Stem cell repair after blood brain barrier disruption and high-dose chemotherapy

血脑屏障破坏和大剂量化疗后的干细胞修复

• 批准号: 9186006
• 负责人: Monica Smith Pearl
• 金额: $ 20.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186006
• 关键词: Area; Astrocytes; Autonomic nervous system; Autopsy; Basic Science; Blood - brain barrier anatomy; Bone Marrow Transplantation; Brain; Brain Injuries; Brain Stem; Brain Stem Neoplasms; Cancer cell line; Catheters; Cell Adhesion Molecules; Cell Transplants; Cells; Central Nervous System Neoplasms; Cerebrum; Chemotherapy-Oncologic Procedure; Childhood; Clinical; Conscious; Diffuse intrinsic pontine glioma; Discipline; Disease model; Dose; Drug Delivery Systems; Engineering; Engraftment; Etiology; Extravasation; Future; Genetic Engineering; Goals; Hematology; High Dose Chemotherapy; Histologic; Homeostasis; Human; Imaging Techniques; Immunology; In Vitro; Injury; Intervention; Intra-Arterial Infusions; Intracranial Neoplasms; Lead; Learning; Longevity; Magnetic Resonance Imaging; Mannitol; Melphalan; Memory; Methodology; Methods; MicroRNAs; Microglia; Mitotic; Modeling; Monitor; Motor; Mus; Neuraxis; Neuroglia; Neurologic Deficit; Neurons; Oligodendroglia; Operative Surgical Procedures; Oryctolagus cuniculus; Pathology; Patients; Perfusion; Pharmaceutical Preparations; Population; Process; Progenitor Cell Engraftment; Radiation therapy; Rattus; Regulation; Research Project Grants; Resistance; Reticular Formation; Risk; Role; Sensory; Severities; Shivering; Small Interfering RNA; Stem cell transplant; Stem cells; Structure; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Toxic effect; Translating; Transplantation; Treatment Failure; Work; aptamer; base; basilar artery; brain parenchyma; brain tissue; cancer cell; cancer stem cell; cell type; chemotherapy; course development; drug distribution; drug efficacy; effective therapy; experimental study; improved; innovation; minimally invasive; neoplastic cell; nerve stem cell; neuro-oncology; neurochemistry; neurogenesis; neurotoxic; neurotoxicity; neurovascular; oncology; phase I trial; public health relevance; regenerative; repaired; restoration; targeted treatment; tool; treatment strategy; tumor; tumor eradication; vascular bed; white matter

 DESCRIPTION (provided by applicant): The absence of effective treatment options for patients with brainstem tumors and other highly aggressive, unresponsive CNS tumors emphasizes the need for innovative strategies that combine advanced imaging techniques, minimally invasive delivery methods, and targeted therapeutic agents. Current challenges to successful tumor treatment include the intrinsic chemoresistance of tumor cells and an intact blood-brain barrier (BBB), which effectively impedes the delivery of most therapeutic molecules. More specific, tailored therapeutic agents are emerging, however, even the most potent therapeutic molecules identified from in vitro experiments will be ineffective if they cannot penetrate the BBB to reach the cancer cells. The study of drug distribution, therefore, is crucial to determining a drug's efficacy. Otherwise, potential drugs will be regarded as ineffective, while they are in fact being inadequately delivered to the tumor. We have successfully developed a unique MRI-guided neurointerventional platform for predictable, local intra- arterial (IA) delivery of therapeutic agents to the brainstem after focal BBB disruption (BBBD). We are able to precisely document trans-catheter perfusion using real-time GE-EPI MRI and pre-define an area for selective BBBD and subsequent super-selective therapeutic agent administration. While our current methodology utilizes the chemotherapy drug melphalan, this delivery strategy can be applied to a variety of therapeutic agents including other chemotherapy drugs, siRNA, microRNA, aptamers, and future discoveries. In this proposal we will compare the differences in drug distribution after BBBD with and without the aid of predicting the targeted area in advance. We will determine the cellular neurotoxicity after IA BBBD and chemotherapy via the basilar artery, both in terms of severity of injury and time course for development. We will also assess the feasibility of glial progenitor cells (GRPs) engraftment to determine their role in repair afte chemotherapy. This information can be readily translated into our ongoing Phase I trial, "Intra-arterial Chemotherapy for the Treatment of Progressive DIPG", (NCT01688401). We have assembled a team of basic science and clinical experts across the disciplines of pediatric neuro-oncology, interventional neuroradiology, and MRI research for this project. While our proposal is generally targeted for brainstem pathologies, this MRI-guided neurointerventional platform can be applied to various other CNS tumors and neurovascular pathologies that require selective, targeted therapeutic delivery.

 描述（由申请人提供）：脑干肿瘤和其他高度侵袭性、无反应的CNS肿瘤患者缺乏有效的治疗选择，因此需要结合联合收割机先进成像技术、微创给药方法和靶向治疗药物的创新策略。目前成功的肿瘤治疗面临的挑战包括肿瘤细胞的内在化学抗性和完整的血脑屏障（BBB），这有效地阻碍了大多数治疗分子的递送。更具体的、定制的治疗剂正在出现，然而，即使是从体外实验中鉴定出的最有效的治疗分子，如果它们不能穿透血脑屏障到达癌细胞，也将是无效的。因此，药物分布的研究对于确定药物的疗效至关重要。否则，潜在的药物将被视为无效，而 它们实际上没有被充分地递送到肿瘤。我们成功开发了一种独特的MRI引导神经介入平台，用于可预测的局部动脉内（IA）输送 在局灶性血脑屏障破坏（BBBD）后，治疗剂的脑干。我们能够使用实时GE-EPI MRI精确记录经导管灌注，并预先定义选择性BBBD和后续超选择性治疗剂给药的区域。虽然我们目前的方法利用化疗药物美法仑，但这种递送策略可以应用于各种治疗剂，包括其他化疗药物，siRNA，microRNA，适体和未来的发现。在本建议中，我们将比较BBBD后药物分布的差异，并提前预测靶向区域的帮助。我们将确定IA BBBD和经基底动脉化疗后的细胞神经毒性，包括损伤的严重程度和发展的时间过程。我们还将评估胶质祖细胞（GRP）移植的可行性，以确定其在化疗后修复中的作用。这些信息可以很容易地转化为我们正在进行的I期试验，“动脉内化疗治疗进展性DIPG”，（NCT 01688401）。我们已经为这个项目组建了一个由儿科神经肿瘤学、介入神经放射学和MRI研究等学科的基础科学和临床专家组成的团队。虽然我们的建议通常针对脑干病变，但这种MRI引导的神经介入平台可应用于需要选择性靶向治疗的各种其他CNS肿瘤和神经血管病变。