In case of GBM CSC lines 040325 and Imatinib chemical structure 061205, the EC50s for GLV 1h285 and GLV 1h189 are very similar, possibly due to a higher level of differentiation of the tumor tissue these lines were derived from. Indeed, in response to exposure Inhibitors,Modulators,Libraries Inhibitors,Modulators,Libraries to recombinant BMP 4, the 061205 cell line shows reduced growth inhibition compared to other cell lines. How ever, this seems to be the exception than the rule among the nine primary cell lines tested, but also indicating the important utility of the basic oncolytic activity of the VACV platform for tumor growth inhibition. Similarly in case of the serum grown glioma cell lines, U87, U251 and U373, very small differences in growth inhibition were observed between GLV 1h189 and GLV 1h285.

As is well documented, growing primary tumor samples under serum conditions selects for a population of cells with a more differentiated phenotype and a genetic makeup different from the original tumor sample. Hence, it is not surprising to see lack of superior growth inhib ition for the BMP 4 producing virus in differentiated Inhibitors,Modulators,Libraries glioma lines since BMP 4 is believed to target undiffer entiated, stem cell like cells. Furthermore, seeing a pref erence for the BMP 4 virus to replicate and rapidly Inhibitors,Modulators,Libraries carry out second and later round infections in the GBM CSC cells is further reassuring as to an undifferentiated, stem cell like population comprising Inhibitors,Modulators,Libraries a significant part of the culture that has a genetic makeup similar to the original tumor. In this study we confirmed in animal xenograft models that the GBM CSCs reproduce the disease much more closely as it occurs in patients.

Compared to a represen tative serum grown glioma cell line, U87 which remained restricted to one side of the brain, the GBM CSCs migrated to the contralateral cerebral hemisphere possibly via the corpus callosum, a hallmark migratory pattern observed in GBM patients. Furthermore, as is the case with GBM patients the GBM CSC tumors were found to be highly vascular compared to the U87 generated kinase inhibitor Tipifarnib tumors. Working with such GBM CSC models could possibly facilitate greater translation of preclinical data in the clinic. In the GBM CSC animal models we observed a benefit in treating the tumor with the BMP 4 virus without any overt side effects in two different tumor burden settings. Under a low tumor burden setting, the BMP 4 virus caused tumor regression and kept the tumor in check to below the signal when the tumor was first infected up to 51 dpi. This resulted in significant survival advantage compared to the untreated control group and the paren tal virus treated group. At a higher tumor burden, the BMP 4 virus delayed tumor growth compared to the parental virus.