Impact of extracellular potassium on oncolytic therapy

项目概述：溶瘤病毒疗法（OV）使用具有复制能力的病毒作为癌症治疗剂。 不幸的是，许多潜在的分子机制，介导的肿瘤内复制这些 对病毒的了解还不完全。例如，最近已经证明， 实体瘤内的空间含有高浓度的钾离子（K+），这是由于它们从坏死组织中释放， 细胞然而，这种升高的细胞外[K+]对溶瘤感染的潜在影响从未被研究过。 研究了在目前的提案中，我们提出了新的初步数据，表明高水平的 先前在实体瘤中观察到的细胞外K+对恶性细胞的整体健康无害 但能显著抑制溶瘤粘液瘤病毒的复制。因此，我们假设， 肿瘤内[K+]代表了一种新的限制体内溶瘤感染的离子因子。为了验证这个假设，我们 提出了目前的建议，这将：阐明机制，通过高细胞外[K+]的抑制 粘液瘤病毒复制（目的1），研究肿瘤内高[K+]对溶瘤粘液瘤复制的影响 和体内持久性（目的2），并开发K+抗性重组粘液瘤病毒构建体（目的3）。这 这项工作不仅将增强溶瘤粘液瘤病毒的临床翻译，而且将完全阐明 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.