Irreversible electroporation for combinatorial GBM treatment

项目3摘要 该项目将开发一种组合疗法，以增强高频不可逆电穿孔(H- 用靶向剂进行局部消融，以选择性地靶向肿瘤以外的肿瘤细胞 目前，成功治疗胶质母细胞瘤(GBM)是一个挑战。H-Fire是一种新型的微创 一种消融技术，包括将一系列低能量(强烈但短)的电脉冲发射到 将目标组织放置约5分钟。这些脉冲破坏了靶细胞的细胞膜的稳定性 组织，诱导细胞死亡，而不会造成热损伤。H-Fire创建完整且可预测的单元格 在正常组织和坏死组织之间急剧过渡的消融术。此外，H-Fire只影响一个 处理体积的成分，细胞膜，并保存重要的组织成分，如 支架、髓鞘、血管、结缔组织和神经。我们假设浸润性细胞 (在H-Fire消融区以外)可以使用低剂量的靶向抗GBM药物选择性地杀死 与H-FIRE联合使用，可使肿瘤完全消退，同时防止进一步侵袭 治疗利润率。对于肿瘤细胞以外的直接组织消融区，有一种非破坏性的 血脑屏障(BBB)通透性增加，使这些细胞更容易受到 因此，使IRE和佐剂的组合具有协同作用。通过关注脑癌， 我们将直接解决开发放射和化疗替代方法的需要，这两种方法都 其中有不良反应和有限的疗效。我们P01提案的这个项目3有三个具体的 目标。在目标1中，我们将表征脑瘤组织对氢火的响应的电学特性 细胞和组织尺度的脉冲，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H-FIRE的反应，结合四环素/PEP-1-L-环磷酰胺，来自本P01项目1。数据 这项研究收集的数据将有助于准确预测未来H-Fire治疗的处理量。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BBB的分解。在《目标3》中，我们将 评价四环磷腺苷/PEP-1-L-环磷酰胺联合H-FIRE治疗犬自发性脑瘤的疗效。如果 这项研究的成功将为一种能够改进的新形式的癌症治疗提供基础 对肿瘤和肿瘤边缘以外的浸润性GBM细胞的常规治疗 肿瘤复发的可能性，同时保护重要的健康周围组织。

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.