Novel Signaling Pathway: Route to Potential Therapy for Multiple Myeloma?
Posted: Monday, November 26, 2018
A research team, led by Mikhail A. Nikiforov, PhD, of Wake Forest School of Medicine, Winston-Salem, North Carolina, has identified clofazimine, an older drug currently used to treat leprosy and tuberculosis, as a potential new therapy for patients with multiple myeloma. In preclinical research, the scientists found that clofazimine was effective, with potentially comparable activity to bortezomib.
Polyamine inhibition for cancer therapy is a conceptually appealing approach but has yet to meet success in the clinical setting. It is known that AHR is the central transcriptional regulator of the xenobiotic response. The researchers identified a previously unrecognized regulatory axis between AHR and polyamine metabolism and revealed that clofazimine appears to be an inhibitor of AHR.
As the basis of their study, published in the Journal of Clinical Investigation, the researchers noted that AHR has long been recognized as an attractive target for therapy and that clinical trials for AHR agonists (aminoflavone) or antagonists (StemRegenin 1) have been attempted. However, these trials were terminated early, partly because of excessive toxicity. Thus, the investigators sought to identify small molecules that may be unrecognized AHR antagonists to use as antipolyamine therapies.
After detailed analysis, they found 10 potential compounds. They then treated WI-38 cells with increasing doses of each agent and found that clofazimine alone demonstrated robust reductions in the levels of two genes ODC1 and AZIN1, in a dose-dependent manner. In multiple myeloma cells, AHR functions as an important transcriptional activator of the polyamine biosynthetic pathway, and clofazimine antagonizes this activation.
The researchers concluded: “Overall, our study builds upon the fundamental discovery of a novel AHR/polyamine biosynthesis signaling pathway and provides actionable insights into an anticancer strategy that opens a new niche for an existing medication.”