Potential New Target for Multiple Myeloma Treatment Discovered

A new target that affects myeloma growth, called FABP5, was found by myeloma researchers, according to recent research.

Myeloma investigators from Maine Health Institute for Research, University of Maine, Tufts University, Dana Farber Cancer Institute, University of Vermont and University of England shared the discovery about a molecule that is directly related to the progression of multiple myeloma.

The molecule is called fatty acid binding protein 5 (FABP5) and is involved in fat transport and metabolism. Links between FABP4 and cancer have been demonstrated in prostate, breast, and ovarian cancer, and acute myeloid leukemia. Changes in the FABPs family of molecules that are fatty acid genes can control cellular processes at many levels.  

First, the researchers reviewed myeloma cell lines and found that in the FABP family, the heaviest expression in myeloma cells was FABP5.

They then reviewed the Broad Institute's Broad Institute’s Cancer Dependency Map. Of all the FABPs, only FABP5 exhibited a negative score in all 20 myeloma cell lines, showing a strong reliance on FABP5 for myeloma cell growth. 

Next, they used a gene editing technology called CRISPR to edit out the FABP5 gene and saw a 94% editing efficiency in the myeloma cells. The FABP5 edited cells had slight, but significantly reduced cell numbers at 48, 72, and 96 hours versus the non-edited cells.

They then tested two well known FABP inhibitors on the myeloma cells. The myeloma cells were more sensitive to the inhibitor than the normal cells. When they used RNA sequencing to see further impact, they detected changes to cellular pathways and processes related to myeloma cell survival. 

The FABP inhibitor had anti-myeloma effects both in the lab and in mice and importantly reduced expression of a gene called MYC that is well known to affect myeloma growth and is associated with high-risk myeloma. The FABP inhibitor also impaired myeloma cell metabolism, mitochondrial function and cell viability while also decreasing the myeloma tumor burden. 

Using data from the MMRF's CoMMpass project and OncoMine data, they found that about 70% of the 307 myeloma patients had moderate-to-high expression of FABP5. They also learned that patients with higher FAB5 expression had significantly shorter overall survival and a 2x risk of early death. 

Because FABP5 is a fat and metabolism-related gene, they wondered if it was associated with higher Body Mass Index in patients but found that there did not seem to be a relationship between BMI and the presence of this gene in myeloma patients. 

This discovery is exciting as it could help idnetify patients with higher risk myeloma and may represent a new target for myeloma therapy. The next step is to identify potential inhibitors that could be tested in clinical trials.