Irreversible electroporation for combinatorial GBM treatment

用于 GBM 组合治疗的不可逆电穿孔

基本信息

批准号：
10220883
负责人：
Rafael Vidal Davalos
金额：
$ 19.7万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
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：
2017-08-17 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220883
关键词：
3-Dimensional Ablation Address Adjuvant Adverse effects Affect Aftercare Alternative Therapies Anatomy Anisotropy Area Blood - brain barrier anatomy Blood Vessels Brain Brain Neoplasms Canis familiaris Cell Death Cell membrane Cells Cessation of life Chemotherapy and/or radiation Clinical Complex Connective Tissue Coupled Cyclophosphamide Data Diffuse Dose Electrodes Electroporation Electroporation Therapy Engineering Foundations Frequencies Future Gadolinium General Anesthesia Genetic Geometry Glioblastoma Glioma Histology Homeostasis Human Image In Vitro Individual Infiltration Kidney Liver Location Magnetic Resonance Imaging Malignant - descriptor Malignant Glioma Malignant neoplasm of brain Modeling Myelin Sheath Neoplasm Metastasis Nerve Neurocognitive Deficit Normal tissue morphology Operative Surgical Procedures Pancreas Pathology Patients Penetration Pharmaceutical Preparations Physiologic pulse Physiological Primary Neoplasm Prostate Protocols documentation Quality of life Radiation therapy Rattus Recurrence Regimen Rodent Series Specificity Structure Techniques Technology Testing Therapeutic Therapeutic Agents Tissue Sample Tissues Translations Tumor Tissue Work base blood-brain barrier disruption blood-brain barrier permeabilization brain tissue cancer cell cancer therapy cell killing chemotherapy combinatorial contrast enhanced conventional therapy electric field electrical property human disease human model improved in vivo minimally invasive necrotic tissue neoplastic cell novel novel strategies preservation prevent response scaffold side effect targeted agent targeted treatment therapeutically effective therapy development therapy outcome translational model treatment optimization treatment planning tumor tumor ablation tumor growth

项目摘要

Project 3 Summary This project will develop a combinatorial therapy that enhances high-frequency irreversible electroporation (H- FIRE) focal ablation with targeting agents to selectively target tumor cells which infiltrate beyond the tumor margin, a current challenge to successfully treating glioblastoma (GBM). H-FIRE is a new, minimally invasive ablation technique that involves delivering a series of low energy (intense, but short) bursts of electric pulses 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 sharp transition between normal and necrotic tissue. Furthermore, H-FIRE only affects a single component of the treated volume, the cell membrane, and preserves important tissue components such as scaffolds, myelin sheaths, blood vessels, connective tissue, and nerves. We hypothesize that infiltrative cells (beyond the H-FIRE ablated zone) can be selectively killed using a low dose of a targeted anti-GBM agent in combination with H-FIRE, resulting in complete regression of tumors while preventing further infiltration beyond the treatment margins. For tumor cells outside the zone of direct tissue ablation, there is a non-destructive increase in blood-brain barrier (BBB) permeability, making these cells 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. This Project 3 of our P01 proposal has three Specific Aims. In Aim 1, we will characterize the electrical properties of brain tumor tissues in response to H-FIRE pulses at both the cellular and tissue scales, using a combination of engineered 3D tumor models, as well as excised healthy (canine) and malignant (human, canine) brain tissue. We will also characterize cellular responses to H-FIRE in combination with QUAD-CTX/Pep-1-L-CTX from Project 1 of this P01. The data collected from this study will help accurately predict treatment volume for future H-FIRE treatments. In Aim 2, we will quantify the effects of H-FIRE treatment in rats to assess BBB breakdown in vivo. In Aim 3, we will assess QUAD-CTX/Pep-1-L-CTX coupled with H-FIRE 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 improving conventional treatments for both tumors and the infiltrative GBM cells beyond the tumor margin to eliminate the likelihood of tumor recurrence, while preserving the vital healthy surrounding tissue.

项目3总结该项目将开发一种增强高频不可逆电穿孔（H- FIRE）使用靶向剂进行局部消融，选择性地靶向浸润到肿瘤之外的肿瘤细胞边缘，目前成功治疗胶质母细胞瘤（GBM）的挑战。 H-FIRE 是一种新型微创消融技术，涉及传递一系列低能量（强但短）的电脉冲突发目标组织约 5 分钟。这些脉冲会破坏目标细胞膜的稳定性组织，诱导细胞死亡而不引起热损伤。 H-FIRE 创建完整且可预测的单元正常组织和坏死组织之间急剧过渡的消融。此外，H-FIRE 只影响单个处理体积的组成部分，细胞膜，并保留重要的组织成分，例如支架、髓鞘、血管、结缔组织和神经。我们假设浸润细胞（超出 H-FIRE 消融区域）可以使用低剂量的靶向抗 GBM 药物选择性杀死与 H-FIRE 结合，导致肿瘤完全消退，同时防止进一步浸润治疗裕度。对于直接组织消融区域之外的肿瘤细胞，有一种非破坏性的方法血脑屏障（BBB）通透性增加，使这些细胞更容易受到给药的影响剂，从而使IRE和佐剂的组合具有协同作用。通过关注脑癌，我们将直接解决开发放射和化疗替代方法的需求其中有不良副作用且功效有限。我们 P01 提案的项目 3 有 3 个具体内容目标。在目标 1 中，我们将表征脑肿瘤组织响应 H-FIRE 的电特性使用工程 3D 肿瘤模型的组合，在细胞和组织尺度上发出脉冲，以及切除健康（犬）和恶性（人、犬）脑组织。我们还将表征蜂窝结合本 P01 项目 1 的 QUAD-CTX/Pep-1-L-CTX 对 H-FIRE 的响应。数据本研究收集的数据将有助于准确预测未来 H-FIRE 治疗的治疗量。在目标 2 中，我们将量化 H-FIRE 治疗对大鼠的影响，以评估体内血脑屏障的破坏。在目标 3 中，我们将评估 QUAD-CTX/Pep-1-L-CTX 联合 H-FIRE 治疗犬患者自发性脑肿瘤。如果成功，这项研究将为一种能够改善癌症治疗的新形式奠定基础对肿瘤和超出肿瘤边缘的浸润性 GBM 细胞进行常规治疗，以消除肿瘤复发的可能性，同时保留重要的健康周围组织。