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

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.

项目概要多形性胶质母细胞瘤（GBM）是成人中最常见、最具侵袭性的原发性脑肿瘤。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 GBM 研究和转化为有效治疗之间存在相当大的障碍。是GBM肿瘤的广泛浸润和分子异质性，两者都会导致肿瘤复发治疗后，GBM 患者的平均生存期不到 15 个月。为了有效治疗这些致命肿瘤，它们必须克服 GBM 浸润。和异质性。反义寡核苷酸 (ASO) – 可以调节几乎任何 RNA 分子表达的化合物 – 在本地交付后，ASO 为对抗 GBM 渗透和异质性提供了独特的优势。分布在整个大脑中，这是到达浸润性 GBM 细胞的必要条件。可编程代理，ASO 具有调节多种表达所需的特异性和灵活性基因靶标——表征和对抗 GBM 异质性的有效策略 2016 年，ASO 药物， nusinersen 被 FDA 批准用于治疗脊髓性肌萎缩症，确立了 ASO 在以下领域的临床疗效：然而，一些用于 GBM 的 ASO 候选药物由于高浓度而在临床试验中失败。确定有效的、耐受性良好的 ASO 用于脑肿瘤基因调节将是一个新的课题。开发有效的 GBM 疗法的大门。 Watts 实验室开发了经过化学优化的无毒 ASO，其分布和效力均得到增强然而，它们对 GBM 的影响尚不清楚。识别能够有效且安全地沉默 GBM 驱动因素的 ASO，并评估其对肿瘤进展和治疗的影响在 Jonathan Watts 博士（寡核苷酸化学）、Richard Moser（神经- 肿瘤学）、Sunit Das（GBM 小鼠模型）、Manuel Garber（生物信息学）和 Michael Green（癌症生物学）和治疗），目标 1 将测试化学修饰的 ASO 沉默临床相关 GBM 驱动因素的能力 (ATF5)，在分子上不同的患者来源的 GBM 细胞系中抑制细胞增殖并诱导细胞死亡。然后通过测量 ATF5 沉默来评估化合物在 GBM 小鼠模型中的治疗效果，在目标 2 中，ASO 介导的沉默的后果。将针对 ATF5 的 ASO 注射到小鼠的 GBM 肿瘤中进行研究。治疗反应后，将分离残留的 GBM 细胞进行单细胞 RNA 测序，以表征转录组并确定 ASO 沉默如何扰乱功能异质性。药物组合的合理框架，以尽量减少 GBM 肿瘤耐药性。将 ASO 作为一种新的 GBM 治疗进展和剖析 GBM 进展的工具。