Proteoglycan Targeting Drugs Reduce Tumor Progression in Glioblastoma

CSU Ballroom

Glioblastoma (GBM) is one of the most common and aggressive forms of brain cancer. The survival of GBM is particularly poor with a median survival time of about 15 months. GBM treatment options typically consist of a multidisciplinary approach with surgery, followed by radiation and chemotherapy. However, GBM tumors possess genetic heterogeneity which underlies the inherent ability to resist most treatment options. Additionally, the rapid GBM tumor growth makes the tumor cells refractory to surgery and radiation, leading to frequent relapse. Interestingly, heparan sulfate proteoglycans (HSPG) are involved in GBM tumor progression and can influence treatment options. HPGS play a crucial role in the regulation of growth factor-mediated signaling associated with cell proliferation, adhesion, and migration. Due to their various functions in promoting tumor progression, proteoglycans are an attractive therapeutic target. Here, we have developed clonal GBM cell lines with functional knockouts of both glypicans 1 and 3 through CRISPR-Cas9 editing and clonal expansion. Our clonal expansion techniques generated clones containing 99% double knockouts and 99% wild-type cells. Notably, these double knockout cells have a decreased proliferation and 3-D tumor spheroid growth compared to the wild-type cells. Both clonal cell lines were exposed to treatments of temozolomide as well as novel HSPG-targeting agents Triplatin, and Triplatin-NC to investigate effects on proliferation and 3-D tumor spheroid growth. We propose that glypicans 1 and 3 are a potential focus for the development of molecular-targeted therapies against GBM.