EXTH-36. SCREENING COMPOUNDS THAT TARGET THE DNA DAMAGE RESPONSE FOR BLOOD-BRAIN-BARRIER PERMEABILITY

Abstract

For glioblastoma (GBM), development of strategies that stabilize disease progression and ultimately achieve a cure will require comprehensive approaches towards target selection and design of therapies. Activation of the DNA damage response (DDR) by temozolomide and irradiation induces signaling pathways with actionable therapeutic targets (Akt, Chk1, and Mdm2), providing fertile ground to develop novel anti-GBM combination therapies. Using pediatric and adult GBM cells with clinically relevant molecular profiles, isobologram analyses indicated that combinations of small molecule inhibitors to these DDR-induced targets can synergistically block in vitro cell growth and decrease resistance of GBM cells to temozolomide. Knowing the degree of blood-brain-barrier (BBB) permeability is particularly important in the selection of therapeutic compounds for the treatment of GBM. To this end, we adapted the Mouse Brain Uptake Assay (MBUA), which determines the BBB apparent permeability (Papp, nm/sec) for drugs across an intact BBB with the assumption that uptake rate is an important contributor to brain concentrations. When Papp is plotted as a function of cLogD and compared with calibration compounds, specific mechanistic interpretation is possible. Optimal BBB Papp values fall within the region of brain uptake limited only by cerebral blood flow, and not limited by low passive permeability or active efflux. Inhibitors of interest have been analyzed using the MBUA. BBB permeability, as measured by Papp, was in the order RG7388>RG7112>nutlin3a for MDM2 inhibitors and CHIR124>AZD7762 for Chk1 inhibitors. Survival in an intracranial GBM xenograft model indicated that an intermittent dosing regimen of temozolomide with Akt (GDC0068) and Mdm2 (RG7112) inhibitors exhibiting moderate BBB permeability significantly reduced GBM growth with minimal toxicity. Studies are in progress to determine if the next-generation Mdm2 inhibitor RG7388 with a more favorable BBB Papp can further improve efficacy of combination therapy and offer new therapeutic options for GBM.