Therapeutic response of GBM stem-like cells and the GBM cell of origin

Glioblastoma Multiforme (GBM) is the most common and aggressive type of adult brain cancer that offers only one to two years of survival and results in the growth of brain tumors. GBM was studied by a group of researchers called The Cancer Genome Atlas (TCGA). This group identified four distinct types of GBM that differ from each other based on unique genetic mutations, rate of tumor growth, and response to treatment. Some cancer cells have stem cell properties such as the ability to give rise to multiple cell types and maintenance of self-renewal, which may advance the rate of tumor growth. It is believed that this cancer stem cell population infers resistance to radiation and Temozolomide (TMZ) chemotherapeutic treatment in GBM. TMZ eradicates cells by alkylating their DNA to cause cell death. Working with primary patient derived GBM stem-like cell cultures, we show that the cultures separate into different response groups that will be used in later studies to classify the cultures into TCGA subgroups. Additionally, we also show that expression of the DNA repair enzyme, MGMT, which removes TMZ induced DNA alkylation, infers GBM culture resistance to TMZ. Though much work has been conducted on the genetic anomalies prevalent and efficacy of treatment of GBM, little is known about the cell of origin in GBM. In fact, the cell of origin for GBM has not yet been identified. The main purpose of the second portion of this research project is to determine the role genetic mutations in the tumor suppressor gene, PTEN, and the oncogenic gene, KRAS, in specific brain cells and their potential to produce GBM tumors in mouse brains. We hypothesize that loss of PTEN and over expression of KRAS in NG2, which is a proteoglycan found on neural progenitor cells, positive mouse cells will result in tumor formation. A CRE-LOX breeding system was used to successfully generate genetic mutations in the mice. We have successfully bred mice that express Pten and contain Kras genetic mutations. We are currently conducting the final genetic cross to determine whether tumors will form from the NG2 positive cells. We have successfully identified groups of our GBM neursophere cultures that differ from each other based on their response to treatment. This data will be used when we begin to classify our cultures into one of the four TCGA GBM subgroups. Additionally, identifying the cell type of origin for GBM will also provide important insight on how to combat this cancer to develop more targeted cancer therapy in the future.

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