Developing miR-10b targeting for glioblastoma

开发针对胶质母细胞瘤的 miR-10b 靶向药物

• 批准号: 10353413
• 负责人: Anna M. Krichevsky
• 金额: $ 40.07万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10353413
• 关键词: 5' Untranslated Regions; Ablation; Adenovirus Vector; Adult; Affect; Allografting; Antisense Oligonucleotides; Apoptosis; Binding; Biochemical; Bioinformatics; Biological Assay; Biological Markers; Biology; Brain Neoplasms; CRISPR/Cas technology; Carcinoma; Cells; Chimera organism; Clinical; Clinical Trials; Code; Data; Dependence; Dependovirus; Development; Diagnosis; Engineering; Europe; Gene Expression; Genes; Genetic Transcription; Glioblastoma; Glioma; Gliomagenesis; Goals; Growth; High-Throughput RNA Sequencing; Human; Immunocompetent; Investigational Therapies; Lead; Ligation; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; MicroRNAs; Modeling; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Neuroglia; Oncogenic; Oncology; Patients; Pattern; Physiological; Polyribosomes; Population; Primary Brain Neoplasms; Proteins; Proteomics; RNA Binding; Regulator Genes; Research; Role; Safety; Signal Pathway; Specificity; System; Technology; Therapeutic; United States; Untranslated RNA; Viral; Virus; Work; Xenograft procedure; addiction; aggressive therapy; base; base editing; brain cell; brain tissue; cancer cell; cancer type; comparative efficacy; efficacy evaluation; glioma cell line; in vivo; in vivo Model; insight; loss of function mutation; molecular subtypes; mouse model; neoplastic cell; neuro-oncology; novel; novel therapeutics; pediatric patients; stem cells; therapeutic gene; therapeutic target; therapy resistant; translation to humans; tumor; tumor growth; tumor progression; uptake; vector; virtual

Despite  significant  research  and  clinical  efforts,  survival  of  patients  with  most  common  and  aggressive  primary  brain  tumor  glioblastoma  (GBM)  has  only  marginally  changed  over  the  past  25  years  and  is  only  around  fifteen  months.  There  is,  therefore,  an  urgent  need  for  new  molecular  targets,  concepts  and  approaches to treating GBM. In the recent years, microRNA (miRNA) emerged as a new and promising class  of targetable molecules that holds great potential in oncology. Our work on oncogenic miRNAs led us to focus  on  miR-­10b,  a  unique  miRNA  highly  expressed  in  all  GBM  subtypes  but  absent  in  normal  neuroglial  cells  of  the  brain.  miR-­10b  controls  the  growth  of  malignant  gliomas;;  moreover,  it  appears  essential  for  viability  of  heterogeneous glioma cells and glioma-­initiating stem cells (GSC). Inhibition or loss of miR-­10b is, therefore,  lethal  for  glioma.  Our  preliminary  data  suggests  that,  among  several  targeting  approaches,  CRISPR-­Cas9-­ based  miR-­10b  gene  ablation  eradicates  established  intracranial  GBM  in  mice  more  effectively.  Importantly,  despite  the  fundamental  addictive  role  of  miR-­10b  in  GBM,  and  the  potential  of  its  targeting,  molecular  mechanisms underlying miR-­10b activity are poorly understood and largely unconventional. The overall goal  of  this  proposal  is,  therefore,  two-­fold:  first,  to  investigate  molecular  mechanisms  underlying  GBM  dependence  on  miR-­10b,  and  second,  develop  efficient  therapeutic  strategies  based  on  miR-­10b  gene  editing.  Elucidation  of  the  signaling  pathways  regulated  by  miR-­10b,  and  development  of  approaches  for  its  therapeutic  targeting  will  have  an  impact  on  both  basic  and  clinical  neuro-­oncology,  and  cancer  more  generally.  The  work  for  Specific  Aim  1  will  characterize  endogenous  miR-­10b  interactome  and  identify  principal miR-­10b targets in glioma and glioma stem cells. Using a combination of functional assays, CLEAR-­ CLIP  and  CRISPR-­Cas9-­based  technologies,  and  quantitative  proteomics,  we  will  define  physiologically  important  protein-­coding  and  non-­coding  targets  underlying  GBM  addiction  to  miR-­10b.  Specific  Aim  2  will  investigate  the  effects  of  CRISPR-­Cas9-­based  miR-­10b  gene  editing  on  growth  and  invasion  of  orthotopic   glioma. Using human GSC-­derived xenografts and immunocompetent GL261 orthotopic GBM mouse models,  as  well  as  primary  normal  neuroglial  cells,  we  will  examine  efficacy  and  safety  of  various  engineered  CRISPR-­Cas9 systems and viral vehicles for targeted miR-­10b ablation in GBM. We will further compare off-­ target  effects  of  antisense  oligonucleotide  based  and  gene  editing  based  targeting  strategies.  The  proposed  work  promises  to  yield  significant  new  insights  into  the  biology  of  malignant  gliomas  and  may  lead  to  the  development of new, common, and potent therapies for all GBM subtypes.

