Abstract B35: Enhanced antitumor efficacy by combining oncolytic herpes simplex virus and Aurora A kinase inhibition in models of neuroblastoma and malignant peripheral nerve sheath tumor
| Autor: | Tilat A. Rizvi, Les Sprague, Keri A. Streby, Pin-Yi Wang, Duo Chen, Jeff Ecsedy, Joe Conner, Meghan Franczek, Katherine E. Chaney, Brooke Nartker, Nancy Ratner, Timothy P. Cripe, Ami V. Patel, Chun-Yu Chen, Mark A. Currier |
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| Rok vydání: | 2016 |
| Předmět: |
Cancer Research
business.industry Aurora A kinase DNA virus Malignant peripheral nerve sheath tumor medicine.disease medicine.disease_cause Virology Pediatric cancer Oncolytic virus chemistry.chemical_compound Herpes simplex virus Oncology chemistry Neuroblastoma Alisertib Cancer research medicine business |
| Zdroj: | Cancer Research. 76:B35-B35 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.pedca15-b35 |
| Popis: | We previously reported xenograft models of neuroblastoma and malignant peripheral nerve sheath tumor (MPNST) are responsive to direct intratumoral injection of oncolytic Herpes Simplex Viruses (Parikh et al., Ped Blood Can 44:469, 2005; Mahller et al., Ped Blood Can 46:745, 2006; Mahller et al., Can Res 68:1170, 2008). We have confirmed these findings using an oncolytic HSV, Seprehvir (HSV1716), which is in clinical trials that include pediatric patients (NCT00931931, NCT02031965). The models showed wide variability, however, with some models having maintained complete responses and others showing only delayed growth. Because DNA viruses are highly dependent on normal nuclear machinery for DNA synthesis/replication and virus packaging/assembly, we postulated that increased transit time in mitosis may be beneficial to an oncolytic DNA virus. Aurora A Kinase is an enzyme critical for formation of centrioles and mitotic spindles during mitosis and is often dysregulated in cancer. The selective AAK inhibitor, Alisertib (MLN8237), arrests cells in G2/M and has significant activity in models of neuroblastoma (data from the Pediatric Preclinical Testing Program) and in MPNST (data from our prior study: Patel et al., Clin Can Res 18:5020, 2012). We found tumor responses in xenograft models using the combination of Seprehvir and Alisertib was more than additive. Immunohistochemical staining for HSV antigens revealed a marked difference in the extent and spread of virus as early as 24 hrs after virus injection. Our preliminary data assessing kinetics of virus infection suggest that Alisertib pretreatment enhances virus uptake and spread, accounting for the combinatorial effects. These data strongly suggest alisertib pretreatment “primes” tumor cells, making them highly susceptible to virus infection and spread and greatly accelerates the virolytic effects. Overall, our findings support clinical testing of Alisertib combined with Seprehvir in patients with refractory neurogenic tumors such as neuroblastoma and MPNST. Citation Format: Mark Currier, Tilat Rizvi, Brooke Nartker, Duo Chen, Chun-Yu Chen, Pin-Yi Wang, Les Sprague, Meghan Franczek, Ami Patel, Katherine Chaney, Keri Streby, Jeff Ecsedy, Joe Conner, Nancy Ratner, Timothy Cripe. Enhanced antitumor efficacy by combining oncolytic herpes simplex virus and Aurora A kinase inhibition in models of neuroblastoma and malignant peripheral nerve sheath tumor. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B35. |
| Databáze: | OpenAIRE |
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