Scientific Publications by FDA Staff

J Neurooncol 2018 Feb;136(3):463-74

Analysis of the cancer genome atlas (TCGA) database identifies an inverse relationship between interleukin-13 receptor alpha1 and alpha2 gene expression and poor prognosis and drug resistance in subjects with glioblastoma multiforme.

Han J, Puri RK

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. A variety of targeted agents are being tested in the clinic including cancer vaccines, immunotoxins, antibodies and T cell immunotherapy for GBM. We have previously reported that IL-13 receptor subunits alpha1 and alpha2 of IL-13R complex are overexpressed in GBM. We are investigating the significance of IL-13Ralpha1 and alpha2 expression in GBM tumors. In order to elucidate a possible relationship between IL-13Ralpha1 and alpha2 expression with severity and prognoses of subjects with GBM, we analyzed gene expression (by microarray) and clinical data available at the public The Cancer Genome Atlas (TCGA) database (Currently known as Global Data Commons). More than 40% of GBM samples were highly positive for IL-13Ralpha2 mRNA (Log2 >/= 2) while only less than 16% samples were highly positive for IL-13Ralpha1 mRNA. Subjects with high IL-13Ralpha1 and alpha2 mRNA expressing tumors were associated with a significantly lower survival rate irrespective of their treatment compared to subjects with IL-13Ralpha1 and alpha2 mRNA negative tumors. We further observed that IL-13Ralpha2 gene expression is associated with GBM resistance to temozolomide (TMZ) chemotherapy. The expression of IL-13Ralpha2 gene did not seem to correlate with the expression of genes for other chains involved in the formation of IL-13R complex (IL-13Ralpha1 or IL-4Ralpha) in GBM. However, a positive correlation was observed between IL-4Ralpha and IL-13Ralpha1 gene expression. The microarray data of IL-13Ralpha2 gene expression was verified by RNA-Seq data. In depth analysis of TCGA data revealed that immunosuppressive genes (such as FMOD, CCL2, OSM, etc.) were highly expressed in IL-13Ralpha2 positive tumors, but not in IL-13Ralpha2 negative tumors. These results indicate a direct correlation between high level of IL-13R mRNA expression and poor patient prognosis and that immunosuppressive genes associated with IL-13Ralpha2 may play a role in tumor progression. These findings have important implications in understanding the role of IL-13R in the pathogenesis of GBM and potentially other cancers.