Abstract
Recently, investigators showed that mice with syngeneic murine gliomas that were treated with a neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ134.5 gene, enabling replication in tumor cells but precluding infection of normal cells. Previous studies have shown antitumor effects of other oHSV against a number of adult tumors including hepatocellular carcinoma and renal cell carcinoma. The purpose of the current study was to investigate the oncolytic potential of M002 against difficult to treat pediatric liver and kidney tumors. We showed that the oHSV, M002, infected, replicated, and decreased cell survival in hepatoblastoma, malignant rhabdoid kidney tumor, and renal sarcoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly increased survival and decreased tumor growth. Finally, these studies showed that the primary entry protein for oHSV, CD111 (nectin-1) was present in human hepatoblastoma and malignant rhabdoid kidney tumor specimens. We concluded that M002 effectively targeted these rare aggressive tumor types and that M002 may have potential for use in children with unresponsive or relapsed pediatric solid tumors.
Highlights
Despite major advances over the past 20 years in the treatment of pediatric malignancies, there remain a number of pediatric solid tumors that have limited therapies in the face of unresponsive or relapsed disease
Immunoblotting with CD111 specific antibody demonstrated that CD111 was present in whole cell lysates of HuH6, G401, and SK-NEP-1 cell lines
The CD111 staining was scored by a pathologist (E.M.M.) blinded to the specimens and the mean stain scores were compiled based upon stain intensity
Summary
Despite major advances over the past 20 years in the treatment of pediatric malignancies, there remain a number of pediatric solid tumors that have limited therapies in the face of unresponsive or relapsed disease. Many of these tumors involve solid organs such as the liver or kidneys, and include hepatoblastoma, malignant rhabdoid renal tumors, and non-osseous sarcomas. Solid organ sarcomas are some of the most rare and difficult solid tumors to treat in children These include extra-osseous Ewing’s sarcomas and primitive neuroectodermal tumors (PNET), which are both highly aggressive and carry poor prognoses [8]. Up to 50% of patients presenting with solid organ sarcomas have metastases at diagnosis, and the 5-year disease free survival rate is less than 50% [9,10,11]
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