Leukogene Therapeutics awarded $2M to develop myeloma treatment

A promising new compound that has shown to be effective against treatment-resistant multiple myeloma in preclinical trials at the Medical University of South Carolina received a $2 million grant to optimize the compound and develop it into an investigational new drug.

The phase II 2 Small Business Technology Transfer (STTR) grant was awarded to the MUSC startup company Leukogene Therapeutics Inc. in collaboration with MUSC researcher and company founder, Nathan G. Dolloff, Ph.D. Dolloff is an assistant professor in the Department of Cell and Molecular Pharmacology & Experimental Therapeutics and a researcher with the Hollings Cancer Center. Dolloff and his team will use the STTR award to further develop the new compound into a drug that could be used with proteasome inhibitors in treatment-resistant multiple myeloma.

Proteasome inhibitors have contributed to the dramatic improvement in multiple myeloma treatment and outcomes over the past 15 years. They disrupt the normal ebb and flow of protein synthesis and breakdown in cells by blocking the activity of the proteasome, which is the cell's major protein degradation machinery. This causes excess proteins to accumulate, which is highly toxic to some cancer cell types. Multiple myeloma is a cancer of plasma cells, a type of white blood cells that normally help fight off infection by producing a large quantity of proteins called antibodies. Because these cells produce a great deal of protein, they are prime targets for proteasome inhibitor treatment.

Although proteasome inhibitors work really well up front, patients eventually become resistant to the treatment. The compound Dolloff is developing is intended to provide patients with resistant multiple myeloma a new therapeutic avenue.

"Nearly all myeloma patients eventually reach that stage when their physician tells them they have explored all the options, and there's nothing else," says Dolloff. "Our goal has always been to develop that next treatment option and get it to patients as quickly as possible."

Using resistant cell lines they started to develop in 2012, Dolloff's team screened over 20,000 compounds, hoping to find one that reversed resistance to proteasome inhibitors in myeloma cells. Finally, they found the molecule for which they had been searching. This compound amplified the effects of proteasome inhibitors in a large panel of multiple myeloma cells, including those that had been made resistant, and reduced the number of cancer cells in mice with myeloma, helping them to survive longer.

While proteasome inhibitors kill cancer cells by preventing the breakdown of proteins, Dolloff's compound targets instead their synthesis, preventing proper folding, which is essential to protein function. Normally, the proteasome would target the unfolded or misfolded proteins for degradation to avoid the build-up of these dysfunctional proteins. However, proteasome inhibitors block the breakdown, leading to the buildup of toxic misfolded proteins. In principle, the compound developed by Dolloff could offer a one-two punch when administered together with proteasome inhibitors.

"We're creating a lot of misfolded junk proteins, and that, in and of itself, is toxic to myeloma cells," says Dolloff. "But because we are also blocking the breakdown side with proteasome inhibitors, we have a two-hit strategy that is extremely effective at killing myeloma cells."

The phase II STTR grant funds Dolloff and his team for two years to optimize this compound and select a lead molecule to take into clinical trials. During this time, they will improve the drug-like properties of the molecule, optimize its dose and treatment schedule in animal models and start the pharmacology and toxicology experiments that are necessary to turn the compound into an investigational new drug.

"Our plan is, within the next six to 12 months, to find and develop the strongest possible drug candidate," says Dolloff. "This will be the one that we hope to see utilized in patients."

During that time, Leukogene Therapeutics Inc. will also be preparing for the product manufacturing and toxicology studies that the Food and Drug Administration requires before clinical testing in humans. The company plans to seek industry partners to help accelerate the development process and provide a new product to cancer patients as fast as possible.

The team is also exploring whether its new class of drug is effective in other cancer types and whether it can enhance the activity of other cancer therapies, not just proteasome inhibitors. Preliminary findings suggest that is the case.

"One of the exciting things is that we think this goes well beyond myeloma, and we can apply this to a lot of different cancers," says Dolloff. "We may even be able to enhance a few drugs other than proteasome inhibitors."

This work was funded by an earlier STTR grant in the amount of $225,000; a technology transfer grant from MUSC's Foundation for Research Development and the South Carolina Clinical and Translational Research (SCTR) Institute, a Clinical and Translational Science Awards hub funded by the National Institutes of Health; and a SCTR-funded High-Risk, High Rewards pilot grant. The South Carolina COBRE program in Oxidants, Redox Balance and Stress Signaling also provided funding that enabled the project.