Abstract 2647: TGF-β type I receptor inhibitor (TEW-7197) diminishes myeloma progression by multiple immunomodulatory mechanisms in combination with ixazomib
Authors: Kim Byung-Gyu , Sergeeva Olga , Luo George , Choi Sung Hee , Lee Zhenghong , Kim Seong-Jin , Letterio John , Malek Ehsan 
Published: July 2017

Abstract
Background: Multiple myeloma (MM) is an incurable cancer of plasma cells. MM thrives in the bone marrow tumor microenvironment (TME) where several factors sustain MM growth and viability. TGF-β is a multi-functional cytokine elaborated by MM cells and by cells in the bone marrow (BM) TME. TGF-β stimulates MM progression through promotion of catabolic bone remodeling, IL-6 secretion and Th17 T cell development, which act in concert to induce osteolytic bone disease, immune suppression and myeloma progression. Therefore, we evaluated the anti-MM therapeutic potential of a small molecule inhibitor of the TGF-β type I receptor kinase (TβRI), TEW-7197, in combination with the proteasome inhibitor, ixazomib. Currently, TEW-7197 is being evaluated in phase I clinical trials in patients with solid tumors, and exposure to this agent is associated with an acceptable tolerability profile.
Methods: The preclinical immunocompetent 5T33MM model (C57BL/KaLwRij) was used to characterize the role of TGF-β signaling in the BM TME. Mice bearing 5T33MM cells expressing luciferase were treated with TEW-7197, ixazomib and the combination of TEW-7197 plus ixazomib daily for 3 weeks, and evaluated for MM growth by bioluminescence imaging (BLI). Cellular and molecular assays were performed in human RPMI8226 and U266 as well as murine 5T33MM cells via apoptosis, real-time PCR and Western blotting. Immunological assays were performed via immunohistochemistry and FACS analyses. Peripheral blood monoclonal protein concentration, M-spike, was measured by ELISA.
Results: TEW-7197 attenuated the growth and viability of human and murine MM cells by inducing apoptosis and it inhibited TGF-β-induced activation of Smad2/3 in MM cells in vitro. In our 5T33MM preclinical model, oral administeration of TEW-7197 as single agent inhibited MM progression as measured by peripheral blood monoclonal protein concentration and BLI before and after treatment. TEW-7197 also induced a decrease in mortality and an increase in body weight of mice bearing MM. TEW-7197 alone or combination with ixazomib also attenuated TGF-β activation of Smad2/3, reduced the expansion of CD11b+Gr-1+ myeloid derived suppressor cells (MDSCs) in BM TME, and diminished the population of Foxp3+ regulatory T cells (Treg) in the spleen. Combination therapy of TEW-7197 plus ixazomib prolonged survival and exhibited a synergistic anti-tumor effect when compared to either TEW-7197 or ixazomib alone by significant a reduction in both the M-spike and BLI.
Conclusion: Our data demonstrate that the small molecule inhibitor of the TβRI, TEW-7197, effectively modulate the MM TME and is associated with a potent anti-myeloma effect in an immunocompetent murine model of MM. These data provide a rationale for clinical evaluation of the combination therapy of ixazomib and TEW-7197 as a potential therapeutic strategy to improve outcomes in patients with MM.
Citation Format: Byung-Gyu Kim, Olga Sergeeva, George Luo, Sung Hee Choi, Zhenghong Lee, Seong-Jin Kim, John Letterio, Ehsan Malek. TGF-β type I receptor inhibitor (TEW-7197) diminishes myeloma progression by multiple immunomodulatory mechanisms in combination with ixazomib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2647. doi:10.1158/1538-7445.AM2017-2647