Development of Advanced Oligonucleotides for Glioblastoma Therapeutics

用于胶质母细胞瘤治疗的先进寡核苷酸的开发

基本信息

批准号：
10363662
负责人：
Samantha Sarli
金额：
$ 3.15万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10363662
关键词：
Adjuvant Adult Advanced Development Aftercare Antisense Oligonucleotides Autopsy Bioinformatics Biology Brain Brain Neoplasms Cancer Biology Cell Death Cell Line Cell Proliferation Cells Chemicals Chemistry Chemotherapy and/or radiation Clinical Clinical Trials Complement Development Diagnosis Drug Combinations Epigenetic Process Evolution Excision Expectancy FDA approved Fluorescence-Activated Cell Sorting Gene Expression Gene Silencing Gene Targeting Genes Genetic Glioblastoma Glioma Goals Growth Heterogeneity In Vitro Infiltration Injections Invaded Lead Malignant - descriptor Malignant Neoplasms Measures Mediating MicroRNAs Modality Molecular Monitor Mus Neuraxis Neurologist Nucleic Acids Nucleotides Oligonucleotides Operative Surgical Procedures Pathway interactions Patient-Focused Outcomes Patients Pattern Pharmaceutical Preparations Phase Primary Brain Neoplasms RNA Recurrence Research Residual Tumors Residual state Resistance Specialist Specificity Spinal Muscular Atrophy Technology Testing Therapeutic Time Tissue Sample Tissues Toxic effect Transforming Growth Factor Beta 2 Translations Treatment Efficacy Tumor Biology Work brain tissue clinical efficacy clinically relevant combat design drug candidate effective therapy efficacious treatment flexibility humane endpoint improved in vivo insight migration mouse model neoplastic cell nervous system disorder neuro-oncology new therapeutic target novel phosphodiester programs single-cell RNA sequencing standard care sugar synthetic nucleic acid targeted treatment therapeutic RNA therapy resistant tool transcription factor transcriptome treatment response tumor tumor growth tumor heterogeneity tumor progression virtual

Adjuvant Adult Advanced Development Aftercare Antisense Oligonucleotides Autopsy Bioinformatics Biology Brain Brain Neoplasms Cancer Biology Cell Death Cell Line Cell Proliferation Cells Chemicals Chemistry Chemotherapy and/or radiation Clinical Clinical Trials Complement Development Diagnosis Drug Combinations Epigenetic Process Evolution Excision Expectancy FDA approved Fluorescence-Activated Cell Sorting Gene Expression Gene Silencing Gene Targeting Genes Genetic Glioblastoma Glioma Goals Growth Heterogeneity In Vitro Infiltration Injections Invaded Lead Malignant - descriptor Malignant Neoplasms Measures Mediating MicroRNAs Modality Molecular Monitor Mus Neuraxis Neurologist Nucleic Acids Nucleotides Oligonucleotides Operative Surgical Procedures Pathway interactions Patient-Focused Outcomes Patients Pattern Pharmaceutical Preparations Phase Primary Brain Neoplasms RNA Recurrence Research Residual Tumors Residual state Resistance Specialist Specificity Spinal Muscular Atrophy Technology Testing Therapeutic Time Tissue Sample Tissues Toxic effect Transforming Growth Factor Beta 2 Translations Treatment Efficacy Tumor Biology Work brain tissue clinical efficacy clinically relevant combat design drug candidate effective therapy efficacious treatment flexibility humane endpoint improved in vivo insight migration mouse model neoplastic cell nervous system disorder neuro-oncology new therapeutic target novel phosphodiester programs single-cell RNA sequencing standard care sugar synthetic nucleic acid targeted treatment therapeutic RNA therapy resistant tool transcription factor transcriptome treatment response tumor tumor growth tumor heterogeneity tumor progression virtual

