A new class of cancer drugs, SMAC mimetics, induces apoptosis by mimicking a protein that regulates cancer cell survival. The drugs have shown promising results in studies on many fronts. In animal and cell-line studies, the drugs killed cancer cells and shrank tumors. Now National Cancer Institute (NCI) researchers are hoping to put them to the test in clinical trials with patients who have the ABC subtype of diffuse large B-cell lymphoma (DLBCL).
Of the 2 distinct molecular DLBCL subtypes, ABC DLBCL is the least curable, the researchers note. A hallmark of the ABC subtype is the continuous activation of the B-cell receptor (BCR) signaling pathway, which promotes cell growth and survival by overriding signals for apoptosis. When other research suggested that blocking a protein in the NF-ΚB protein complex in the BCR pathway was effective, the NCI researchers also began to look at other potentially targetable proteins.
In preliminary studies, the researchers showed that the proteins cIAP1 and cIAP2 control the activity of the BCR signaling pathway in ABC DLBCL. Birinapant, one of the SMAC mimetics in clinical development, reduced cIAP1 and cIAP2 levels in ABC cell lines. Further research showed that birinapant had the effect only in those cancer cells that depend on BCR signaling for survival.
According to NCI, SMAC mimetics are well tolerated and seem to be safe. In animal studies, birinapant “substantially shrank tumors while causing no evident toxicity.”