title: Treatment of medulloblastoma with oncolytic measles viruses expressing the angiogenesis inhibitors endostatin and angiostatin.
abstract: BACKGROUND
  Medulloblastoma 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.
  
  
  METHODS
  Oncolytic 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.
  
  
  RESULTS
  Medulloblastoma 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.
  
  
  CONCLUSIONS
  These 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.
authors.forename: Brian
authors.initials: B
authors.lastname: Hutzen
authors.forename: Hemant Kumar
authors.initials: HK
authors.lastname: Bid
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pierson
authors.forename: Kimerly
authors.initials: K
authors.lastname: Powell
authors.forename: Anna
authors.initials: A
authors.lastname: Bratasz
authors.forename: Corey
authors.initials: C
authors.lastname: Raffel
authors.affiliation: The Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205, USA. adam.studebaker@nationwidechildrens.org.
authors.forename: Adam W
authors.initials: AW
authors.lastname: Studebaker
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D043168:Angiostatins / Q000037:antagonists & inhibitors*; D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D043169:Endostatins / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008459:Measles virus / Q000235:genetics / Q000502:physiology*; D008527:Medulloblastoma / Q000473:pathology / Q000628:therapy*; D051379:Mice; D009374:Neoplasms, Experimental; D050130:Oncolytic Virotherapy / Q000009:adverse effects*; D050504:Oncolytic Viruses / Q000235:genetics; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins; D043168:Angiostatins