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项目摘要

PROJECT SUMMARY Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor in adults. Despite significant progress being made in characterizing the genetic, epigenetic, and molecular drivers of GBM, effective therapies remain limited. A considerable hurdle between GBM research and translation into efficacious treatment is the extensive infiltration and molecular heterogeneity of GBM tumors, both of which cause tumor recurrence after treatment. Consequently, the average survival expectancy for GBM patients is less than 15 months after diagnosis. For therapies to be effective in treating these lethal tumors, they must overcome both GBM infiltration and heterogeneity. Antisense oligonucleotides (ASOs) – compounds that can modulate the expression of virtually any RNA molecule – offer distinct advantages for combating GBM infiltration and heterogeneity. Following local delivery, ASOs distribute throughout the brain, a necessary feat to reach infiltrative GBM cells. Moreover, as sequence- programmable agents, ASOs possess the specificity and flexibility required to modulate expression of multiple gene targets – an effective strategy to characterize and combat GBM heterogeneity. In 2016, the ASO drug, nusinersen, was FDA approved to treat spinal muscular atrophy, establishing the clinical efficacy of ASOs in the central nervous system. However, several ASO drug candidates for GBM have failed in clinical trials due to high toxicity and low potency. Identifying potent, well-tolerated ASOs for gene modulation in brain tumors would open the door to developing effective GBM therapies. The Watts lab has developed chemically-optimized, non-toxic ASOs with enhanced distribution and potency in the brain following local CNS delivery. However, their effect on GBM is unknown. The goal of this proposal is to identify ASOs that potently and safely silence GBM drivers, and assess the impact on tumor progression and resistance in vivo. With support from Drs. Jonathan Watts (oligonucleotide chemistry), Richard Moser (neuro- oncology), Sunit Das (GBM mouse models), Manuel Garber (bioinformatics), and Michael Green (cancer biology & therapeutics), Aim 1 will test the ability of chemically-modified ASOs to silence a clinically-relevant GBM driver (ATF5), inhibit cell proliferation, and induce cell death in molecularly-distinct patient-derived GBM cell lines. Lead compounds will then be evaluated for therapeutic efficacy in a GBM mouse model by measuring ATF5 silencing, tumor growth, and mouse survival following treatment. In Aim 2, the consequences of ASO-mediated silencing on GBM tumor biology will be investigated. ASOs targeting ATF5 will be injected into GBM tumors of mice. After treatment response, residual GBM cells will be isolated for single-cell RNA sequencing to characterize the transcriptome and determine how ASO silencing perturbs functional heterogeneity. This aim will establish a rational framework for drug combinations to minimize GBM tumor resistance. Collectively, the proposed project will advance ASOs as a novel GBM therapeutic and as a tool to dissect GBM progression.

项目摘要胶质母细胞瘤多形（GBM）是成年人中最频繁，最具侵略性的原发性脑肿瘤。尽管在表征GBM的遗传，表观遗传和分子驱动因素方面取得了重大进展，有效疗法仍然有限。 GBM研究与转化为有效治疗之间的巨大障碍是GBM肿瘤的广泛浸润和分子异质性，两者都会引起肿瘤复发治疗后。因此，GBM患者的平均生存率在不到15个月后诊断。为了使疗法有效治疗这些致死肿瘤，它们必须克服两种GBM浸润和异质性。反义寡核苷酸（ASOS） - 可以调节几乎任何RNA分子表达的化合物 - 为打击GBM浸润和异质性提供了明显的优势。当地交货后，ASOS 在整个大脑中分布，这是渗透性GBM细胞的必要壮举。而且，作为序列 - 可编程代理，ASO具有调节多重表达所需的特异性和灵活性基因靶标 - 表征和打击GBM异质性的有效策略。 2016年，ASO药物， Nusinersen被FDA批准用于治疗脊柱肌肉萎缩，确立了ASOS的临床效率中枢神经系统。但是，由于较高的临床试验，几种GBM的ASO候选药物均失败毒性和低效力。确定脑肿瘤基因调节的有效，耐受性良好的ASO将打开开发有效的GBM疗法的门。瓦特实验室已经开发了化学优化的，无毒的ASO，具有增强的分布和效力局部中枢神经系统交付后的大脑。但是，它们对GBM的影响尚不清楚。该提议的目的是确定潜在，安全地使GBM驱动因素沉默的ASO，并评估对肿瘤进展的影响体内抗性。在博士的支持下。乔纳森·瓦茨（Jonathan Watts）（寡核苷酸化学），理查德·摩泽（Richard Moser）（Neuro- 肿瘤学），Sunit DAS（GBM鼠标模型），Manuel Garber（生物信息学）和Michael Green（癌症生物学＆Therapy），AIM 1将测试化学改装的ASOS使与临床相关的GBM驱动器保持沉默的能力（ATF5），抑制细胞增殖，并诱导分子衍生的GBM细胞系中的细胞死亡。带领然后，通过测量ATF5沉默，将评估化合物在GBM小鼠模型中的治疗效率，治疗后肿瘤生长和小鼠存活。在AIM 2中，ASO介导的沉默的后果将研究GBM肿瘤生物学。靶向ATF5的ASO将注入小鼠的GBM肿瘤中。后治疗反应，将分离残留的GBM细胞以进行单细胞RNA测序以表征转录组并确定ASO沉默如何功能异质性。这个目标将建立一个药物组合的合理框架，以最大程度地减少GBM肿瘤耐药性。拟议的项目集体将作为一种新型的GBM疗法发展，并作为剖析GBM进展的工具。