The impact of hemi-brain irradiation on accumulation of PI3K/mTOR inhibitors with limited (GDC-0980) and robust (GNE-317) blood-brain barrier penetrationDigital Poster Discussion Session (DPD 08) Biology 2 - Head/Neck and CNS Tumors (#11)

TT Sio1, RK Oberoi2, MP Grams1, KM Furutani1, SK Gupta1, ZC Wilson1, JL Pokorny1, DO Iyekegbe Jr.1, KK Bakken1, MA Schroeder, BL Carlson1, K Chang1, WF Elmquist2, JN Sarkaria1

1Department of Radiation Oncology, Mayo Clinic, Rochester, MN; 2Department of Pharmaceutics, University of Minnesota, Minneapolis, MN

Introduction• Commonly believed that RT can improve penetration of small

molecules into brain and tumors• However, this has not been quantitatively established

Methods• C57BL/6 mice were treated with hemi-brain irradiation

– By a tungsten collimated high-dose-rate 192Ir beam

• Experiment 1: One group of mice was irradiated with 40 Gy in a single fraction and euthanized up to 160 hours later

• Experiment 2: Mice were treated with 4 Gy x10 fractions, and euthanized up to 6 weeks after the end of RT

• All mice were orally dosed with GNE-317 (30 mg/kg) and GDC-0980 (7.5 mg/kg) concomitantly 1 hr before euthanasia, and irradiated and unirradiated brain hemispheres and plasma were collected

• Drug concentrations in both hemispheres and plasma were assessed by mass spectrometry

Results

• Consistent with previous data, the mean ± SD brain-to-plasma ratio for GNE-317 and GDC-0980 in unirradiated brain for all animals was 0.91 ± 0.23 and 0.048 ± 0.018, respectively

• For drug levels in the irradiated brains, the brain-to-plasma ratio for the 2 drugs was 1.01 ± 0.27 and 0.054 ± 0.020.

• To readily compare the effects of radiation on drug accumulation at each time-point, the drug levels in unirradiated vs. irradiated brain were compared by a paired t-test– No significant difference in accumulation of GNE-317 or

GDC-0980 associated with irradiation at any of the time-points investigated

• Neither fractionated nor single-dose RT had significant impact on the accumulation of either GNE-317 or GDC-0980 in the brain

• Specifically, RT did not significantly increase the penetration of the brain-impenetrant GDC-0980 compound

• Further experiments investigating the effect of RT on the blood-brain-tumor-barrier are currently ongoing