In an article published online October 12, 2018, by Leukemia, Medical University of South Carolina investigators report that a new compound enhances the efficacy of proteasome inhibitors (PIs), the standard-of-care for the treatment of multiple myeloma (MM), in cell culture and in preclinical models. 

The efficacy and safety of the novel combination regimen will need to be validated in humans, but preclinical findings are promising and suggest that it could help overcome PI resistance in MM.

Most patients with MM eventually develop resistance to PIs. To address this problem, the MUSC team began by screening thousands of compounds in hopes of finding one that, when combined with PIs, could synergistically kill PI-resistant myeloma cells.

The team was led by Nathan G. Dolloff, Ph.D., an assistant professor in the Department of Cell and Molecular Pharmacology & Experimental Therapeutics and a member of Hollings Cancer Center at MUSC.

FDA-approved PIs

The team identified a molecule, compound E61, that amplified the effects of several FDA-approved PIs in resistant MM cells. Interestingly, it did not kill more than normal cells, showing that the drug was selective for malignant cells.

The new molecule, by itself and in combination with the PI bortezomib, also significantly prolonged median survival in a mouse model, a striking result for a compound that had not yet chemically modified.

The team then started a structure-activity relationship (SAR) program, making and testing hundreds of new E61 derivatives. SAR studies enable investigators to examine which parts of the molecule are essential for activity and guide them to improve a compound by giving it better potency and drug-like properties.

These studies led to the development of the lead candidate, called E64FC26. The team then went on to view the pharmacological properties of its new lead and show activity in multiple mouse models of MM. Compared to mice that received no drug treatment or just a single-agent PI, the combination of E64FC26 and the PI extended survival the most.

"One of the most compelling aspects of our study was showing the compound works in combination with PIs in vivo," said Reeder M. Robinson, Ph.D., a postdoctoral fellow in the Dolloff laboratory and first author on the  Leukemia article. "A new drug can work well on cancer cells in a dish, but there's a lot of things that can go wrong and cause it to be ineffective when you test it in mice. "

MM is a cancer of the plasma cell, a type of white blood cell that resides in our bone marrow and produces antibodies that help the immune system fight off infection. Cancerous MM plasma cells produce and secrete high levels of antibody proteins, making them vulnerable to disturbances in protein balance.