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

项目摘要 该项目将最终发展一种组合疗法，提高高频 不可逆电穿孔（H-FIRE）局灶性消融，在以下方面超越传统疗法： 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， 微创消融技术包括输送一系列低能量的电脉冲， 能量，但强度（~1000 V）和时间短（~1 us），靶组织持续约5分钟。这些 脉冲使靶组织的细胞膜不稳定，诱导细胞死亡而不引起热损伤。 损害H-FIRE创建完全和可预测的细胞消融，在正常细胞之间有急剧的过渡， 和坏死组织。此外，H-FIRE保留了重要的组织成分，如细胞外基质， 基质、髓鞘、血管、结缔组织和神经。我们假设浸润细胞 （在H-FIRE处理区之外）可以使用低剂量的抗GBM药物选择性地杀死。 与H-FIRE组合，导致肿瘤完全消退，同时防止浸润超过 肿瘤边缘对于组织消融区以外的肿瘤细胞， 因此，血脑屏障通透性降低，使它们对所施用的药剂更敏感， 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学疗法替代方法的需要， 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 为H-FIRE靶向渗透到GBM的浸润性小生境中开发优化的治疗参数， H-FIRE和脂质体阿霉素的组合在3D微工程中进行了测试， 肿瘤/血脑屏障模型（BBB）。在目标2中，我们将利用侵袭性GBM的啮齿动物模型， 3D模型验证，并在更大范围内测试组合治疗方案的功效。 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， 自发性脑肿瘤。如果成功，这项研究将为新的 一种能够超越常规治疗的癌症治疗形式，用于靶向大块肿瘤， 以及肿瘤边缘以外的浸润性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 与标准治疗相关的不良副作用。

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.