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Immunomodulatory drugs (IMiDs) and BRD4 inhibitors hold promise for treating primary effusion lymphoma (PEL), according to preclinical research.
The IMiDs lenalidomide and pomalidomide had antiproliferative effects in PEL cell lines, and lenalidomide exhibited synergistic cytotoxicity with the BRD4 inhibitors JQ-1, IBET151, and PFI-1.
In mouse models of PEL, treatment with lenalidomide and JQ-1 significantly prolonged survival.
Preet Chaudhary, MD, PhD, of the University of Southern California, Los Angeles, and his colleagues reported these results in Oncogene.
The researchers first tested lenalidomide and pomalidomide in 9 PEL cell lines. Both drugs exhibited antiproliferative effects, at clinically achievable doses, in 6 of the cell lines (BC-3, BCBL-1, JSC-1, VG-1, UMPEL-1, and UMPEL-3).
The IMiDs displayed activity in the remaining 3 cells lines (BC-1, BCP-1, and APK-1) as well, but only at high doses (ranging from 2.6 μM to 10 μM for lenalidomide and from 226 nM to 744 nM for pomalidomide).
Looking into the mechanism of IMiDs in PEL, the researchers found these drugs induce G1 cell-cycle arrest without inducing Kaposi’s sarcoma-associated herpes virus lytic cycle reactivation.
Further investigation revealed that interferon α, β, and γ are cytotoxic to PEL, but they are not essential for the antiproliferative effects of IMiDs. On the other hand, cereblon-dependent suppression of IRF4 and rapid degradation of IKZF1 are essential.
The researchers also found that knocking down MYC enhanced IMiD activity. This led them to BRD4 inhibitors, which are known to target MYC transcription.
The team tested lenalidomide in combination with JQ-1, IBET151, and PFI-1. The IMiD was “highly synergistic” with all 3 BRD4 inhibitors in BC-3 and BCBL-1 cell lines.
In both cell lines, treatment with lenalidomide and JQ-1 significantly decreased the expression of MYC and IRF4 at protein and mRNA levels. The treatment also resulted in G1 cell cycle arrest, cleavage of poly (ADP-ribose) polymerase, and apoptosis.
So the researchers tested this combination in a mouse model of PEL (NOD-SCID mice injected with BC-3 cells). And they observed a significant improvement in median survival for mice that received combination treatment, compared to lenalidomide or JQ-1 alone—51 days, 35 days, and 42 days, respectively (P≤0.01).
