Leukogene receives STTR grant to optimize compound for treatment-resistant multiple myeloma

A $2 million phase 2 Small Business Technology Transfer (STTR) grant to optimize a promising new compound that has shown efficacy in preclinical studies against treatment-resistant multiple myeloma has been awarded to a Medical University of South Carolina (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 at MUSC and a member of MUSC 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 that they have explored all the options and that 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 that 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, unfolded or misfolded proteins would then be targeted to the proteasome for degradation to avoid the build-up of these dysfunctional proteins. However, in the presence of proteasome inhibitors, the breakdown is blocked, leading to the build-up 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 2 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 twelve months, to find and develop the strongest possible drug candidate," says Dolloff. "This will be the one that we hope to see in patients."

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

The team is also exploring whether their 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."

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