues Toll-like receptors Translating Translational Research United States National Institutes of Health Universities Vaccination Virus Work Xenograft Model Xenograft procedure anti-tumor immune response antitumor effect base biomaterial compatibility chemosensitizing agent chemotherapy clinical translation cytotoxicity diagnostic technologies diagnostic tool differential expression glioma cell line improved inhibitor insight kinase inhibitor knock-down melanoma molecular diagnostics nanofiber neoplastic cell nervous system infection neuro-oncology new technology novel overexpression repaired senescence small molecular inhibitor stem therapy resistant tumor tumor heterogeneity tumorigenesis vaccine evaluation

项目摘要

Protein Phosphatase 2A Inhibition and its Interaction with Chemotherapy and Radiotherapy Effects: We previously studied the inhibitory activity of LB100, a first-in-class small molecular inhibitor of Protein Phosphatase 2A (PP2A), in the mouse xenograft human GBM animal model. This compound had a mild effect as a single agent in slowing animal GBM growth. However, its effects against GBM increased when combined with radiation or chemotherapy. LB-100 was well-tolerated against solid tumors in a Phase 1 clinical trial conducted outside the NIH, suggesting that LB-100 would also be well-tolerated if used in clinical trials of glioblastoma patients. We continue to study PP2A. We are exploring PP2A inhibition as a chemosensitizer or radiosensitizer in GBM therapeutics (1,2). Protein Arginine Methyltransferase 5 Inhibition in Models of Glioblastoma Under Dr. Banasavadi, the Molecular and Therapeutics Unit of SNB studies the role of Protein Arginine Methyltransferase 5 (PRMT5) in brain tumors. PRMT5 catalyzes the symmetric di-methylation of arginine residues and is overexpressed in GBM (3). Our previous research showed that inhibition of PRMT5 causes senescence in stem-like GBM tumor cells. We also showed that combined inhibition of PRMT5 and PP2A had a more significant anti-GBM effect than either agent alone. We published a manuscript this year that reviewed the medical and scientific literature regarding the potential impact of PP2A inhibition on brain tumor therapeutics. Trametinib is a dual-kinase inhibitor used for the treatment of advanced malignant melanoma. Adaptive treatment resistance to trametinib precluded its clinical translation in GBM. We tested whether inhibition of PRMT5 can enhance the efficacy of trametinib against GBM. PRMT5 depletion enhanced trametinib-induced cytotoxicity in GBMNS. PRMT5 knockdown significantly decreased trametinib-induced AKT and ERBB3 escape pathways. However, ERBB3 inhibition alone failed to block trametinib-induced AKT activity, suggesting that the enhanced antitumor effect imparted by PRMT5 knockdown in trametinib-treated GBMNS