GMI-1271 is an E-selectin antagonist, under development by GlycoMimetics, that is in clinical testing as a possible way to restore sensitivity to a commonly used chemotherapy in patients with multiple myeloma and acute myeloid leukemia.
E-selectin is an adhesion molecule found on the surface of certain bone marrow cells (vascular endothelial cells in the marrow), allowing cancer cells with a corresponding ligand molecule on their surface to bind with marrow cells. A subpopulation of myeloma cells generates E-selectin ligands and attach to the marrow, which protects these cancer cells from the effects of chemotherapy. As a result, aggressive forms of multiple myeloma become insensitive to proteasome inhibitor-based chemotherapy.
The proteasome is an important complex in the maintenance of cell stability, eliminating proteins targeted for destruction. In this way, proteasome helps with cellular regulation and cellular survival, evading cellular stresses that can kill cells.
When a stressor is felt, cell death processes are triggered to avoid damage to neighboring cells. In cancer cells, because the proteasome works differently, important proteins that regulate cell death (apoptosis) may be eliminated, which stops those processes and allows the cancer to spread.
Proteasome inhibitors bind to the proteosome complex, protecting proteins and increasing the amount of proteins inside the cell, which trigger the natural cell death processes that promote the elimination of cancer.
Several cancers, however, are not sensitive to proteasome inhibitor-based chemotherapy.
How GMI-1271 works
GMI-1271 lowers adhesion between cells by blocking the site where E-selectin links to other cells, potentially moving cancerous cells out of the protective environment of the bone marrow, making them more vulnerable to chemotherapy.
The drug has the potential to restore a tumor’s sensitivity to proteasome inhibitor-based chemotherapy, helping myeloma patients “naturally kill” cancer cells.
Studies with GMI-1271
GMI-1271 has been tested in healthy volunteers in three different clinical trials (NCT02703051, NCT02271113, NCT02168595). Another Phase 1, open-label and dose-escalation clinical trial (NCT02811822) is currently recruiting participants with multiple myeloma resistant to proteasome inhibitor-based chemotherapy (bortezomib or carfilizomib) in Ireland. In this study, GMI-1271 will be added to standard chemotherapy to test whether sensitivity to the proteasome inhibitor can be restored.
GMI-1271 is also being tested in a Phase 1/2 clinical trial (NCT02306291) in about 100 patients with acute myeloid leukemia in the U.S., Australia, and Ireland. In this study, participants take GMI-1271 in combination with chemotherapy and samples are tested to determine if levels of E-selectin correlate with response to GMI-1271 treatment. Updated data from this trial will be presented at the 2017 American Society for Clinical Oncology (ASCO) Annual Meeting, which will take place in Chicago between June 2–6, 2017.
A recently completed Phase 1/2 clinical trial (NCT02744833) also assessed its safety, tolerability, and efficacy of GMI-1271 in patients with calf-level deep vein thrombosis. Results are not yet available.
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