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Therapeutic disruption of Connexin43-mediated microtubule regulation to target glioblastoma cancer stem cells

Connexin43 介导的微管调节对胶质母细胞瘤干细胞的治疗破坏

基本信息

批准号：
9346494
负责人：
Samy Lamouille
金额：
$ 22.5万
依托单位：
ACOMHAL RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9346494
关键词：
Adult Alkylating Agents Apoptosis Binding Biochemical Biochemistry Biodistribution Biological Assay Brain Neoplasms Cell Communication Cell Maintenance Cell Proliferation Cell Survival Cell physiology Cells Central Nervous System Diseases Characteristics Chemotherapy-Oncologic Procedure Clinic Clinical Trials Collaborations Communication Connexin 43 Connexins Cytotoxic Chemotherapy Data Dimensions Disease Drug Delivery Systems Encapsulated Excision FDA approved FOXP3 gene Failure Fostering Foundations Future Gap Junctions Glioblastoma Glioma Goals Heterogeneity Human Hypoxia In Vitro Ions Legal patent Letters Licensing Link Malignant Neoplasms Mediating Medical Microscopy Microtubules Mission Modeling Names Nature Newly Diagnosed Operative Surgical Procedures Optics Organoids Patient-Focused Outcomes Patients Peptides Pharmaceutical Preparations Physiological Polyanhydrides Population Propane Property Proteins Public Health Radiation Radiation therapy Recurrence Refractory Regulation Research Research Institute Research Personnel Resistance Resolution South Carolina Stem cells Techniques Testing Therapeutic Therapeutic Effect Therapeutic Intervention Treatment Protocols Tumor Initiators Tumorigenicity United States National Institutes of Health Universities Validation Virginia Work aggressive therapy base biomaterial compatibility cancer cell cancer stem cell cell behavior chemotherapy copolymer effective therapy experience human disease improved in vitro Assay in vivo in vivo Model innovation irradiation migration mouse model nanoparticle neoplastic cell neurosurgery new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics outcome forecast particle peptidomimetics pre-clinical prevent reconstruction sebacic acid self-renewal small molecule stem cell population temozolomide tool treatment strategy tumor tumor microenvironment tumor progression tumorigenic

项目摘要

Project Summary Glioblastoma (GBM) is one of the most lethal incurable human diseases. Even with aggressive therapies including surgical resection followed by radiotherapy and chemotherapy using temozolomide (TMZ), the median survival for GBM patients is only 14 months. In fact, GBM cancer cells are highly infiltrative and comprise a sub- population of glioma stem cells (GSCs) with tumorigenic properties regulated by the tumor microenvironment, and often resistant to chemotherapy and irradiation treatments. The remaining GSCs can then enter an active state of self-renewal, and asymmetric division that recapitulates the heterogeneous tumor. As a result, all treated GBM patients will experience tumor recurrence and subsequent surgeries and toxic radiotherapy and chemotherapy regimens are harmful for the patient and often remain insufficient. There is therefore an urgent need for new therapeutic drug to target GSCs and treat this devastating disease. Glioblastoma resistance to TMZ correlates with the expression of the gap junction protein Connexin43 (Cx43), a protein which enables communication between cells, and increased levels of Cx43 are observed in GSCs. The function of Cx43, is not limited to forming channels for the passage of ions and small molecules between cells, but also participates in cell proliferation, migration and apoptosis. Therefore, targeting Cx43 activity holds promise to treat GBM and prevent tumor recurrence. In this proposed research we use a novel Cx43 mimetic peptide named JM2 (juxtamembrane 2) that encompasses the microtubule binding sequence of Cx43. Our preliminary data show that JM2 alters Cx43 binding to microtubule, decreases the formation of Cx43 gap junctions, and inhibits cell- cell communication in GSCs. Most importantly, we reveal the therapeutic potential of JM2 in decreasing GSC survival in vitro and in vivo. With the goal of developing a new therapy based upon JM2 to target GSCs in GBM, our overall objective is to generate JM2-loaded polyanhydride biodegradable nanoparticles (JM2-NPs) for sustained delivery of JM2 to GSCs. We will use high-resolution microscopy techniques including stochastic optical reconstruction microscopy (STORM) and biochemistry assays to analyze the effect of JM2-NPs in GSCs derived from human primary GBM cells freshly isolated from dissected patient tumor. Finally, we will assess the therapeutic effect of JM2-NPs on GSCs ex vivo using a three dimensional patient GBM-derived organoid model, and in vivo using an orthotopic GBM mouse model. These results will validate the potent effect of JM2 peptide for treatment of high Cx43/chemoresistant GSCs and present a therapeutic opportunity to prevent GBM tumor recurrence. The proposed research is significant because this innovative approach will not only allow us to develop novel therapies for lethal GBM but also will lay foundation on potential clinical trials in newly diagnosed GBM patients in the near future. Finally, our new JM2-loaded nanoparticles may be scalable to other CNS diseases that could benefit from targeting Cx43-microtubule interaction.