尽管有重大的研究和临床努力，患者的生存最常见和侵略性

项目成果

Inhibition of the epigenetically activated miR-483-5p/IGF-2 pathway results in rapid loss of meningioma tumor cell viability.

抑制表观遗传活化的miR-483-5p/igf-2途径会导致脑膜瘤肿瘤细胞活力的快速丧失。

• DOI: 10.1007/s11060-023-04264-z
• 发表时间: 2023-03
• 期刊: JOURNAL OF NEURO-ONCOLOGY
• 影响因子: 3.9
• 作者: Uhlmann, Erik J.;Mackel, Charles E.;Deforzh, Evgeny;Rabinovsky, Rosalia;Brastianos, Priscilla K.;Varma, Hemant;Vega, Rafael A.;Krichevsky, Anna M.
• 通讯作者: Krichevsky, Anna M.

Exploration of the Noncoding Genome for Human-Specific Therapeutic Targets-Recent Insights at Molecular and Cellular Level.

探索分子和细胞水平上人类特异性治疗靶标的非编码基因组。

• DOI: 10.3390/cells12222660
• 发表时间: 2023-11-20
• 期刊: Cells
• 影响因子: 6

HOXDeRNA activates a cancerous transcription program and super-enhancers genome-wide.

HOXDeRNA 激活癌性转录程序和全基因组超级增强子。

• DOI: 10.1101/2023.06.30.547275
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Deforzh,Evgeny;Kharel,Prakash;Karelin,Anton;Ivanov,Pavel;Krichevsky,AnnaM
• 通讯作者: Krichevsky,AnnaM

Promoter and enhancer RNAs regulate chromatin reorganization and activation of miR-10b/HOXD locus, and neoplastic transformation in glioma.

• DOI: 10.1016/j.molcel.2022.03.018
• 发表时间: 2022-05-19
• 期刊: MOLECULAR CELL
• 影响因子: 16
• 作者: Deforzh, Evgeny;Uhlmann, Erik J.;Das, Eashita;Galitsyna, Aleksandra;Arora, Ramil;Saravanan, Harini;Rabinovsky, Rosalia;Wirawan, Aditya D.;Teplyuk, Nadiya M.;El Fatimy, Rachid;Perumalla, Sucika;Jairam, Anirudh;Wei, Zhiyun;Mirny, Leonid;Krichevsky, Anna M.
• 通讯作者: Krichevsky, Anna M.

Co-cultures of Glioma Stem Cells and Primary Neurons, Astrocytes, Microglia, and Endothelial Cells for Investigation of Intercellular Communication in the Brain.

神经胶质瘤干细胞与原代神经元、星形胶质细胞、小胶质细胞和内皮细胞的共培养，用于研究大脑中的细胞间通讯。

• DOI: 10.3389/fnins.2019.00361
• 发表时间: 2019
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Wei,Zhiyun;Kale,Shubham;ElFatimy,Rachid;Rabinovsky,Rosalia;Krichevsky,AnnaM
• 通讯作者: Krichevsky,AnnaM