Impact of extracellular potassium on oncolytic therapy

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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.