Screening for adjuvant gliobalstoma therapeutics

胶质母细胞瘤辅助治疗的筛选

基本信息

批准号：
9127592
负责人：
BAKHOS A TANNOUS
金额：
$ 37.41万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9127592
关键词：
Accounting Adjuvant Adjuvant Therapy Adult Alkylating Agents Apoptosis Astrocytes Biological Assay CCL4 gene Cell Survival Cells Central Nervous System Neoplasms Cessation of life Chemicals Cherry - dietary DNA DNA Adducts DNA Repair Data Analyses Diagnosis Dose Drug Targeting Drug resistance Enzymes Failure Fibroblasts Futile Cycling Genetic Genotype Glioblastoma Glioma Guanine Lead Lesion Libraries Luciferases Malignant - descriptor Malignant neoplasm of brain Mediating Methylation Molecular Newly Diagnosed Normal Cell Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phase II Clinical Trials Phenotype Positioning Attribute Preclinical Drug Evaluation Primary Brain Neoplasms Progression-Free Survivals Radiation Radiosurgery Randomized Recurrence Recurrent tumor Reporter Resistance Source Specificity Stem cells System Testing Therapeutic Time Transferase Triage Update Validation analog base cell killing conventional therapy cytotoxicity drug candidate high throughput screening killings neoplastic cell novel novel therapeutics phase 3 study promoter public health relevance relating to nervous system research study response screening small molecule standard of care stem cell population stem cell therapy success temozolomide tumor tumor initiation

项目摘要

DESCRIPTION (provided by applicant): More than half of the 18,000 patients diagnosed with malignant primary brain tumors in the U.S. each year have glioblastoma (GBM), the most common and most aggressive primary malignant brain tumor in adults. Over the last two decades, the major breakthrough in the treatment for GBM has been the addition of the DNA alkylating agent temozolomide (TMZ) to the standard of care (surgery and radiation) yielding an increase in the median survival from 12.1 months to 14.6 months. Despite this advancement, 90% of GBM patients die within 5 years, a colossal failure attributed to TMZ resistance. One of the major predictor of GBM response to TMZ is the MGMT promoter methylation status. This enzyme removes the DNA adduct, induced by TMZ, leading to cell survival. Thus, patients whose tumors have transcriptional silencing of the MGMT gene, mediated by promoter methylation, are most likely to benefit from TMZ. Given that all glioblastomas recur to a tumor lesion with acquired resistance to TMZ, novel adjuvant therapies could be highly beneficial to GBM patients. Recently, it was shown that a subpopulation of tumor cells, called glioblastoma stem cells (GSCs or tumor initiating cells), are responsible for tumor recurrence and resistance to conventional therapies. In this proposal, we will use a multiplex secreted reporter system for high-throughput screening to find drugs that either synergizes with TMZ on GBM stem cells from both newly diagnosed and recurrent tumors, irrespective of the MGMT status, or that kills a specific GBM stem cells subtype. We will simultaneously screen in the same well for drugs which act on three different GBM stem cells subpopulations: (1) obtained from newly diagnosed tumors with methylated MGMT promoter; (2) newly diagnosed GBM with unmethylated MGMT promoter; (3) recurrent TMZ-resistant tumors. We will use primary GBM stem cells dissociated from patient tumors sections and grow them as neural spheres which maintain the phenotype/genotype of the original tumor. Dose- and time-dependent experiments of our drug hits will be performed and validated using secondary screening assays in culture. A set of analogues of the most promising hits will be purchased, if available commercially, or synthesized by medicinal chemistry to make these drugs "fit-for-purpose", to facilitate their study in cells, and for pull down assays to find targets of drug hits. Finally, specificity of drug hits o glioblastoma will be tested using a panel of normal cells and stem cells in culture.

描述：在美国诊断出的18,000名大脑肿瘤的患者中，有一半以上是成年人中最常见，最具侵略性的原发性恶性脑肿瘤。（TMZ）对护理标准的态度）从12.1个月的中位数增加到14.6个月，而GBM患者则在5年内死亡。 TMZ诱导的地址，导致细胞的存活，其肿瘤具有MGMT基因的转录沉默，所有胶质母细胞瘤都会重现具有对TMZ患者的耐药性的肿瘤病变。称为胶质母细胞瘤干细胞，是用于肿瘤复发和对转化疗法的抗性，我们将使用一个多重分泌的记者系统用于高通量筛选的系统，以在GBM茎上具有TMZ MGMT状态或杀死特定的GBM干细胞亚型。原始肿瘤的近代型甲型的基因型。 - 用途”，以促进他们的研究在细胞中，用于培养的药物和干细胞。