Irreversible electroporation for combinatorial GBM treatment

用于 GBM 组合治疗的不可逆电穿孔

• 批准号: 9978745
• 负责人: Rafael Vidal Davalos
• 金额: $ 17.26万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9978745
• 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; Necrosis; Neoplasm Metastasis; Nerve; Neurocognitive Deficit; 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; Treatment Efficacy; 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; neoplastic cell; novel; novel strategies; preservation; prevent; response; scaffold; side effect; targeted agent; targeted treatment; therapy development; therapy outcome; translational model; treatment optimization; treatment planning; tumor; tumor ablation; tumor growth

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，增强高频不可逆电穿孔（H- FIRE）用靶向剂进行局部消融，以选择性靶向浸润到肿瘤外的肿瘤细胞 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 一种消融技术，涉及提供一系列低能量（强，但短）的电脉冲， 目标组织约5分钟。这些脉冲使靶细胞的细胞膜不稳定， 组织，诱导细胞死亡而不引起热损伤。H-FIRE创建完整和可预测的细胞 在正常和坏死组织之间具有急剧过渡的消融。此外，H-FIRE仅影响单个 治疗体积的组成部分，细胞膜，并保留重要的组织成分， 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）可以使用低剂量的靶向抗GBM剂选择性地杀死， 与H-FIRE组合，导致肿瘤完全消退，同时防止进一步浸润 治疗边缘。对于直接组织消融区域外的肿瘤细胞， 血脑屏障（BBB）通透性增加，使这些细胞对所施用的药物更敏感。 因此，使IRE和佐剂的组合具有协同作用。通过关注脑癌， 我们将直接致力于开发替代放疗和化疗的方法， 这些药物具有不良副作用和有限的功效。我们P01提案的项目3有三个具体的 目标。在目标1中，我们将描述脑肿瘤组织响应H-FIRE的电特性 脉冲在细胞和组织规模，使用工程3D肿瘤模型的组合，以及 切除健康（犬）和恶性（人，犬）脑组织。我们还将描述细胞 对本P01项目1中H-FIRE与QUAD-CTX/Pep-1-L-CTX组合的反应。数据 从本研究中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治疗在大鼠中的作用以评估体内BBB破坏。在目标3中，我们 评估QUAD-CTX/Pep-1-L-CTX与H-FIRE联用治疗犬患者自发性脑肿瘤。如果 如果成功，这项研究将为一种新的癌症治疗方法提供基础， 对于肿瘤和超出肿瘤边缘的浸润性GBM细胞的常规治疗， 降低肿瘤复发的可能性，同时保留重要的健康周围组织。