Multiple myeloma accounts for roughly 10% of blood cancers and has only a 53% five-year survival rate. Although treatments for myeloma patients have greatly improved within the past two decades, the disease is still incurable.
Now, new research shows that fatty acid binding protein 5 (FABP5), which is involved in fat transport and metabolism, is key to the progression of multiple myeloma. The authors noted that FABP5 could be used as a marker to help identify people with more aggressive forms of myeloma and may represent a new target for multiple myeloma treatment.
This work is published in eLife, in the article, “Targeting the fatty acid binding proteins disrupts multiple myeloma cell cycle progression and MYC signaling.”
“Despite recent findings that multiple myeloma cells uptake and transport fatty acids, there are few treatments that specifically target molecules involved in metabolism in myeloma cells,” said Mariah Farrell, research associate at Maine Health Institute for Research. “We wanted to study the cancer-promoting potential of the fatty acid binding proteins in myeloma cells, to determine if this could be a valid target for therapeutics.”
The team began their studies in multiple myeloma cell lines by looking at relative amounts of each type of fatty acid binding protein (FABP). They found that FABP5 was the most abundant form in both mouse and human myeloma cells, and human myeloma cell lines were predicted to have a strong reliance on FABP5 for their survival.
Next, myeloma cells, the authors described, were treated with FABP inhibitors and examined for cell cycle state, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation properties. The responses of the treated cells to the inhibitors were also assessed with RNA-Seq and proteomic analysis.
The researchers found that FABP5 knockouts had “diminished proliferation, increased apoptosis, and metabolic changes in vitro.”
These studies revealed that blocking FABP family members’ activity hampers myeloma cell growth. In addition, patient data suggested that higher expression of FABP5 in tumor cells correlated with worse outcomes.
There were multiple effects in the cells, but most notably, they observed that the Myc pathway—a key survival pathway used by cancer cells—was decreased when FABP proteins were blocked. This suggests that the Myc pathway may be one way that FABPs help tumors survive.
To assess whether FABP5 is linked to tumor progression in people with myeloma, the team retrospectively analyzed data from 779 myeloma patients from the Multiple Myeloma Research Foundation’s CoMMpass Study. They found that myeloma patients, on average, had the highest expression of FABP5; moderate expression of FABP6, FABP4, and FABP3, and essentially no expression of the other FABP subtypes.
Overall, patients with higher amounts of FABP5 in their myeloma cells had significantly shorter time to disease progression and shorter overall survival. In addition, their retrospective analysis of 414 newly diagnosed myeloma patients showed that those who had high-risk myeloma with poorer prognosis had higher FABP5 gene expression than those with a more favorable prognosis. Lastly, FABP5 expression was found to be increased in patients who had relapsed disease, compared with patients who were newly diagnosed.
Taken together, these studies suggest that patients with high amounts of FABP5 in their myeloma cells had a 64% higher chance of disease progression, and a two-fold increase in the risk of death, compared to patients with low FABP5 expression.
They also found that, although FABP5 has known roles in lipid metabolism, the association with myeloma progression and survival was not influenced by patient body mass index (BMI)—suggesting it could be a robust marker of myeloma risk in all patients, not only those patients whose risk might be increased by obesity.
“Overall we’ve found that blocking the FABPs can prevent the growth of myeloma cells, mainly by slowing the cells’ proliferation. We were excited to see that clinical datasets also show that tumors expressing higher FABP5 are more aggressive compared to tumors with less FABP5, making it a key target molecule for new myeloma treatments,” concluded Michaela Reagan, PhD, faculty scientist at Maine Health Institute for Research and associate professor at Tufts University School of Medicine. “The next step is to work towards a better understanding of the activity and safety of existing FABP-blocking drugs in mouse myeloma models so we can design and develop the best candidates to take into clinical trials.”