Abstract 293: Inhibition of BET proteins augments nab-paclitaxel-gemcitabine-based chemotherapy response in preclinical models of pancreatic cancer
Authors: Awasthi Niranjan , Singh Sandeep , McCauley Ross D. , Schwarz Johann RE , Schwarz Margaret A. , Schwarz Roderich E. 
Published: August 2019

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) often presents with metastatic activity, leading to an extremely poor prognosis. Nanoparticle albumin-bound paclitaxel (NPT) in combination with gemcitabine (NPT+GEM) is a standard treatment for PDAC patients, resulting in a survival of ~8.5 months. Bromodomain and extraterminal domain (BET) proteins are epigenetic regulators of gene expression and are involved in cancer pathogenesis. Targeted inhibition of BET protein is currently under investigation for several cancers. We hypothesize that BET protein pathway inhibition by iBet-762 will enhance nab-paclitaxel-gemcitabine-based standard chemotherapy response in PDAC.

METHODS: In vitro cell proliferation assays were performed using WST-1 reagent. Protein expressions were determined by Western Blot analysis. In vivo animal survival and tumor growth experiments were performed in NOD-SCID mice.

RESULTS: BET inhibitor (iBET-762) and standard chemotherapy (NPT+Gem) had a dose-dependent in vitro growth inhibitory effect on several PDAC cell lines tested. Inhibition in cell proliferation at 1 μM drug concentration in NPT+Gem, iBET-762 and NPT+Gem+iBet-762 treatment groups was 64%, 27%, 76% in AsPC-1; 43%, 13%, 69% in Panc-1; and 42%, 51%, 75% in MIA PaCa-2 cells. Immunoblot analysis demonstrated that iBET-762 decreased the expression of oncogenic proteins c-Myc, β-catenin, vimentin and phospho-AKT, while increasing the expression of apoptosis-related proteins such as cleaved PARP-1 and cleaved caspase-3 and cell cycle inhibitor proteins P21 and P27. In subcutaneous xenografts, compared to controls, NPT+Gem and iBet-762 decreased tumor growth by 72% and 57%, respectively (p&lt;0.02). Importantly, the combination therapy group (NPT+Gem+iBet-762) had an additive effect on tumor growth inhibition (98%, p&lt;0.0001). In a peritoneal dissemination model, median animal survival compared to controls (21 days) was increased by NPT+Gem (33 days, a 57% increase) and iBet-762 (30 days, a 43% increase) therapy. This was further increased in the combination therapy group NPT+Gem+iBET-762 (44 days, a 110% increase).

CONCLUSION: These findings demonstrate that nab-paclitaxel-gemcitabine-based standard chemotherapy response can be enhanced through specific inhibition of BET proteins by iBET-762 in preclinical models of PDAC. The data support the potential of this combinatorial therapeutic strategy for clinical PDAC therapy.

Citation Format: Niranjan Awasthi, Sandeep Singh, Ross D. McCauley, Johann RE Schwarz, Margaret A. Schwarz, Roderich E. Schwarz. Inhibition of BET proteins augments nab-paclitaxel-gemcitabine-based chemotherapy response in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 293.