TREATMENT OF MENINGIOMA WITH TH-302 IN A PDX MOUSE MODEL AND CELL LINE

Meningioma account for 36% of intracranial tumors and 4.7-7.2% demonstrate aggressive clinical behavior. Current treatments are limited to surgery and radiation. We investigated hypoxia activated prodrugTH302 in patient-derived xenograft model of malignant meningioma. Female athymic nude mice were implanted subcutaneously with human meningioma tissue obtained intraoperatively. After 80 days of tumors growth animals were randomized into four groups 1) Control(n=1), 2) XRT (n=4), 3) TH302(n=5), and 4) XRT+TH302(n=4). Mice were either focally radiated using LINAC system in five fractions of 3Gy given daily to a total of 15 Gy, treated with TH302 at 50mg/kg started on day 3 of radiation for 9 doses every other day or combination of both. Tumor volume was measured by a digital caliper until endpoint of 4000 mm3 was reached. H&E, IHC and western blot analysis were performed to further elucidate mechanism of action in meningioma. Additionally, CH157MN meningioma cell line is being used for drug concentration screening (0.1uM - 500uM) to determine IC50 under normaxia and hypoxia conditions using MTT assay. Tumor growth in 1)Control: 1199 mm3 to 4371 mm3 in 35 days, 2)XRT: 890 mm3 to 4220 mm3 in 91 days, 3)TH302: 660 mm3 to 4894 mm3 in 130 days and 4)XRT+TH302: 890 mm3 to 4266 mm3 in 155 days. FFPE H&E and CA9 stained sections show increase in necrotic regions while decrease in hypoxia in XRT/TH302 vs XRT. Western blot showed increase in Chk1, Rad51, and Polβ in XRT+TH302. Our in vivo study shows that mice treated with XRT+TH302 compared to XRT alone have prolonged survival with p<0.0206 with decreased rate of tumor growth likely from TH302-dependent DNA damage of hypoxic cells resulting in cell death.