Antitumor efficacy of M3814 as a radiation sensitizer in neuroendocrine tumor (NET) preclinical models.

Abstract

e15699 Background: Recent FDA approval of peptide receptor radiotherapy paved the way for radiation-based treatment for gastroenteropancreatic neuroendocrine tumors (GEPNETs). M-3814, a DNA-dependent Protein Kinase Inhibitor (DNA-PKi), is known to potentiate the effects of radiation therapy in various solid tumor in vivo models. Currently there is no data evaluating anti-tumor efficacy of DNA-PK inhibitors in preclinical NET models. M-3814 inhibits DNA damage repair mechanism; antitumor efficacy of M-3814 in NETs is unknown. Methods: The efficacy of M-3814 in combination with radiation therapy (XRT) was evaluated in QGP-1 (pancreatic NET cell line) mouse model. Mice were injected with QGP-1 cells (5 mice) in 100 µL of PBS into the flank of mice with a 27-gauge needle. When tumor volumes reached average ~200 mm3, tumors were excised, separated into equal size tumor pieces and implanted subcutaneously into athymic nude mice. Next, mice were randomized into 4 groups for treatment with either placebo (n = 5), M-3814 (n = 5) alone (100 mg/Kg body weight (BW), XRT (n = 5) alone or in combination with M-3814 (n = 5). Treatment started when palpable tumors were established (200 mm3). Mice received M-3814 by gavage 30 minute prior to radiation therapy and irradiated with 4 daily doses of XRT at 2Gy per dose. Results: XRT and XRT+M-3814 treatment significantly decreased tumor size compared to control group. Combination treatment resulted in marked anti-tumor activity compared to both control group and XRT group. Tumors treated with XRT+M-3814 were also visibly less vascular. (Images will be provided in the poster). M-3814 alone had no effect on tumor growth as expected. Similar mouse weight changes were observed in both XRT and XRT+M-3814 treatment groups. Conclusions: M-3814 is a potent radiation sensitizer in preclinical neuroendocrine models. Strong antitumor activity was observed in QGP-1 xenograft model with marked reduction of tumor growth. Our enthusiasm for current project is driven not only by its inherent scientific importance, but also by its translational potential and the possibility to provide a more effective and less toxic radiation based treatment regimen for neuroendocrine tumors. [Table: see text]