Systems biology of intratumoral heterogeneity in glioblastoma

胶质母细胞瘤瘤内异质性的系统生物学

基本信息

批准号：
10544035
负责人：
Nitin S Baliga
金额：
$ 74.76万
依托单位：
INSTITUTE FOR SYSTEMS BIOLOGY
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：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10544035
关键词：
3&apos Untranslated Regions Adjuvant Automobile Driving Autopsy Behavior Binding Biopsy CRISPR screen Cells Characteristics Chemicals Chromatin Clinical Clinical Trials Complex Cytotoxic agent Data Data Analyses Development Drug Combinations Drug Screening Drug resistance Elements Event Evolution Excision FDA approved Female Flow Cytometry Formulation Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Glioblastoma Glioma Heterogeneity Hospitals Intervention Label Letters Link Literature Location Malignant Neoplasms Malignant neoplasm of brain Maps Mesenchymal Methodology MicroRNAs Modeling Molecular Multiomic Data Mus Mutation Oncogenic Oranges Outcome Pathway Analysis Pathway interactions Patient Selection Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Population Population Heterogeneity Predisposition Process Prognosis Radiation therapy Recurrence Recurrent tumor Regimen Regulation Research Resistance Resolution Science Selection for Treatments Sensitivity and Specificity Signal Transduction Somatic Mutation Survival Rate System Systems Biology Testing Tumor Subtype Validation Xenograft procedure causal variant chemotherapy cis acting element clinically relevant cytotoxic drug action drug repurposing fractionated radiation gene network genetic predictors high throughput screening individual patient insight male model development molecular subtypes multiple omics neoplastic cell non-genetic novel off-label use patient response predictive modeling prevent promoter response single-cell RNA sequencing standard of care stem-like cell stressor temozolomide transcription factor transcription regulatory network transcriptome sequencing tumor tumor heterogeneity tumor microenvironment

项目摘要

PROPOSAL SUMMARY (revisions in orange font ) Patients with glioblastoma (GBM) have a 12-14 month median survival rate, ~10% chance of 5-year survival, and ~90% likelihood of recurrence, even after receiving standard of care (SOC), which involves tumor resection, fractionated radiation therapy (XRT), and chemotherapy with temozolomide (TMZ). There is growing evidence that this poor prognosis and dismal therapy responsiveness emerges from interplay of tumor cell heterogeneity and non-genetic, treatment-induced shifts of cellular phenotypic states. Notably, the SOC has been shown to drive a shift of tumor cells from a drug-susceptible proneural (PN) subtype to a drug-resistant mesenchymal (MES) subtype. This partly explains why primary GBM tumors of the classical or PN subtype often recur as the more aggressive and drug-resistant MES subtype. To complicate matters further, extrinsic signals and stressors can drive dedifferentiation of a heterogeneous tumor cell population into immature, glioma stem-like cells (GSCs), which have been implicated in tumor recurrence. GSCs are resistant to multiple cytotoxic drugs like TMZ, which motivates the need for discovering novel cytotoxic drugs, including drugs repurposed from other indications, to treat GBM. Notably, we have discovered that off-label FDA-approved drugs are effective against patient-derived GSCs (PD-GSCs) increasing median survival of patients by >3X, but can also induce transition of a surviving subpopulation from a susceptible PN subtype to a MES subtype – called PN-to-MES transition (PMT). Here, we propose to elucidate at single-cell resolution the mechanisms by which diverse drugs induce PMT within a heterogeneous population of GSCs. We hypothesize that early response to drug treatments will vary by mechanisms of action of drugs and patient-specific characteristics of PD-GSCs, but cytotoxic events will drive these responses onto a common pathway that can be targeted with genetic and chemical interventions to block drug-induced PMT. We will test this hypothesis by single-cell profiling of longitudinal changes in transcription (scRNA-seq), chromatin accessibility (scATAC-seq), and phenotypes of up to 34 patient-derived GSCs (PD-GSCs) across 76 FDA approved anti-proliferative compounds. We will integrate the longitudinal multi- omic profiles to discover the transcriptional regulatory network (TRN) that mechanistically drives drug-induced PMT in each PD-GSC. By comparing TRNs across PD-GSCs and drug treatments, we will identify, perturb, and characterize mechanisms of drug-induced PMT in each PD-GSC. Using FDA-approved drugs mapped to validated mechanisms, we will perform high throughput screens to evaluate the sensitivity and specificity of our model-driven approach to identify drug combinations that synergistically kill PD-GSCs, without inducing PMT. Outcomes of this project include (i) methodology to elucidate single-cell resolution TRNs within subpopulations of a heterogeneous tumor, (ii) insight into mechanisms of drug-induced PMT in PD-GSCs, and (iii) a rational strategy to repurpose, and tailor FDA-approved combination drug regimens for off-label use in treating GBM. Lines: 30 (0 under/over)

提案摘要（修订橙色字体）胶质母细胞瘤（GBM）患者的生存率中位数为12-14个月，5年生存的机会约为10％，即使在接受肿瘤切除术的护理标准（SOC）之后，复发的可能性也〜90％。分级放射治疗（XRT）和替莫唑胺（TMZ）的化学疗法。越来越多的证据肿瘤细胞异质性的相互作用出现了这种不良的预后和沮丧的治疗反应能力和非遗传，治疗诱导的细胞表型态的转移。值得注意的是，SOC已被证明驱动肿瘤细胞从可启发性的隆起（PN）亚型转移到耐药性间充质（MES）亚型。这部分解释了为什么经典或PN亚型的主要GBM肿瘤通常会反复出现更具侵略性和耐药性MES亚型。进一步的问题，外部信号和压力源可以将异质肿瘤细胞群体的去分化为未成熟的胶质瘤干细胞（GSC），在肿瘤复发中隐含。 GSC对多种细胞毒性药物具有抗药性 TMZ，它激发了发现新型细胞毒性药物的需求，包括重新使用的药物适应症，以治疗GBM。值得注意的是，我们发现标签外FDA批准的药物对患者来源的GSC（PD-GSC）将患者中位存活率提高> 3倍，但也可以诱导过渡从易感PN亚型到MES亚型的幸存亚群 - 称为PN-MES转变（PMT）。在这里，我们建议在单细胞分辨率下阐明潜水员药物影响的机制 PMT在GSC的异质种群中。我们假设早期对药物治疗的反应将因药物的作用机理和PD-GSC的患者特异性特征而有所不同，但是细胞毒性事件将会将这些反应驱动到一个可以用遗传和化学干预措施的公共途径上阻止药物引起的PMT。我们将通过纵向变化的单细胞分析来检验这一假设转录（SCRNA-SEQ），染色质可及性（SCATAC-SEQ）和表型最多34个患者衍生 76个FDA批准的抗增殖化合物的GSC（PD-GSC）。我们将整合纵向多 OMIC轮廓发现转录调节网络（TRN），该网络可机械驱动药物诱导的每个PD-GSC中的PMT。通过比较跨PD-GSC和药物治疗的TRN，我们将确定，扰动和表征每个PD-GSC中药物诱导的PMT的机制。使用映射到FDA批准的药物经过验证的机制，我们将执行高吞吐量屏幕以评估我们的灵敏度和特异性模型驱动的方法是鉴定在没有诱导PMT的情况下协同杀死PD-GSC的药物组合。该项目的结果包括（i）阐明亚群中单细胞分辨率TRN的方法（ii）对PD-GSC中药物诱导的PMT机制的洞察力，以及（iii）有理改革的策略，并量身定制FDA批准的组合药物方案，用于治疗GBM的标签外使用。线：30（0下/以上）