High-frequency Irreversible Electroporation (H-FIRE) combinatorial GBM treatment

高频不可逆电穿孔 (H-FIRE) 组合 GBM 治疗

基本信息

批准号：
9249285
负责人：
Rafael Vidal Davalos
金额：
$ 33.45万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
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：
2017-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249285
关键词：
Ablation Address Adjuvant Adjuvant Chemotherapy Adverse effects Anatomy Animal Model Anisotropy Area Biological Preservation Blood - brain barrier anatomy Blood Vessels Brain Brain Neoplasms Canis familiaris Cell Death Cell Nucleus Cell membrane Cells Cessation of life Clinical Clinical Course of Disease Connective Tissue Coupled Data Development Devices Diffuse Dimensions Dose Electrodes Electroporation Electroporation Therapy Engineering Excision Extracellular Matrix Foundations Frequencies Functional disorder Gene Expression General Anesthesia Geometry Glioblastoma Glioma Heterogeneity Histologic Homeostasis Human Hybrids Image In Vitro Individual Infiltration Length Liposomal Doxorubicin Liposomes Location Magnetic Resonance Imaging Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of liver Malignant neoplasm of pancreas Malignant neoplasm of prostate Mathematics Methodology Methods Modeling Molecular Profiling Morphology Muscle Contraction Myelin Sheath Necrosis Neoplasm Metastasis Nerve Neurocognitive Operative Surgical Procedures Outcome Pathology Patients Penetration Permeability Pharmaceutical Preparations Physiologic pulse Physiological Precision therapeutics Preparation Primary Neoplasm Protocols documentation Quality of life Radiation Radiation therapy Rattus Recurrence Renal carcinoma Rodent Rodent Model Series Shapes Structure Study models Techniques Testing Therapeutic Tight Junctions Tissue Engineering Tissues Translations Treatment Efficacy Treatment Protocols Validation Work base cancer cell cancer therapy cell growth cell killing chemotherapy combinatorial contrast enhanced conventional therapy efficacy testing electric field electrical property improved in vivo killings liposomal delivery minimally invasive neoplastic cell novel novel therapeutics prevent protein expression three-dimensional modeling traditional therapy treatment planning treatment site treatment strategy tumor tumor ablation tumor growth

项目摘要

Project Summary This project will culminate in the development of a combinatorial therapy that enhances high-frequency irreversible electroporation (H-FIRE) focal ablation, surpassing traditional therapies in terms of ability to selectively target infiltrative cells beyond the tumor margin of glioblastoma (GBM). H-FIRE is a new, minimally invasive ablation technique that involves delivering a series of electric pulses that are low in energy, but intense (~1000 V) and short (~1 us) to targeted tissue for approximately 5 minutes. These pulses destabilize the cell membranes of the targeted tissue, inducing cell death without causing thermal damage. H-FIRE creates complete and predictable cell ablation with a sharp transition between normal and necrotic tissue. Furthermore, H-FIRE preserves important tissue components such as extracellular matrix, myelin sheaths, blood vessels, connective tissue, and nerves. We hypothesize that infiltrative cells (beyond the H-FIRE treated zone) can be selectively killed using a low dose of an anti-GBM drug in combination with H-FIRE, resulting in complete regression of tumors while preventing infiltration beyond the tumor margins. For tumor cells outside the zone of tissue ablation, there is a non-destructive increase in blood-brain barrier permeability, thus, making them more susceptible to the administered agents and thus making the combination of IRE and adjuvant agents synergistic. By focusing on brain cancer, we will be directly addressing the need to develop alternative approaches to radiation and chemotherapy, both of which have adverse side effects and limited efficacy. The project has three Specific Aims. In Aim 1, we will develop optimized treatment parameters for H-FIRE targeting penetration into the infiltrative niche of GBM, with a combination of H-FIRE and delivery of liposomal doxorubicin tested in a 3D micro-engineered tumor/blood-brain-barrier model (BBB). In Aim 2, we will leverage rodent models of invasive GBM for both 3D model validation, and testing of the efficacy of combinatorial treatment protocols in a more physiological relevant in vivo setting. In Aim 3, we will assess our combinatorial treatment strategy to treat spontaneous brain tumors in canine patients. If successful, this study will provide the foundation for a new form of cancer therapy capable of surpassing conventional treatments for targeting of the bulk tumor, as well as the infiltrative GBM cells beyond the tumor margin. If successful, this hybrid approach will eliminate the likelihood of tumor recurrence, while preserving the vital healthy surrounding tissue and minimizing the adverse side effects that are associated with standard therapies.

项目摘要该项目将最终导致组合疗法的开发，从而增强高频不可逆的电穿孔（H火）局灶性消融，在能力方面超过了传统疗法有选择地靶向渗透细胞超出胶质母细胞瘤（GBM）的肿瘤边缘。 H火是一个新的微创消融技术涉及传递一系列低水平的电脉冲能量，但强烈（〜1000 V）和短（约1 US）到靶组织约5分钟。这些脉冲破坏了靶组织的细胞膜，诱导细胞死亡而不引起热量损害。 H火路可创建完整且可预测的细胞消融，正常之间有急剧的过渡和坏死组织。此外，H火将保留重要的组织成分，例如细胞外基质，髓鞘，血管，结缔组织和神经。我们假设浸润细胞（超越H火路处理区）可以使用低剂量的抗GBM药物选择性地杀死与H火相结合，导致肿瘤的完全消退，同时防止浸润肿瘤边缘。对于组织消融区域以外的肿瘤细胞，有无损的增加因此，在血脑屏障的渗透性中，使其更容易受到管理药物的影响从而使IRE和佐剂的结合结合在一起。通过关注脑癌，我们将直接解决需要开发替代方法的辐射和化学疗法的需求，这两种方法具有不良副作用和有限的功效。该项目具有三个特定的目标。在AIM 1中，我们将开发优化的治疗参数，以靶向靶向渗透到GBM的渗透生态位， H火与在3D微工程中测试的脂质体阿霉素的递送结合肿瘤/血脑屏障模型（BBB）。在AIM 2中，我们将利用两者的侵入性GBM的啮齿动物模型 3D模型验证以及组合治疗方案的功效的测试更多生理相关的体内环境。在AIM 3中，我们将评估我们的组合治疗策略以治疗犬类患者的自发脑肿瘤。如果成功，这项研究将为新的癌症治疗的形式，能够超过靶向大体肿瘤的常规治疗以及超出肿瘤边缘的浸润性GBM细胞。如果成功，这种混合方法将消除肿瘤复发的可能性，同时保留了周围组织至关重要的健康并最小化与标准疗法相关的不良副作用。