SCIO-469, a Potent and Selective Inhibitor of p38a MAPK, Normalizes the Bone Marrow Microenvironment and Inhibits Multiple Myeloma Cell Proliferation in In Vitro and In Vivo Models.
Authors: Nguyen Aaron N. , Reddy Mamatha , Henson Margaret , Stebbins Elizabeth G. , O’Young Gilbert , Ma Jing Y. , Haghnazari Edwin , Kapoun Ann M. , Medicherla Satya , Protter Andy , Navas Tony A. , Higgins Linda S. 
Published: October 2019

Abstract
Despite recent advances in the treatment of multiple myeloma (MM), this disease remains incurable. Accumulating evidence suggest that the bone marrow (BM) microenvironment of MM plays a critical role in tumor growth, survival, and drug resistance. A key aspect of this tumor-supportive environment is elevated levels of cytokines and other soluble factors. Most prominent among these is IL-6, which acts as a survival factor for MM cells and promotes their proliferation, migration, and drug resistance. Other mediators also implicated in the disease are VEGF and TNFa. The p38 MAPK is activated by a multitude of signals, including pro-inflammatory cytokines (e.g., TNFa and IL-1ß) and environmental stress. Furthermore, p38 activation has been shown to be important for the synthesis and secretion of IL-6, VEGF, and TNFa. Consequently, inhibition of p38 is postulated to reduce the production of these factors implicated in MM and to have therapeutic benefit by suppressing the tumor-supportive state of the BM microenvironment. Here, we demonstrate that SCIO-469, a specific and potent inhibitor of p38a MAPK, strongly inhibits MM cell proliferation by affecting MM cells directly as well as the BM microenvironment. SCIO-469 directly inhibits MM cell proliferation in long term culture. Importantly, SCIO-469 potently inhibits IL-6 and VEGF secretion from BM stromal cells (BMSC). To examine the effect of inhibiting BMSC-derived factors important in MM, we measured MM cell proliferation using transwell plates that separate BMSC from MM cells via a porous membrane. In transwell plates containing only MM cells, MM cell proliferation was modest and was inhibited by SCIO-469. In contrast, the presence of BMSC in transwell inserts dramatically increased the proliferation of MM cells over the course of the study. This result suggests that factors (e.g., IL-6) secreted by BMSC greatly stimulate MM cell proliferation. When SCIO-469 was added to these transwell cultures containing BMSC, MM cell proliferation was inhibited significantly. Consistent with these results, we show that levels of IL-6 under these conditions mirror exactly the proliferation of MM cells; IL-6 level is high in vehicle-treated cultures and is suppressed in SCIO-469-treated cultures. Finally, in a mouse xenograft plasmacytoma model of MM, we show that p38 inhibition significantly inhibited the increase in MM tumor volume. Collectively, our data indicate that SCIO-469 is a suppressor of the BM microenvironment and an effective inhibitor of MM cell proliferation in vitro and in vivo. Since SCIO-469 also inhibits secretion of osteoclast-stimulating factors (RANKL, IL-11, and MIP1a) in the microenvironment, SCIO-469 may not only inhibit MM cell survival but may also alleviate bone-related pathologies (bone destruction and osteolytic lesions) commonly associated with MM. Therefore, SCIO-469 may offer great promise for an improved outcome for patients with MM.