Viruses and human brain tumors: cytomegalovirus enters the fray (original) (raw)
HCMV DNA and proteins have been found in tumors of different origins, including 90%–100% of high-grade glial brain tumors (24). Unlike polyomaviruses, CMV is not considered to be oncogenic itself and has likewise not been used as an oncolytic virus. In this issue of the JCI, Baryawno et al. report their work examining the prevalence of HCMV in medulloblastomas and whether the presence of the virus can be used to target medulloblastoma therapeutically (10). Of the 37 primary medulloblastomas examined by Baryawno et al. for the presence of HCMV, 92% expressed HCMV immediate early proteins and 73% expressed late proteins. Similarly, HCMV proteins were detected in all 8 medulloblastoma cell lines tested, including within the CD133+ putative tumor-initiating cell population.
Baryawno and colleagues then went on to test whether either ganciclovir, which targets the DNA polymerase during HCMV replication, or the COX-2 inhibitor celecoxib, which prevents HCMV replication by decreasing PGE2 levels, affected medulloblastoma growth (10). They found that ganciclovir decreased the clonogenic capacity of HCMV-positive cell lines but had no effect on HCMV-negative lines. This effect was augmented by the addition of celecoxib. While this study did not address these questions, it will be important to test what effect the drugs have on cell growth in vitro, and whether the effects are cytotoxic or cytostatic.
In a flank xenograft model, Baryawno et al. found that medulloblastoma tumor volume could be reduced by approximately 40% in mice treated with either valganciclovir or celecoxib alone, and by 72% with a combined drug regimen (10). Similar to the in vitro data, HCMV-negative xenografts were not affected by the drug treatment, supporting the hypothesis that the effect was specific to HCMV-positive tumor cells. Future preclinical studies looking at whether this drug treatment can extend the survival of mice in an orthotopic xenograft model and whether these drugs can be effectively combined with other chemotherapeutic agents and/or radiotherapy will be key.
The data presented by Baryawno et al. demonstrating in vivo reduction of tumor size following treatment with valganciclovir and celecoxib (ref. 10 and Figure 1) are intriguing, as they raise a new potential route through which viruses may be exploited to treat brain tumors. The relatively low toxicity and good blood brain barrier penetration of these agents make them attractive for clinical use, eliminating many of the barriers that still face oncolytic viral therapies. However, the claim of Baryawno and colleagues that their observations suggest a pathogenic role for HCMV in medulloblastoma (10) is less well substantiated. As for polyomavirus, a causal role for HCMV in medulloblastoma development has yet to be shown.
Effect of valganciclovir and celecoxib on medulloblastoma cell lines expressing HCMV proteins as observed by Baryawno and colleagues (10). Injection of medulloblastoma cell lines expressing HCMV proteins into the flanks of nude mice results in tumors (Control), which are reduced in size following treatment with either valganciclovir, which targets the DNA polymerase during HCMV replication, or the COX-2 inhibitor celecoxib, which prevents HCMV replication by decreasing PGE2 levels. Treatment with a combination of celecoxib and valganciclovir causes a greater reduction in tumor size than either drug alone. LP, HCMV late protein; IE, HCMV immediate early protein.