Oberoi, Rajneet K.

Abstract Background Most oncology therapeutics have limited distribution into the brain, and developing strategies to overcome this limitation would be clinically impactful. While therapeutic radiation is often cited as a strategy to accomplish this, there are no published studies demonstrating the effect of radiation on drug distribution into the brain or brain tumors. Methods Mice were treated with brain radiation (6 Gy × 5, 4 Gy × 10; 40 Gy × 1) and dosed with drugs (levetiracetam, cefazolin, nedisertib, brigimadlin, apitolisib, or GNE-317) at times ranging from just prior to months after radiation. Plasma and tissue drug concentrations were measured by LC-MS/MS. Results Radiation did not significantly enhance drug delivery into brain tissue for levetiracetam, cefazolin, GNE-317, apitolisib, or nedisertib at any time post-radiation. Even a single, supra-therapeutic dose of radiation (40 Gy) did not significantly affect brain distribution of GNE-317 or apitolisib (P ≥ .07) from 16 to 160 hours post-radiation. For brigimadlin, radiation (6 Gy × 5) was associated with a modest but significant increase in drug accumulation only at 72 hours post-radiation (brain-to-plasma ratio 0.014 ± 0.006 vs. 0.025 ± 0.010, respectively; P = .04), but not at any other timepoint (24 hours, 15, 28, 94, 133, 183 days; P > .05). Similarly, radiation (6 Gy × 5) of orthotopic tumors did not increase levels of brigimadlin in GBM10 or GBM108 or nedisertib in GBM108 (P > .05). Conclusions Radiation had no meaningful impact on drug delivery into brain or brain tumors for the drugs tested.

Abstract Drug delivery to glioblastoma multiforme (GBM) is influenced by the presence of blood-brain barrier (BBB). PI3K/mTOR/AKT is frequently dysregulated in GBM and some agents targeting this pathway have limited distribution across the BBB due to activity of efflux transporters p-glycoprotein (P-gp) and breast cancer resistance protein1 (BCRP1). GNE-317 and GDC-0980 are structurally related PI3K/mTOR inhibitors with the former molecule optimized for brain delivery. Here the influence of the BBB on tumor distribution and resultant efficacy was evaluated in flank and intracranial tumors. Pharmacokinetic-pharmacodynamic approaches were used in GBM10 (patient-derived) and U87 (cell line) orthotopic xenograft models to evaluate the influence of delivery on efficacy. We investigated the brain distribution of GNE-317 and GDC-0980 in tumor-bearing (GBM10 and U87) athymic nu/nu mice and non-tumor-bearing (FVBn) mice. BBB-integrity in both GBM10 and U87-models was evaluated using Texas-Red(TR)-linked 3kD dextran prior to euthanasia. GNE-317 and GDC-0980 were administered orally at 30mg/kg and 7.5mg/kg, respectively, for all studies. Brain distribution studies were performed in FVB-wild type (WT) and P-gp/Bcrp knockout mice (TKO) and brain and plasma exposures (area-under-curve, AUC) were determined. Comparison of tumor pharmacokinetic-pharmacodynamic endpoints at 1- and 6-hr post single oral dose will be reported. GBM10 showed heterogeneous disruption of BBB-integrity, while U87 tumors exhibited homogenous and uniform disruption of BBB by analysis of TR-dextran accumulation within orthotopic xenografts. The brain-to-plasma AUC0-tlast ratio in FVBn-wild type was ∼10-fold higher in GNE-317(0.75) vs. GDC-0980 (0.07). Survival studies in intracranial tumors with U87 demonstrated no difference in survival between the GNE-317 vs. GDC-0980 treated groups (median survival∼26 days (GNE-317), 34 days(GDC-0980), p=0.07), and both treatments significantly extended survival compared to vehicle control (p<0.0003, ∼12 days). Survival with GNE-317 in GBM10 xenografts (median survival 42 days vs. 35 days for control, p<0.0003) was greater than the GDC-0980 treated group (median survival 32 days vs. 35 days in control, p=0.79); both treatments were not significantly different from each other (p=0.08). To evaluate the relative efficacy in the complete absence of the BBB, the effects on tumor growth are being evaluated in flank tumor models. These studies demonstrate that efficacy of a PI3K/mTOR inhibitor with low brain penetrance (GDC-0980) is marginally inferior to the related brain penetrant GNE-317 in tumor models with a partially intact BBB. Since GBM patients have regions of intact BBB, these data suggest that the brain penetration of targeted agents may be a critical factor that determines treatment efficacy in patients. Citation Format: Rajneet K. Oberoi, William F. Elmquist, Rajendar Mittapalli, Jenny Pokorny, Jann Sarkaria. Influence of the blood-brain barrier on drug distribution and efficacy of PI3K/mTOR inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4479. doi:10.1158/1538-7445.AM2014-4479