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

高频不可逆电穿孔 (H-FIRE) 组合 GBM 治疗

• 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
• 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

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.

项目概要 该项目最终将开发出一种增强高频的组合疗法 不可逆电穿孔（H-FIRE）局灶消融，在能力方面超越了传统疗法 选择性靶向胶质母细胞瘤 (GBM) 肿瘤边缘以外的浸润细胞。 H-FIRE 是一种新的、 微创消融技术，涉及提供一系列低能量的电脉冲 能量，但对目标组织的强度高（约 1000 V）且短（约 1 us），持续约 5 分钟。这些 脉冲使目标组织的细胞膜不稳定，诱导细胞死亡而不引起热 损害。 H-FIRE 可实现完整且可预测的细胞消融，并在正常细胞之间实现急剧转变 和坏死组织。此外，H-FIRE 保留了重要的组织成分，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 （在 H-FIRE 治疗区域之外）可以使用低剂量的抗 GBM 药物选择性杀死 与 H-FIRE 结合，导致肿瘤完全消退，同时防止浸润超出 肿瘤边缘。对于组织消融区域外的肿瘤细胞，有非破坏性的增加 血脑屏障的通透性，因此，使他们更容易受到所施用的药物的影响， 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要，这两种方法 其具有不良副作用且功效有限。该项目有三个具体目标。在目标 1 中，我们将 为 H-FIRE 开发优化的治疗参数，目标是渗透到 GBM 的浸润生态位， 在 3D 微工程中测试了 H-FIRE 和脂质体阿霉素递送的结合 肿瘤/血脑屏障模型（BBB）。在目标 2 中，我们将利用侵入性 GBM 的啮齿动物模型来实现 3D 模型验证以及组合治疗方案有效性测试 生理相关的体内环境。在目标 3 中，我们将评估我们的组合治疗策略以治疗 犬患者的自发性脑肿瘤。如果成功，这项研究将为新的研究奠定基础 能够超越针对大块肿瘤的传统治疗的癌症治疗形式，例如 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，同时保留重要的健康周围组织并最大限度地减少肿瘤复发的可能性 与标准疗法相关的不良副作用。