项目概要胶质母细胞瘤（GBM）是最致命的人类无法治愈的疾病之一。即使采用积极的治疗包括手术切除，然后使用替莫唑胺（TMZ）进行放疗和化疗，中位 GBM患者的生存期只有14个月。事实上，GBM 癌细胞具有高度浸润性，并包含一个亚具有受肿瘤微环境调节的致瘤特性的神经胶质瘤干细胞（GSC）群体，并且通常对化疗和放射治疗具有抵抗力。然后剩余的 GSC 可以进入活跃状态自我更新的状态，以及概括异质肿瘤的不对称分裂。结果，全部接受治疗 GBM患者将经历肿瘤复发以及随后的手术和毒性放疗以及化疗方案对患者有害，而且往往仍然不够。因此有一个紧急的需要新的治疗药物来靶向 GSC 并治疗这种毁灭性的疾病。胶质母细胞瘤耐药 TMZ 与间隙连接蛋白 Connexin43 (Cx43) 的表达相关，该蛋白能够使在 GSC 中观察到细胞之间的通讯以及 Cx43 水平增加。 Cx43的功能，不是仅限于形成细胞间离子和小分子通道的通道，但也参与细胞增殖、迁移和凋亡。因此，靶向 Cx43 活性有望治疗 GBM 和防止肿瘤复发。在这项拟议的研究中，我们使用了一种名为 JM2 的新型 Cx43 模拟肽（近膜 2）包含 Cx43 的微管结合序列。我们的初步数据显示 JM2 改变 Cx43 与微管的结合，减少 Cx43 间隙连接的形成，并抑制细胞- GSC 中的细胞通讯。最重要的是，我们揭示了 JM2 在降低 GSC 方面的治疗潜力体外和体内的存活率。目标是开发一种基于 JM2 的新疗法来靶向 GBM 中的 GSC，我们的总体目标是生成负载 JM2 的聚酸酐可生物降解纳米颗粒 (JM2-NP) 向 GSC 持续交付 JM2。我们将使用高分辨率显微镜技术，包括随机光学重建显微镜 (STORM) 和生物化学测定分析 JM2-NPs 在 GSC 中的作用源自从解剖的患者肿瘤中新鲜分离的人原代 GBM 细胞。最后，我们将评估使用三维患者 GBM 衍生类器官模型，JM2-NP 对离体 GSC 的治疗效果，并使用原位 GBM 小鼠模型进行体内实验。这些结果将验证 JM2 肽的有效作用用于治疗高 Cx43/化疗耐药性 GSC，并提供预防 GBM 肿瘤的治疗机会复发。拟议的研究意义重大，因为这种创新方法不仅使我们能够开发针对致命 GBM 的新疗法，同时也将为新诊断的潜在临床试验奠定基础 GBM患者在不久的将来。最后，我们新的负载 JM2 的纳米颗粒可以扩展到其他 CNS 可以从靶向 Cx43-微管相互作用中受益的疾病。