Molecule enhances PI activity in multiple myeloma
The investigators observed similar effects in a human xenotransplant MM model.
These mice were randomized to receive treatment with vehicle, E64FC26 (2 mg/kg for 3 days/week), bortezomib (0.25 mg/kg for 2 days/week), or a combination of the two agents.
E64FC26 increased median survival by 2 weeks compared with vehicle-treated mice (P<0.0001). By day 36, no vehicle-treated mouse survived, compared with 100% of the E64FC26-treated mice.
Single-agent bortezomib increased survival by 6 days (P=0.0007).
And the combination produced the greatest improvement in median survival, increasing it by 20 days (P<0.0001).
The investigators reported no overt toxicity or body weight fluctuation for mice treated with E64FC26 or the combination.
“These results provide preclinical proof of concept for the strategy of targeting PDI with this new class of compound for the treatment of MM,” the researchers concluded.
“One of the strengths of this study is that we spanned almost the entire drug discovery process,” Dr. Dolloff said. “We screened thousands of compounds, found an exciting molecule, deconvoluted what its binding target was, synthesized hundreds of derivatives to make it better, and then conducted animal studies.”
“The study has everything from biochemistry and cell biology to medicinal chemistry and animal pharmacology in it. There is still a lot of work to be done before this drug is ready for clinical trials in humans, but it has been a rewarding project, and I’m looking forward to the next steps.”
Dr. Dolloff is founder of Leukogene Therapeutics, Inc., which has licensed patents from MUSC, and a second study author is an inventor on patents. The other authors declared no conflicts of interest.
The research was supported by the National Institutes of Health/National Cancer Institute, the South Carolina Clinical & Translational Research Institute, the MUSC Hollings Cancer Center, and by the Hollings Cancer Center T32 Ruth L. Kirschstein National Research Service Award Training Program.
