Abstract 2961: The novel roles of fatty acid binding proteins in multiple myeloma
Authors: Farrell Mariah , D'Amico Anastasia , Campbell Heather Fairfield , Murphy Connor , Reagan Michaela Ruth 
Published: July 2021

Background: Our goal was to determine the role of the fatty acid binding protein (FABP) family in multiple myeloma (MM) using cancer dependency mapping and RNA sequencing, and to assess the potential for combined targeting of FABPs with other MM therapies. We reported at the ASH 2020 Meeting that targeting FABPs in vitro induces apoptosis, cell cycle arrest, and cell death using the FABP inhibitors BMS309403 and SBFI-26. These inhibitors alone, or in combination, reduced tumor bioluminescence and increased survival in a SCID-beige MM1S mouse model. Lastly, we showed the clinical relevancy and excellent potential for targeting the FABPs by analyzing published human MM datasets.

Methods: Herein, we searched Crispr screen data from The Cancer Dependency Map (DepMap.org) to quantify MM cell dependency on all the FABP members. We also performed RNA sequencing of human MM1S MM cells treated with BMS309403, SBFI-26, or both for 24 hours and analyzed the gene and pathway changes using dbString analysis. Lastly, we tested dexamethasone (dex) with SBFI-26 in the SCID-beige GFP+Luc+MM1S in vivo model.

Results: Using DepMap, MM cells were most highly dependent on FABP5, which fell within the top 25% of essential genes for MM cells. FABP5 was also the most highly expressed FABP in 3 cell lines (MM1S, OPM2 and RPMI8226) in our RNA sequencing data, and was expressed by primary MM cells. Our RNA sequencing data revealed many changes in MM1S cells after treatment with BMS309403, SBFI-26, or both; the greatest number of genes changed was with the combination treatment BMS309403 + SBFI-26 (either up- or down-regulated) versus vehicle controls. Interestingly, the central node in the dbString analysis of downregulated genes after combination treatment (FC&lt;-1.5, p&lt;0.05) out of 154 genes was Myc, suggesting that disruption of the Myc pathway caused the cell cycle arrest, decreased proliferation, and increased apoptosis in MM cells treated with FABP inhibitors. 196 upregulated genes (p&lt;0.05, FC&gt;1.5) were identified in MM cells with the combination treatment including CD44, PECAM, and IGFBP7; the “cellular response to interferon gamma” gene ontology term was an up-regulated biological process. Lastly, although our in vitro data supported the combination of SBFI-26 + dex, we did not observe a decrease in tumor bioluminescence using the combination of 1 or 9 mg/kg dex plus 1 mg/mL SBFI-26 3X/week in the MM1S mouse model. Future studies using different doses of these and other drugs (eg. lenalidomide and bortezomib) to more thoroughly investigate the combination potential for FABP inhibitors with common anti-MM therapies are planned.

Conclusion: Targeting the FABPs holds great potential as a novel, safe therapy for MM patients. We identified the Myc signaling pathway as a potential mediator of FABP action. As Myc is a commonly upregulated oncogene in MM and other cancers, we believe there may be great untapped potential for targeting FABPs, especially FABP5, in MM and other cancers.

Citation Format: Mariah Farrell, Anastasia D'Amico, Heather Fairfield Campbell, Connor Murphy, Michaela Ruth Reagan. The novel roles of fatty acid binding proteins in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2961.