Abstract
Malignant peripheral nerve sheath tumor (MPNST) and neuroblastoma models respond to the investigational small molecule Aurora A kinase inhibitor, alisertib. We previously reported that MPNST and neuroblastomas are also susceptible to oncolytic herpes virus (oHSV) therapy. Herein, we show that combination of alisertib and HSV1716, a virus derived from HSV-1 and attenuated by deletion of RL1, exhibits significantly increased antitumor efficacy compared to either monotherapy. Alisertib and HSV1716 reduced tumor growth and increased survival in two xenograft models of MPNST and neuroblastoma. We found the enhanced antitumor effect was due to multiple mechanisms that likely each contribute to the combination effect. First, oncolytic herpes virus increased the sensitivity of uninfected cells to alisertib cytotoxicity, a process we term virus-induced therapeutic adjuvant (VITA). Second, alisertib increased peak virus production and slowed virus clearance from tumors, both likely a consequence of it preventing virus-mediated increase of intratumoral NK cells. We also found that alisertib inhibited virus-induced accumulation of intratumoral myeloid derived suppressor cells, which normally are protumorigenic. Our data suggest that clinical trials of the combination of oHSV and alisertib are warranted in patients with neuroblastoma or MPNST.
Highlights
Aurora A Kinase is a serine/threonine kinase that serves many functions in cell division, being both directly and indirectly involved with centrosome formation, spindle assembly, and cytokinesis [1,2,3]
Overexpression of Aurora A Kinase has been observed in multiple malignancies including bladder, breast, colon, pancreatic, malignant peripheral nerve sheath tumor (MPNST), and neuroblastoma [1, 3, 4]
As a mechanism for the enhanced cell killing, we found that oncolytic herpes simplex virus (oHSV) infected cells exert a paracrine effect on uninfected cells that increases their sensitivity to alisertib
Summary
Aurora A Kinase is a serine/threonine kinase that serves many functions in cell division, being both directly and indirectly involved with centrosome formation, spindle assembly, and cytokinesis [1,2,3]. Due to its involvement in mitosis and association with cancer, small molecule Aurora A Kinase inhibitors, including alisertib (MLN8237), are currently under investigation as therapeutics in numerous cancer types. Multiple reports underscore the anti-tumor efficacy of alisertib in tumor models where it causes cell cycle arrest and apoptosis in cancer cells [3]. In wild type HSV-1, the ICP34.5 gene product counteracts host protein kinase R (PKR) activated by the anti-viral interferon response to infection [7,8,9]. Without ICP34.5 expression, interferon responses in normal tissues result in PKR activation and phosphorylation of the ribosomal eIF2α subunit, leading to the arrest of both protein synthesis and virus production. Many cancer types exhibit dysfunctional interferon signaling and/or activation of the MAP kinase pathway, which inhibits PKR [10], rendering cells susceptible to ICP34.5-null HSV-1. ICP34.5 deletion allows HSV1716 to selectively infect and replicate in tumor cells, while sparing healthy tissues
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