TGF-β, a multifunctional cytokine, is produced in multiple myeloma (MM) cells and cells in the bone marrow (BM) tumor microenvironment (TME), where it also stimulates MM progression through the promotion of catabolic bone remodeling, IL-6 secretion, and Th17 T cell development.
In a preclinical mouse model presented at the 2017 AACR Annual Meeting, researchers evaluated the anti-MM therapeutic potential of TEW-7197, a small molecule TGF-β type I receptor kinase inhibitor, as a single agent or in combination with ixazomib. “Our data demonstrate that TEW-7197 effectively modulates the MM TME and is associated with a potent anti-myeloma effect in an immunocompetent murine model of MM,” lead author Byung-gyu Kim, DVM, of Case Western Reserve University in Cleveland, Ohio, said during his presentation of the results.
The preclinical immunocompetent 5T33MM model was used to characterize the role of TGF-β signaling in the BM TME. Mice with 5T33MM cells expressing luciferase were treated with TEW-7197, ixazomib, or combination TEW-7197 plus ixazomib daily for 3 weeks.
On quantitative polymerase chain reaction analysis, 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.
As a single agent, Dr. Kim and colleagues found that TEW-7197 inhibited MM progression (per peripheral blood monoclonal protein concentration and bioluminescence imaging before and after treatment) and induced a decrease in mortality and an increase in body weight.
TEW-7197 alone or in combination with ixazomib also attenuated TGF-β activation of Smad2/3, reduced the expansion of CD11b+Gr-1+ myeloid derived suppressor cells in BM TME, and diminished the population of Foxp3+ regulatory T cells in the spleen.
Combination therapy prolonged survival in mice and had a synergistic anti-tumor effect by significant reduction in both M-spike and BLI, compared with either TEW-7197 or ixazomib alone. “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,” the authors concluded.
TEW-7197 is also being evaluated in phase I clinical trials in patients with solid tumors and is associated with an acceptable toxicity profile.
Kim B, Sergeeva O, Luo G, et al. TGF-β type I receptor inhibitor (TEW-7197) diminishes myeloma progression by multiple immunomodulatory mechanisms in combination with ixazomib. 2647/6. Presented at the 2017 AACR Annual Meeting, April 3, 2017; Washington, DC.