Systems biology of intratumoral heterogeneity in glioblastoma

胶质母细胞瘤瘤内异质性的系统生物学

• 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
• 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' 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

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)

建议书摘要（ 橙子字体 ) 胶质母细胞瘤（GBM）患者的中位生存率为12-14个月，5年生存率约为10%， 和~90%的复发可能性，即使在接受标准治疗（SOC）（包括肿瘤切除术）后， 分次放疗（XRT）和替莫唑胺（TMZ）化疗。越来越多的证据 这种不良的预后和令人沮丧的治疗反应性是由肿瘤细胞异质性的相互作用引起的， 和非遗传的、治疗诱导的细胞表型状态的转变。值得注意的是，SOC已被证明 促使肿瘤细胞从药物敏感的前神经（PN）亚型转变为耐药的间充质 (MES)亚型这部分解释了为什么经典或PN亚型的原发性GBM肿瘤经常复发， 更具攻击性和耐药性的MES亚型。更复杂的是，外在信号和压力源 可以促使异质性肿瘤细胞群去分化为未成熟的神经胶质瘤干细胞样细胞 （GSC），其已涉及肿瘤复发。GSC对多种细胞毒性药物具有耐药性， TMZ，它激发了发现新的细胞毒性药物的需求，包括从其他药物中重新利用的药物。 适应症，以治疗GBM。值得注意的是，我们发现FDA批准的标签外药物对 患者来源的GSC（PD-GSC）使患者的中位生存期延长> 3倍，但也可诱导转化 从易感PN亚型到MES亚型的存活亚群-称为PN到MES转变 （PMT）。在这里，我们建议阐明在单细胞分辨率的机制，不同的药物诱导 GSC异质群体中的PMT。我们假设药物治疗的早期反应将 细胞毒性事件因药物的作用机制和PD-GSC的患者特异性特征而异，但细胞毒性事件将 将这些反应驱动到一个共同的途径上，可以通过遗传和化学干预来靶向， 阻断药物诱导的PMT。我们将通过单细胞纵向变化来检验这一假设， 转录（scRNA-seq）、染色质可及性（scATAC-seq）和多达34个患者来源的表型。 GSC（PD-GSC）涵盖76种FDA批准的抗增殖化合物。我们将整合纵向多- 组学特征，以发现转录调控网络（TRN），其机制驱动药物诱导的 每个PD-GSC中的PMT。通过比较PD-GSC和药物治疗中的TRN，我们将识别，干扰， 表征每种PD-GSC中药物诱导PMT的机制。使用FDA批准的药物， 验证机制，我们将进行高通量筛选，以评估我们的灵敏度和特异性， 模型驱动的方法来鉴定协同杀死PD-GSC而不诱导PMT的药物组合。 该项目的成果包括（i）阐明亚群内单细胞分辨率TRN的方法 异质性肿瘤，（ii）深入了解PD-GSC中药物诱导PMT的机制，以及（iii）合理的 策略，以重新调整和定制FDA批准的联合药物方案，用于治疗GBM的标签外使用。 线数：30（0低于/高于）