resulted from AKT inhibition and not ERBB3 inhibition. In orthotopic murine xenograft models, PRMT5-depletion extended the survival of tumor-bearing mice, and combination with trametinib further increased survival. This study was published in the journal Neuro-Oncology Advances (4). Dr. Banasavadi also collaborated on another project testing the impact of NOTCH blockade on virus-induced immunotherapy in GBM (5). Further, he contributed to a project exploring the ability of insulin-functionalized electrospun nanofiber matrices with or without mesenchymal stem cells to enhance tendon repair in a rat Achilles injury model (6,7). Study of an Etiologic Role of Human Endogenous Retroviruses in Glioma Pathogenesis Dr. Ashish Shah in SNB collaborated with the laboratories of Dr. Avindra Nath in the Section of Infections of the Nervous System (SINS)in NINDS and Dr.Zhengping Zhuang in NOB/NCI to evaluate the role of endogenous retroviruses in glioma pathogenesis. Dr. Shah reviewed the scientific literature regarding the role of human endogenous retroviruses in glioma etiology and its potential therapeutic implications (8). This review suggested that HERVs can serve a dichotomous role as an oncogenic driver or a stimulator of the antiviral immune response. Dr. Shah then completed laboratory studies characterizing HERV expression in several glioma cell lines using a custom ensemble workflow developed through the NINDS Bioinformatics core (9). He found that regional methylation is involved in regulating the expression of endogenous retroviruses in glioma cell lines, as previously shown in other cancers. In collaboration with Dr. Avindra Nath in NINDS, Dr. Shah demonstrated that differential expression of the endogenous retroviral element HERV-K is associated with shortened survival of glioblastoma patients. With the University of Miami and NINDS investigators, Dr. Shah published an article on GBM in patients with HIV and another on a GBM pharmacogenomic therapeutic strategy (10,11). Immunotherapy of Glioblastoma The Protein Phosphatase 2A (PP2A) inhibitor described above, LB-100, was found to enhance the antitumor effects of an immune checkpoint inhibitor in an animal model of glioblastoma. We published a report with Dr. Zhuang and other Neuro-Oncology Branch, NCI (NOB/NCI) colleagues showing that pharmacologic inhibition of protein phosphatase-2A achieved durable immune-mediated antitumor activity when combined with PD-1 blockade. This combination of a PP2A inhibitor and PD-1 blockade may be translated to human clinical trials by our collaborators in NOB/NCI. The SNB laboratory also collaborated with NOB/NCI to study the immune effects of vaccination with Mannan-BAN (Biocompatible Anchor for Cell Membrane), toll-like receptor (TLR) ligands, and Anti-CD40 antibody (MBTA) against primary