Defining the Roles of Bone Marrow Adipocytes and FABP4/5 Signaling in Multiple Myeloma Drug Resistance

Mainehealth, Portland ME

Investigators

Linked publications & trials

Abstract

ABSTRACT – MERIT EXTENSION The overall goal of this MERIT Extension research project is to support the original goals of our parent grant and build logically on our findings, while staying within the scope of the parent grant. My parental R37 focuses on examining how fatty acid-binding proteins (FABPs) impact multiple myeloma (MM), an incurable blood cancer that results from mutations that accumulate in the plasma cell. Myeloma cells grow in the rich soil of the bone marrow (BM), first very slowly, and then more quickly and aggressively, causing degradation of the bone and development of drug resistant clones. Although therapies exist, novel approaches to myeloma therapy are needed. Our prior work suggested that myeloma cells can become drug resistant and proliferate faster through support from proteins called fatty acid-binding proteins 4 and 5 (FABP4 and FABP5). In Specific Aim 1 of our parent award, we are analyzing how BM adipocytes and the FABPs contribute to myeloma by using novel, three-dimensional (3D), tissue engineered cancer models as well as FABP inhibition methods. In Specific Aim 2, we use mouse models to study the roles of the FABP members in MM, as well as the roles of BM adipocytes. The long-term goal of our work is to understand molecules and mechanisms driving MM growth; this Extension and Parent project specifically will identify new mediators driving MM and propose paradigm- shifting concepts to guide the development of new anti-MM therapies. The proposed studies in this Extension build on our prior and ongoing work in the Parent award, and add complementary data and translational significance to the findings. Both Extension Aims will be used to identify translationally significant effects and mechanisms of FABP actions on tumor cells and on the tumor immune microenvironment. Our Extension Specific Aim 1 is to Create FABP5 and FABP6 knockdown (KD) MM cells and phenotype these cells in vitro & in vivo. Our Extension Specific 2 is to Investigate the effects of obesity on MM growth and drug resistance, and the roles of FABPs in this process using FABP inhibitors and Fabp4/5dKO in vivo models. This Extension will explore the roles of the FABPs in MM cell growth, survival, and drug resistance in vitro and in vivo using oral administration of the FABP inhibitor BMS309403 and using a FABP4/5dKO (double homozygous knockout) mouse model. Analyses of tumor and non-tumor BM microenvironment cells, as well as mouse serum, blood, and other tissues are intended to illuminate the actions of FABP inhibition not only on tumor cells, but also on surrounding cells and the mouse overall. This work in thoroughly understanding the potential roles and mechanisms of action for the FABPs in MM is essential in moving towards clinical use.