Impact of extracellular potassium on oncolytic therapy

项目简介：溶瘤病毒疗法(OV)使用复制能力强的病毒作为癌症治疗药物。 不幸的是，许多调节这些病毒在肿瘤内复制的潜在分子机制 病毒仍然没有完全被理解。例如，最近已经证明，细胞外的 实体肿瘤内的间隙含有高浓度的钾离子(K)，因为它们是从坏死处释放出来的 细胞。然而，这种升高的胞外[K]对溶瘤感染的潜在影响从来没有 学习。在目前的提案中，我们提出了新的初步数据，表明 以前在实体瘤中观察到的细胞外K不会损害恶性肿瘤细胞的整体健康 但能显著抑制溶瘤粘液瘤病毒的复制。因此我们假设提升了 瘤内[K]是一种新的限制体内溶瘤感染的离子因子。为了检验这一假设，我们 提出目前的建议：阐明高细胞外[K]‘抑制S的机制 粘液瘤病毒复制(目标1)，研究瘤内高剂量S对溶瘤性粘液瘤复制的影响 和体内持久性(目标2)，并开发抗K重组粘液瘤病毒构建体(目标3)。这 这项工作不仅将加强溶瘤粘液瘤病毒的临床翻译，还将彻底阐明一种 影响溶瘤病毒复制的新机制。

Project Summary: Oncolytic virotherapy (OV) uses replication competent viruses as cancer therapeutics. Unfortunately, many of the potential molecular mechanisms which mediate the intratumoral replication of these viruses' remain incompletely understood. For example, it has recently been demonstrated that the extracellular space within solid tumors contains high concentrations of potassium ions (K+) due to their release from necrotic cells. The potential impact of this elevated extracellular [K+] on oncolytic infection, however, has never been studied. In the current proposal we present new preliminary data demonstrating that the elevated levels of extracellular K+ previously observed in solid tumors are not detrimental to the overall health of malignant cells but can significantly inhibit the replication of oncolytic myxoma virus. We therefore hypothesize that elevated intratumoral [K+] represents a novel ionic factor restricting oncolytic infection in vivo. To test this hypothesis, we present the current proposal which will: elucidate the mechanism through which high extracellular [K+]'s inhibit myxoma virus replication (Aim 1), study the impact of high intratumoral [K+]'s on oncolytic myxoma replication and persistence in vivo (Aim 2), and develop a K+ resistant recombinant myxoma virus construct (Aim 3). This work will not only enhance the clinical translation of oncolytic myxoma virus but also elucidate a completely novel mechanism impacting the replication of oncolytic viruses.