Inhibiting Fatty Acid Binding Protein Family Members Decreases Multiple Myeloma Cell Proliferation Through Effecting the myc Pathway

FABP inhibition leads to increased survival of myeloma bearing mice and decreased cell growth by inhibiting MYC signaling.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1016/thumbnail.jp

Multiple myeloma cells Graphs and Figures inhibit adipogenesis, increase senescencerelated and inflammatory gene transcript expression, and alter metabolism in preadipocytes

Myeloma cells alter metabolism & induce senescence in adipocyte-lineage cells, suggesting that senescence-associated proteins are involved in multiple myeloma.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1032/thumbnail.jp

Investigating the Effect that Inhibiting FABP4 or FABP5 May Have in Myeloma Cell Proliferation

In the bone marrow microenvironment, adipocytes and multiple myeloma cells have an intricate bidirectional relationship. Adipokines have been linked to shifting typical behavior in many cancers such as proliferation. Our previous research found that adipocyte secreted Fatty Acid Binding Proteins (FABPs) contribute to tumor growth, invasion, and survival. To test if external FABPs are important to myeloma cells, recombinant FABP4 or FABP5 was spiked into myeloma cell lines (MM1.S and OPM2) in serum and serum-free conditions. This data was cell counted using bioluminescence imaging (BLI). Analysis showed that there was no impact on cell growth with the spike in. Thus, external FABPs are not important to myeloma cells. It was hypothesized that intracellular inhibition of FABP4 or FABP5 in myeloma cells would decrease proliferation and tumor burden, providing a novel mechanism to treat the cancer. To test the effect that FABPs may have on myeloma cell growth, a cell line was treated with inhibitors of FABP4, FABP5, and a co-treatment in cell culture. BLI was used to cell count the myeloma cells at time 0, 24, 48, and 72 hours. Analysis of the inhibitor spike in showed that myeloma cell growth was decreased over time with the inhibitor treatment. In a mouse model it was concluded that inhibition of FABP4, FABP5, or a co-treatment did decrease myeloma cell growth and tumor burden over time. Furthermore, the inhibitors increased mouse survival. This supports the idea that FABP inhibitors could prove as a future cancer therapeutic

Targeting the fatty acid binding proteins disrupts multiple myeloma cell cycle progression and MYC signalin

Multiple myeloma is an incurable plasma cell malignancy with only a 53% 5-year survival rate. There is a critical need to find new multiple myeloma vulnerabilities and therapeutic avenues. Herein, we identified and explored a novel multiple myeloma target: the fatty acid binding protein (FABP) family. In our work, myeloma cells were treated with FABP inhibitors (BMS3094013 and SBFI-26) and examined in vivo and in vitro for cell cycle state, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation properties. Myeloma cell responses to BMS309403, SBFI-26, or both, were also assessed with RNA sequencing (RNA-Seq) and proteomic analysis, and confirmed with western blotting and qRT-PCR. Myeloma cell dependency on FABPs was assessed using the Cancer Dependency Map (DepMap). Finally, MM patient datasets (CoMMpass and GEO) were mined for expression correlations with clinical outcomes. We found that myeloma cells treated with FABPi or with knockout (generated via CRISPR/Cas9 editing) exhibited diminished proliferation, increased apoptosis, and metabolic changes in vitro. FABPi had mixed results in vivo, in two pre-clinical MM mouse models, suggesting optimization of in vivo delivery, dosing, or type of FABP inhibitors will be needed before clinical applicability. FABPi negatively impacted mitochondrial respiration and reduced expression of MYC and other key signaling pathways in MM cells in vitro. Clinical data demonstrated worse overall and progression-free survival in patients with high expression in tumor cells. Overall, this study establishes the FABP family as a potentially new target in multiple myeloma. In MM cells, FABPs have a multitude of actions and cellular roles that result in the support of myeloma progression. Further research into the FABP family in MM is warrented, especially into the effective translation of targeting these in vivo