Abstract 4714: In vivo efficacy of BET inhibitor BAY 1238097 in preclinical models of melanoma and lung cancer
Authors: Klingbeil Olaf , Haendler Bernard , Stresemann Antje , Merz Claudia , Walter Annette , Fernández-Montalván Amaury Ernesto , Ocker Matthias , Siegel Stephan , Lejeune Pascale 
Published: July 2016

Abstract
Bromodomain and extra terminal domain (BET) family proteins which bind to acetylated lysines of histones and regulate gene transcription are promising targets in oncology. We have previously shown that the BET inhibitor BAY 1238097 possesses strong activity in a number of hematological models, both in vitro and in vivo (AACR 2015). Here we show that BAY 1238097 is also able to inhibit the growth of solid tumors such as melanoma and lung tumors.
BAY 1238097 was evaluated in vitro against a panel of melanoma cell lines and was effective in BRAF wild-type as well as BRAF mutant models. When given to C57BL/6 mice at the maximum tolerated dose (MTD) of 15 mg/kg, p.o., qd, BAY 1238097 showed efficacy against the B16/F10 syngeneic model with a T/C of 31% on day 12 post tumor inoculation (T/C≤42% = active according to NCI criteria). In this study, dacarbazine was less active than BAY 1238097 with a T/C of 44%. This was also the case in a patient-derived melanoma model resistant to dacarbazine where BAY 1238097 was found active with 39% T/C. Potent efficacy of BAY 1238097 was also observed against the human LOX-IMVI model in SCID mice either using a daily dose of 15 mg/kg or a q3d schedule at 45 mg/kg (MTD), leading to 10% and 13% T/C, respectively on day 12. Dose-dependent down-regulation of the MYC oncogene was demonstrated ex vivo in B16/F10 tumors as well as in mice peripheral blood mononuclear cells (PBMCs) with maximal effect observed between 3 to 6h post oral treatment with BAY1238097. In addition, strong up-regulation of HEXIM1 mRNA was observed in tumors and PBMCs from the mice.
BAY 1238097 was also evaluated in a number of in vitro and in vivo studies in lung cancer cell lines. It was strongly active in KRAS mutant non-small cell lung cancer (NSCLC) (DV-90, NCI-H1373, LCLC-97TM1) and small cell lung cancer (SCLC) models (NCI-H69, NCI-H146, NCI-H526) with IC50 values below 1 μM. Down-regulation of c-Myc protein expression upon treatment with 1 μM was observed in all three sensitive NSCLC models. In the NCI-H1373 model, an induction of caspase 3/7 activity was observed upon 24h of treatment in vitro. In the same model implanted in vivo, a strong reduction of tumor growth was observed following daily oral application of BAY 1238097 (12 mg/kg). The treatment was well tolerated with a T/C of 16% at day 15 after start of treatment. A similar antitumor activity was obtained by applying the compound intravenously twice a week at 100 mg/kg and ex vivo analysis revealed time-dependent regulation of MYC and HEXIM1 after treatment. In vivo efficacy was not limited to NSCLC as daily oral application of BAY 1238097 (10 mg/kg) to the SCLC xenograft model NCI-H526 resulted in high efficacy with 7% T/C on day 21.
Taken together, these positive results in preclinical models of melanoma and lung tumors warrant further evaluation of BET inhibition in solid tumors in the clinic.
Citation Format: Olaf Klingbeil, Bernard Haendler, Antje Stresemann, Claudia Merz, Annette Walter, Amaury Ernesto Fernández-Montalván, Matthias Ocker, Stephan Siegel, Pascale Lejeune. In vivo efficacy of BET inhibitor BAY 1238097 in preclinical models of melanoma and lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4714.