and metastatic tumors of the CT26 murine colon carcinoma cell line. MBTA triggered a potent antitumor immune response, including against intracranial metastatic tumors (12). The NOB/NCI group plans to test this vaccine in animal models of glioblastoma. Collaborative Efforts to Improve the Treatment of Brain and Spinal Neoplasms The Surgical Neurology Branch works with investigators in other NINDS branches, other NCI branches, including the Neuro-Oncology, Laboratory of Pathology, and Clinical Genetics Branches of NCI, and other sites outside the NIH to find better ways to evaluate and treat brain and spinal malignancies. Several basic, translational, and clinical research publications and review articles this year resulted from these collaborative efforts (13-19).

蛋白质磷酸酶2a抑制及其与化学疗法和放射疗法的相互作用：我们先前研究了小鼠异种移植人类GBM动物模型LB100的抑制活性，LB100是蛋白磷酸酶2a（PP2A）的第一类小分子抑制剂（PP2A）。该化合物在减慢动物GBM生长方面具有轻微的作用。但是，与放射线或化学疗法结合使用时，其对GBM的影响会增加。在NIH外进行的1期临床试验中，LB-100对实体瘤的耐受性很好，这表明如果在胶质母细胞瘤患者的临床试验中使用了LB-100，也将耐受耐受性。我们继续研究PP2A。我们正在探索PP2A抑制作用，作为GBM治疗剂中的化学敏化剂或放射敏剂（1,2）。蛋白精氨酸甲基转移酶5抑制胶质母细胞瘤模型在Banasavadi博士的领导下，SNB的分子和治疗单元研究了蛋白精氨酸甲基转移酶5（PRMT5）在脑肿瘤中的作用。 PRMT5催化精氨酸残基的对称二甲基化，并在GBM中过表达（3）。我们先前的研究表明，对PRMT5的抑制会导致茎样GBM肿瘤细胞的衰老。我们还表明，对PRMT5和PP2A的合并抑制作用的抗GBM效应比单独使用的抗GBM效应更明显。我们今年发表了一份手稿，回顾了有关PP2A抑制对脑肿瘤疗法的潜在影响的医学和科学文献。 Trametinib是一种双激酶抑制剂，用于治疗晚期恶性黑色素瘤。对Trametinib的自适应治疗能力排除了其在GBM中的临床翻译。我们测试了抑制PRMT5是否可以增强曲妥尼对GBM的疗效。 PRMT5耗竭增强了Trametinib诱导的GBMN的细胞毒性。 PRMT5敲低显着降低了Trametinib诱导的AKT和ERBB3逃生途径。然而，仅ERBB3抑制作用就无法阻止曲妥尼诱导的AKT活性，这表明曲线替尼治疗的GBMN中PRMT5敲低的增强抗肿瘤效应是由AKT抑制和ERBB3抑制作用引起的。在原位鼠异种移植模型中，PRMT5止血剂扩大了含肿瘤小鼠的存活，并与曲妥尼结合进一步提高了存活率。这项研究发表在《神经肿瘤学的进步》杂志上（4）。 Banasavadi博士还合作研究了另一个项目，该项目测试了Notch阻断对病毒诱导的免疫疗法在GBM中的影响（5）。此外，他为一个项目做出了贡献，该项目探讨了带有或没有间充质干细胞的胰岛素官能传播纳米纤维基质的能力，以增强大鼠阿基里斯损伤模型中的肌腱修复（6,7）。研究人内源性逆转录病毒在神经胶质瘤发病机理中的病因学作用 Ashish Shah博士在SNB中与Avindra Nath博士的实验室合作，在NINDS的神经系统感染（SIN）和NOB/NCI的Zhengping Zhuang博士评估内源性逆转录病毒在胶质瘤病原上的作用。 Shah博士回顾了有关人内源性逆转录病毒在神经胶质瘤病因及其潜在治疗意义中的作用的科学文献（8）。这篇综述表明，HERV可以作为致癌驱动因素或抗病毒免疫反应的刺激剂发挥二分作用。 Shah博士随后完成了通过NINDS生物信息学核心开发的自定义集合工作流（9），完成了在几个神经胶质瘤细胞系中表达HERV表达的实验室研究。他发现，区域甲基化参与调节神经胶质瘤细胞系中内源性逆转录病毒的表达，如其他癌症先前所示。 Shah博士与Ninds的Avindra Nath博士合作，表明内源性逆转录病毒元件HERV-K的差异表达与胶质母细胞瘤患者的存活率缩短有关。 Shah博士在迈阿密大学和NINDS研究人员的情况下发表了一篇有关HIV患者的GBM的文章，另一篇有关GBM药物基因组基因组治疗策略的文章（10,11）。胶质母细胞瘤的免疫疗法上述蛋白质磷酸酶2a（PP2A）抑制剂LB-100被发现可增强免疫检查点抑制剂在胶质母细胞瘤模型中的抗肿瘤作用。我们与Zhuang博士和其他神经肿瘤学分支NCI（NOB/NCI）的同事发表了一份报告，表明当蛋白质磷酸酶-2a的药理学抑制与PD-1阻滞结合时，蛋白质磷酸酶-2a可实现持久的免疫介导的抗肿瘤活性。 PP2A抑制剂和PD-1封锁的组合可以由我们在NOB/NCI的合作者转化为人类临床试验。 SNB实验室还与NOB/NCI合作研究了用Mannan-Ban（细胞膜生物相容性锚定），Toll样受体（TLR）配体和抗CD40抗体（MBTA）对CT26 Murine Colin colcin carccarccarcrican carcincarcarccarccarcinsy cont的免疫作用。 MBTA引发了有效的抗肿瘤免疫反应，包括针对颅内转移性肿瘤（12）。 NOB/NCI组计划在胶质母细胞瘤动物模型中测试该疫苗。改善大脑和脊柱肿瘤治疗的协作努力手术神经病学部门与其他NINDS分支机构，其他NCI分支机构的研究人员合作，包括神经肿瘤学，病理学实验室和NCI的临床遗传学分支以及NIH以外的其他地点，以找到更好的方法来评估和治疗脑和脊柱恶性肿瘤。这些合作的努力造成了一些基本，转化和临床研究出版物和审查文章（13-19）。