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摘要该项目将开发一种组合疗法，可增强高频不可逆的电穿孔（H- 火焰）与靶向剂的局灶性消融，以选择性地靶向肿瘤超出肿瘤的肿瘤细胞边缘，目前成功治疗胶质母细胞瘤（GBM）的挑战。 H火是一种新的，微创的消融技术涉及提供一系列低能（强烈但短）的电脉冲爆发靶向组织约5分钟。这些脉冲破坏了靶向的细胞膜组织，诱导细胞死亡而不会引起热损伤。 H-Fire创建完整且可预测的单元格在正常和坏死组织之间进行急剧过渡的消融。此外，H火只会影响一个处理体积的成分，细胞膜和保存重要的组织成分，例如脚手架，髓鞘，血管，结缔组织和神经。我们假设浸润细胞（超越H火消融区）可以使用低剂量的靶向抗GBM剂选择性地杀死与H火相结合，导致肿瘤的完全消退，同时防止进一步渗透治疗边缘。对于直接组织消融区域以外的肿瘤细胞，存在无损增加血脑屏障（BBB）渗透性，使这些细胞更容易受到管理代理，因此使IRE和辅助药物协同结合。通过关注脑癌，我们将直接满足开发疗法的辐射和化学疗法的需求，既其中具有不利的副作用和有限的功效。我们P01提案的该项目3具有三个特定的目标。在AIM 1中，我们将表征脑肿瘤组织的电特性，以响应H火。使用工程的3D肿瘤模型的组合以及切除健康（犬）和恶性（人类，犬）脑组织。我们还将表征蜂窝对H-FIRE的响应与本P01项目1的QUAD-CTX/PEP-1-L-CTX结合使用。数据从这项研究中收集的将有助于准确预测未来H火的治疗的治疗量。在AIM 2中，我们将量化H-火灾治疗在大鼠体内评估BBB分解的影响。在AIM 3中，我们将评估Quad-CTX/PEP-1-L-CTX与H-Fire结合以治疗犬类患者的自发脑肿瘤。如果成功的这项研究将为一种能够改善的新形式的癌症疗法提供基础肿瘤和浸润性GBM细胞的常规处理以外的肿瘤边缘以消除肿瘤复发的可能性，同时保留周围重要的健康组织。