P01.02 The role of dopamine signaling in GBM recurrence

Normal 0 false false false EN-US JA X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:”Table Normal”; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:“”; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} Glioblastoma multiforme (GBM) is the most common adult primary brain tumor and is universally lethal due to its high rate of recurrence. The Cancer Stem Cell (CSC) hypothesis posits that GBMs are driven by a rare subset of cells called Glioma Stem Cells (GSCs). GSCs are capable of resist intensive radio- and chemotherapy and give rise to recurrent disease. Recent studies from our laboratory and others have shown that normal GBM cells acquire a stem-like state during anti-glioma therapy. Termed conversion, this process increases the proportion of therapy resistant GSCs and initiate recurrence. We hypothesize that a drug capable of blocking such conversion may prevent the generation of therapy-resistant GSCs, thereby delaying, if not preventing, tumor recurrence. Based on this, we utilized GSC specific reporter system to perform a high-throughput drug screening to identify compounds target conversion. Our initial screening has identified several novel FDA-approved compounds that act as antagonists of neurotransmitter receptors, and that are commonly used as anti-psychotic medication. Further investigation revealed that treatment of patient-derived xenograft (PDX) GBM lines with temozolomide (TMZ) led to the formation of a population of cells that express both CD133, a marker of CSCs, and dopamine receptors 2 and 3 (DR2/3) (control mean CD133+/DRD2+: 19.7%, TMZ mean: 83.8%, p=0.0001). Treating the same PDX lines with a dopamine receptor agonist increased cellular expression of GSC associated transcription factors SOX2, OCT4 and c-Myc. As DRD activation can modulates ion flow and membrane potential, electrophysiology examination revealed that the DR agonist (30nM) depolarizes GBM cells by 6.0 ± 1.3mV (n=7) and we are investigating whether there are differences in the DRD response of GSC versus non-GSC. we found that two anti-psychotics, chlorprothioxene and loxapine, which act as antagonist to DRs, blocked the chemotherapy induced conversion