Median survival from time of diagnosis of glioblastoma multiforme (GBM) or stage IV glioma, the most malignant form of brain cancer, is about one year, despite the current aggressive treatment that combines surgery, radiotherapy, chemotherapy, and bevacizumab (Avastin), a neutralizing antibody targeting VEGF-A. Novel therapies are needed for controlling this aggressive cancer. Ongoing mechanistic and genetic studies of GBM find many properties in common with neural stem cells (NSCs), such as migration through the CNS, extracellular matrix degradation, and differentiation into multiple lineages, suggesting that mechanisms of NSC proliferation can provide clues for treatment of GBM. We propose here to identify and characterize the first functional ligands to an orphan receptor that is required for neural stem cell proliferation and is selectively expressed in the subventricular zone and the dentate gyrus, where NSCs are found. Receptor overexpression drives glioma formation in mice and, in human patients, elevated expression in glioma is highly correlated with poor survival. Unlike many of the transcription factors involved in stem cell function, this receptor has a dual advantage for the discovery of drugs to target GBM. First, it is primarily expressed in NSCs and appears to act at a nodal point for control of proliferation and differentiation;and second, it has the potential to be regulated by small molecule ligands. Ligands to this receptor thus have the potential to block GBM proliferation and suppress tumor growth.
In Aim 1, we plan high throughput screening with a diverse small molecule library of 120,000 compounds utilizing a novel, rigorous specificity protocol that excludes the majority of false positive ligands and has been validated at Orphagen. More potent ligands (EC50 <1.0 mM) will be identified from commercially available analogues and, in Aim 2, we develop a biochemical assay to detect ligand-induced changes in receptor interaction with a key functional interacting protein in order to confirm hits by a complementary receptor screen technology.
In Aim 3, compounds will be tested for regulation of normal NSC gene expression and proliferation. Active compounds will be further examined in clinically-derived human GBM cell cultures to determine if they block tumor cell growth in a receptor-specific manner. If successful, an SBIR Phase 2-funded project would propose to discover and test ligands that suppress human GBM xenotransplant growth in immunocompromised mice. Our overarching goal is to commercialize a novel class of non-cytotoxic drug for treatment of GBM.
Glioblastoma (GBM) is the most common primary brain cancer in adults, accounting for more than half of the 22,000 malignant brain tumor cases expected to be diagnosed in the US in 2010. Treatment can delay cancer progression, but overall median survival remains roughly one year, despite efforts to introduce improved therapies over the past 30 years. We propose to identify the first ligands to a transcription facto that regulates neural stem cell (NSC) proliferation. High level expression of this factor is closel linked to poor prognosis in glioma patients. Our goal is to develop an orally bioavailable small molecule drug that inactivates this transcription factor and inhibits the aggressive clinical behavior of GBM.
