Gliomas account for about 60% of all primary CNS tumors. Glioblastoma (GBM) or grade IV glioma which comprise 51.2% of all gliomas is the most malignant form. Glioblastoma tumors are highly heterogeneous and there is a complex interaction among different types of tumor cells and stromal cells within the tumor. Recently it has been shown that the majority of tumor cells do not have the capacity to recapitulate a phenocopy of the original tumor and that only a small subpopulation of neural stem-like cells in the tumor, called glioma stem cells (GSCs; also known as tumor initiating cells), have that ability upon xenotransplantation in nude mice. These cancer stem cells appear to be more resistant to conventional therapy as compared to their differentiated counterparts. Following current therapy for high-grade glioma tumors, most patients die within a year from a new secondary tumor foci forming within one centimeter of the resected area. These foci are enriched for GSCs, and it is likely that they are responsible for tumor recurrence. An emerging cancer therapeutic approach is to exploit the biochemical changes in tumor cells. Tumors (including GBM) present particularly high levels of oxidative stress, generally caused by an increase in reactive oxygen species (ROS) production or decrease in intracellular ROS-scavengers. This marked increase in ROS is believed to promote cell survival and confer resistance to therapy. Given this different redox state between normal and tumor cells, it is believed that the latter has a greater reliance on their ROS-scavenging capacities. Thus, further increase in oxidative stress can overwhelm this stress response in tumor cells leading to cell death. On the other hand, glioma stem cells have substantially lower metabolic state than their nontumorigenic counterparts and these cells maintain low levels of ROS, essential for their self-renewal. Through high-throughput screening, we identified the natural compounds obtusaquinone to kill glioma cells by inducing high levels of intracellular ROS. We hypothesize that this ROS-inducing small molecule could target both GBM cells as well as GSCs and kill them. In this proposal, we will validate this compound on different GBM and GSCs in culture and in different GSCs intracranial models.
In this proposal, we will validate a natural compound with novel anti-cancer activity for glioblastoma therapy. We will use different intracranial glioblastom models, which infiltrate the brain of mice similar to human tumors in combination with standard of care (temozolomide and radiation). We will also attempt to understand the mechanism by which this drug is killing glioblastoma cells.
Showing the most recent 10 out of 32 publications
