Converting the Glioblastoma Multiforme Tumor-Associated Macrophage Phenotype
Glioblastoma multiforme (GBM), or grade IV astrocytoma, is a highly aggressive pediatric brain tumor that is uniformly fatal despite aggressive chemotherapy and radiation therapy. The malignant GBM cells in these brain tumors secrete hormones that attract normal cells called macrophages. These tumor-associated macrophages then provide the GBM cells with a variety of growth factors that contributes to their aggressiveness. This research proposal seeks to develop means to change these macrophages so that they now fight the malignant GBM cells rather than help them. Other investigators have had success doing this by blocking one of the hormones that the GBM cells secrete to attract the macrophages. However, the GBM cells can use additional hormones to attract macrophages.
As a potentially better means to induce the macrophages within GBMs to help fight the cancer cells, we propose to inhibit two macrophage proteins, called C/EBPb and NF-kB p50, that control genes within their DNA. Work from other groups has shown that targeting these two proteins changes macrophages to help fight cancer. We expect that targeting C/EBPb and NF-kB p50, alone or combined with radiation, chemotherapy, and immunotherapy will help us bring hope to patients with GBM and other high grade astrocytomas.