GlycoMimetics’ GMI-1271 restored the punch of the myeloma treatment Velcade (bortezomib) in mice, which should rekindle hope in patients who failed to respond to Velcade, a study reports.
GMI-1271, which is being tested in clinical trials, blocks E-selectin, an adhesion molecule associated with aggressive myeloma and resistance to Velcade.
Another finding of the preclinical-trial study is that factors that bind E-selectin — that is, cause it to stick to another molecule — are more common in relapsed myeloma tumors.
The results not only support continued development of GMI-1271, but also offer insight into the mechanisms making myeloma aggressive and resistant to treatment, researchers said. The study, “E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271,” was published in the journal Leukemia.
“The results in this preclinical study demonstrate that targeting E-selectin may provide a novel approach to treatment of patients with multiple myeloma and could potentially restore sensitivity to chemotherapy and, in particular, proteasome inhibitor therapy,” Dr. John L. Magnani, vice president and chief scientific officer of GlycoMimetics, said in a press release.
The research team, which included scientists from the National University of Ireland, discovered a molecule involved in E-selectin production that appeared linked to drug resistance in myeloma.
Testing the compound in mice, they found factors that bind E-selectin to the surfaces of a small subset of myeloma cells. When they injected mice with cells that had high levels of the factors, the animals developed a more aggressive disease and died much earlier than mice with normal tumors.
The tumors generated from the cells developed complete resistance to Velcade, a standard myeloma treatment that kills cancer cells by interfering with mechanisms that break down protein.
When researchers administered GMI-1271 alone, there was no effect on the cancer. But the mice responded to a combination of GMI-1271 and Velcade.
The team also looked at the drug’s effect on myeloma tumor samples from humans. They discovered that E-selectin-related gene activity led to poorer outcomes, including significantly shorter progression-free survival.
Another tumor-sample finding was that many patients whose myeloma had relapsed had a higher proportion of cells with E-selectin binding factors than patients who had not relapsed.
Part of the AML trial will involve seeing whether the tumor levels of factors that bind E-selectin correlate with patients’ response to GMI-1271 treatment.
GlycoMimetics has announced that it will present data from the AML trial at the American Society for Clinical Oncology annual meeting in Chicago, June 2-6.