Harnessing artificial microRNA clusters against glioblastoma epigenetic plasticity and resistance to therapy

利用人工 microRNA 簇对抗胶质母细胞瘤表观遗传可塑性和治疗耐药性

• 批准号: 10116510
• 负责人: Pier Paolo Peruzzi
• 金额: $ 41.52万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116510
• 关键词: Abate; Address; Adult; Animal Model; BMI1 gene; Biogenesis; Biological; Biology; Brain; Caring; Cells; Characteristics; Chromatin; Clinical; Complex; DNA Damage; Data; Defense Mechanisms; Diagnosis; Diffusion; Disease; EZH2 gene; Engineering; Epigenetic Process; Genetic Structures; Genetic Transcription; Glioblastoma; Goals; Hybrids; Immune; Immunotherapy; In Vitro; Individual; KDM1A gene; Length; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Messenger RNA; Methods; MicroRNAs; Nature; Neuronal Differentiation; Nucleotides; Oncogenic; Outcome; PRC1 Protein; Pathway interactions; Patients; Pharmacology; Primary Brain Neoplasms; Proteins; RNA; Radiation; Regulation; Research; Resistance; Role; Stress; Structure; Synthetic Genes; Testing; Therapeutic; Time; Toxic effect; Transcript; Transgenes; Tumor Biology; Untranslated RNA; Work; cellular targeting; combinatorial; design; design and construction; experimental study; extracellular vesicles; gain of function; gene therapy; genotoxicity; histone demethylase; immunoregulation; improved; in vivo; innovation; loss of function; neoplastic cell; novel; novel strategies; prevent; response; scaffold; sound; synergism; temozolomide; therapeutic miRNA; therapeutic target; therapy resistant; trafficking; translational approach; tumor; tumor microenvironment

Glioblastoma is the most common primary brain cancer in adults and remains a deadly disease. Despite intense research and clinical efforts, its survival has not significantly improved for the past several decades. A major reason for this recalcitrant nature is the tumor’s ability to escape toxicity from currently available therapies, including Temozolomide (TMZ), radiation, and immune-modulation. This resistance depends on the activation of defense mechanisms in response to damage, and is mediated epigenetically by a complex, multi- component machinery that governs the transcriptional status of the tumor cells. Our studies have defined oncogenic proteins EZH2, BMI1 and LSD1 as crucial components of this epigenetic response. We have also demonstrated that they are regulated by specific microRNAs (miR-124, miR-128 and miR-137), co-expressed in normal brain, and simultaneously lost in glioblastoma. The re-expression of these three microRNAs in glioblastoma provides a strong inhibition against the three proteins and results in a very relevant sensitization of tumor cells to stress, both in vitro and in vivo. The overall goal of this proposal is two-fold: first, to characterize the mechanism whereby the co-activation of EZH2, BMI1 and LSD1 mediates tumor survival, establishing its necessary role in this response; Second, to develop a microRNA-mediated strategy to abate this epigenetic shield that is vital to the tumor, to support a gene therapy approach synergistic with current standard therapies. AIM1 proposes experiments to dissect the role of the EZH2/BMI1/LSD1 epigenetic complex in tumor responses against Temozolomide, radiation, and immunotherapy. AIM2 provides novel solutions to design and construct artificial genes that multiply the payload of microRNAs, and which thus function as an ideal gene therapy platform for multi-targeting this epigenetic response. AIM3 investigates the applicability of multi-microRNA-based therapy in animal models of glioblastoma, to address the vital problem of tumor resistance in vivo. INNOVATION: The proposed study to use artificial microRNA clusters for the control of the complex epigenetic tumor survival response is an innovative and heretofore unexplored approach. Also, this proposal introduces strategies to exploit the unique features of microRNAs biology, processing and intercellular trafficking in the perspective of an integrated gene therapy approach. LONG-TERM OBJECTIVE: We seek to meaningfully impact the care of glioblastoma patients through the application of principles of microRNA clustering, epigenetic interference, and synergism with other therapies.

胶质母细胞瘤是成人中最常见的原发性脑癌，也是一种致命的疾病。尽管