Fatty acid-binding proteins may be potential target for myeloma
Blocking the activity of these proteins could curb growth of myeloma cells
Blocking the activity of a group of proteins called fatty acid-binding proteins (FABPs) may be a useful treatment strategy for multiple myeloma, a new study shows.
“We’ve found that blocking the FABPs can prevent the growth of myeloma cells, mainly by slowing the cells’ proliferation [growth rate],” Michaela Reagan, PhD, the study’s senior author and a faculty scientist at MaineHealth Institute for Research, said in a press release.
“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,” added Reagan, who is also an associate professor at Tufts University School of Medicine.
The study, “Targeting the fatty acid binding proteins disrupts multiple myeloma cell cycle progression and MYC signaling,” was published in eLife.
FABPs help regulate how fatty acids are transported and used in cells
As their name implies, FABPs are a group of proteins that are able to bind to fatty acids, a type of fatty molecule that is used as an energy source and as a part of cellular membranes. FABPs help to regulate how fatty acids are transported and used in cells.
Previous research has shown that myeloma cells use fatty acids to help them grow, which suggests that FABP activity may be a treatment target. Reagan, along with colleagues at several U.S. institutions, set out to test this idea.
“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, the study’s first author and a research associate at MaineHealth 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,” Farrell added.
The team first found that lab-grown myeloma cells produce high levels of certain FABPs, particularly FABP5, and that genetically editing the cells to reduce production of this protein slowed their proliferation.
Spurred by these findings, the scientists tested the effects of treating myeloma cells with two compounds, called BMS309403 and SBFI-26, that broadly block FABP activity.
Treatment with either compounds, but particularly with both, pronouncedly slowed growth in all seven types of lab-grown myeloma cells tested, but had little effect on non-cancerous cells.
We’ve found that blocking the FABPs can prevent the growth of myeloma cells, mainly by slowing the cells’ proliferation [growth rate].
Blocking FABPs disrupted myeloma cells’ ability to produce energy and grow
The researchers then conducted a series of experiments to better understand the underlying mechanisms of FABP-associated slower myeloma cell growth. Their results suggested that FABP suppression reduced the activity of the MYC signaling pathway, which is a key driver of growth and cell survival in many types of cancer.
Findings also indicated that blocking FABPs disrupted myeloma cells’ ability to produe energy and grow and promoted apoptosis, a process of programmed cell death, “while having negligible effects on [non-myeloma] cells,” the researchers wrote.
“Collectively, these data demonstrate the anti-myeloma effects of FABP inhibition, suggest different mechanisms driving this, and thus describe a potentially new target for [multiple myeloma] therapy,” they added.
To see whether FABP5 was linked to tumor progression in people with myeloma, the team retrospectively analyzed data from the Multiple Myeloma Research Foundation’s CoMMpass study and the OncoMine data set.
They found that more than two-thirds of myeloma patients show moderate-to-high levels of the FABP5 protein in their myeloma cells. Also, patients with higher FABP5 levels tended to have faster disease progression and shorter overall survival.
Based on statistical models, patients with high FABP5 levels were estimated to have a “64% increased risk of disease progression or death, and a twofold increased risk of early death,” compared with those with low FABP5 levels, the researchers wrote.
“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,” Reagan said.
BMI did not seem to influence results
While FABP5 is involved in fat metabolism, the links between high FABP5 and myeloma progression and survival were not influenced by body mass index, a ratio of weight to height. This suggests that this protein may be a prognostic biomarker for all myeloma patients, not only those whose risk might be increased by obesity.
The researchers also tested the effects of FABP suppression in two mouse models of multiple myeloma. Treatment with FABP blockers significantly reduced cancer burden and extended survival in both models. However, no beneficial effects were seen when the experiments were repeated in a second group of mice of one of the models.
The scientists are currently working to understand the reasons for these discrepancies so that therapies can be optimized toward potential use in clinics.
“Follow-up analysis needs to be performed before clinical work can be initiated, such as optimizing doses or delivery mechanisms,” the team wrote, also highlighting a need for further preclinical analyses of the safety profile of FABP inhibitors before these compounds can be given to people.