Abstract
BackgroundMedulloblastoma is the most common type of pediatric brain tumor. Although numerous factors influence patient survival rates, more than 30% of all cases will ultimately be refractory to conventional therapies. Current standards of care are also associated with significant morbidities, giving impetus for the development of new treatments. We have previously shown that oncolytic measles virotherapy is effective against medulloblastoma, leading to significant prolongation of survival and even cures in mouse xenograft models of localized and metastatic disease. Because medulloblastomas are known to be highly vascularized tumors, we reasoned that the addition of angiogenesis inhibitors could further enhance the efficacy of oncolytic measles virotherapy. Toward this end, we have engineered an oncolytic measles virus that express a fusion protein of endostatin and angiostatin, two endogenous and potent inhibitors of angiogenesis.MethodsOncolytic measles viruses encoding human and mouse variants of a secretable endostatin/angiostatin fusion protein were designed and rescued according to established protocols. These viruses, known as MV-hE:A and MV-mE:A respectively, were then evaluated for their anti-angiogenic potential and efficacy against medulloblastoma cell lines and orthotopic mouse models of localized disease.ResultsMedulloblastoma cells infected by MV-E:A readily secrete endostatin and angiostatin prior to lysis. The inclusion of the endostatin/angiostatin gene did not negatively impact the measles virus’ cytotoxicity against medulloblastoma cells or alter its growth kinetics. Conditioned media obtained from these infected cells was capable of inhibiting multiple angiogenic factors in vitro, significantly reducing endothelial cell tube formation, viability and migration compared to conditioned media derived from cells infected by a control measles virus. Mice that were given a single intratumoral injection of MV-E:A likewise showed reduced numbers of tumor-associated blood vessels and a trend for increased survival compared to mice treated with the control virus.ConclusionsThese data suggest that oncolytic measles viruses encoding anti-angiogenic proteins may have therapeutic benefit against medulloblastoma and support ongoing efforts to target angiogenesis in medulloblastoma.
Highlights
Medulloblastoma is the most common type of pediatric brain tumor
Construction and oncolytic activity of measles viruses expressing endostatin:angiostatin fusion proteins Human and mouse variants of an E:A fusion protein appended to the human Interleukin-2 signal peptide were cloned into the mluI/AatII restriction site of the parental MV-NIS virus (Figure 1A)
Verification of endostatin:angiostatin production and biological activity In order to determine if MV-hE:A and MV-mE:A infection induced medulloblastoma cells to secrete E:A, we performed enzyme-linked immunosorbent assay (ELISA) and immunoblot analysis with D283med and D425med cell culture supernatants
Summary
Medulloblastoma is the most common type of pediatric brain tumor. numerous factors influence patient survival rates, more than 30% of all cases will be refractory to conventional therapies. Because medulloblastomas are known to be highly vascularized tumors, we reasoned that the addition of angiogenesis inhibitors could further enhance the efficacy of oncolytic measles virotherapy. Modified derivatives of Edmonston MV are currently being tested in phase I clinical trials against both solid and blood cancers and have far been shown to be safe and reasonably effective [10,11,12]. Data from these trials is still forthcoming, efforts to develop a new class of oncolytic MVs with enhanced antitumor properties continue to be made and tested in various preclinical models [13,14]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have