939 poster EFFECTS OF RADIATION-INDUCED ALPHAVBETA3 INTEGRIN MODULATION ON CILENGITIDE EFFICIENCY IN PEDIATRIC GLIOMA CELLS

Abstract

The efficacy of PARP inhibition under treatment conditions of RT plus temozolomide (TMZ) for glioblastoma (GBM) has not been previously reported, therefore we sought to determine the effects of PARP inhibition as well as the molecular determinants of response to PARP inhibitors in combination with standard treatment of GBM. Materials: In the present study, PJ-34, a highly potent PARP inhibitor, was used to investigate the effects of PTEN status on PARP inhibition in combination with RT and TMZ using in vitro and in vivo models of GBM. First, two primary GBM cell lines that lack PTEN expression and two primary GBM cells lines that express PTEN were utilized to determine if PTEN status affects the efficacy of PARP inhibition in combination with RT and TMZ. Next, DNA damage and ATP levels were measured after the addition of a PARP inhibitor to RT and TMZ with respect to PTEN status. The role of glucose metabolism and PI3K/ AKT signaling in the response to PARP inhibition was then characterized in correlation to PTEN status. Finally, a U87-MG xenograft model was used to validate our in vitro findings. Results: Cell lines lacking PTEN were sensitized to PJ-34 in the setting of RT plus TMZ, whereas PTEN expression was associated with resistance. AKT activation was higher in resistant cell lines and was associated with increased ATP levels. Additionally, forced expression of PTEN conferred resistance to PJ-34. Treatment with the glycolytic inhibitor 2-deoxyglucose (2-DG) or the phosphatidylinosotide-3 kinase (PI3K) inhibitor LY294002 sensitized resistant PTEN-expressing cell lines to PJ-34 suggesting PI3K/AKT signaling is likely responsible for resistance in PTEN positive cells. The therapeutic benefits of PARP inhibition observed in PTEN-null cell lines may be dependent on RT, as treatment with TMZ alone prevented sensitization. Conclusions: In summary, PTEN status may be a promising marker to identify tumors that will respond to PARP inhibition when administered with TMZ and RT. Our findings suggest that the ability of PARP inhibitors, such as PJ34, to enhance the anti-tumor effects of RT and TMZ is highly dependent on the equilibrium between PARP’s pro-survival (increased PI3K/AKT signaling) and pro-death (increased DNA damage) functions. To this end, we are the first to report that the ability of PARP inhibition to enhance TMZ and RT response depends on the proteomic profile of GBM tumors, especially PTEN status.