FROM NEOPLASIA
A first-in-class oral inhibitor of valosin-containing protein (VCP) p97 showed significant activity against human B acute lymphoblastic leukemia (B-ALL) cells, including those with the most common fusion genes seen in pediatric and adult B-ALL, researchers reported.
The drug, dubbed CB-5083 (Cleave Biosciences), induces cell death by causing endoplasmic reticulum stress, to which B-ALL cells are “distinctly vulnerable,” wrote Gabriele Gugliotta, MD, PhD, of Cedars-Sinai Medical Center in Los Angeles, Calif., and her coinvestigators. In their study, CB-5083 significantly reduced the viability of 10 B-ALL cell lines tested, and did so at blood concentrations that caused no significant toxicities in mice. Human B-ALL cells also showed no signs of upfront drug resistance, the researchers wrote in Neoplasia.
CB-5083 received an FDA orphan drug designation in 2015 for treating multiple myeloma, and also has shown activity against solid tumors. In the study, exposing BALL1 and OP1 B-ALL cell lines to CB-5083 triggered “early and strong” apoptosis, along with a “robust” cleavage of PARP, the researchers reported (Neoplasia. 2017 Aug 24. doi: 10.1016/j.neo.2017.08.001). http://www.neoplasia.com/article/S1476-5586(17)30258-0/fulltext
The drug also reduced the viability of human B-ALL cells without genes for GRP78, GRP94, or XBP1, suggesting that CB-5083 does not require the presence of these proteins to work, the investigators said. Deficiency of X-box binding protein 1 (XBP1) predicted greater sensitivity to CB-5083, which might mean that XBP1 splicing counteracts drug activity by mitigating endoplasmic reticulum stress, they added. “Finally, vincristine was synergistic with CB-5083 in both BALL1 and OP1 [cell lines],” they wrote. “In summary, the targeting of p97 with CB-5083 is a novel promising therapeutic approach that should be further evaluated in B-ALL.”
The investigators acknowledged support from the Melamed family, Reuben Yeroushalmi, National Research Foundation Singapore, Singapore Ministry of Education, Leukemia Lymphoma Society of America, and University of Bologna, Italy. They did not report having conflicts of interest.
