Leukogene Therapeutics receives funding to develop compound for resistant multiple myeloma


Credit: Photograph by Emma Vought, Medical University of South Carolina

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."

This work was funded by an earlier STTR grant in the amount of $225,000 as well as 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. Additional funding that enabled the project was provided by the South Carolina COBRE program in Oxidants, Redox Balance and Stress Signaling.


About Leukogene Therapeutics, Inc.

Leukogene is a Charleston-based oncology start-up company spun out of the Medical University of South Carolina (MUSC). The company's mission is to accelerate the development of new therapeutics for patients with advanced stage cancer. Leukogene is a National Cancer Institute portfolio company and a client company of the South Carolina Research Authority (SCRA) SC Launch program.

About MUSC

Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 700-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute-designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic programs or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.

About the South Carolina Clinical and Translational Research Institute

The South Carolina Clinical and Translational Research (SCTR) Institute is the catalyst for changing the culture of biomedical research, facilitating sharing of resources and expertise, and streamlining research-related processes to bring about large-scale, change in the clinical and translational research efforts in South Carolina. Our vision is to improve health outcomes and quality of life for the population through discoveries translated into evidence-based practice.

About MUSC Foundation for Research Development

FRD has served as MUSC's technology transfer office since 1998. During that period, FRD has filed patent applications on more than 400 technologies, resulting in over 150 U.S. issued patents. Additionally, FRD has executed more than 150 licenses and spun out more than 50 startup companies. MUSC startups have had products approved by the FDA and acquired by publicly traded corporations while attracting substantial investment dollars into South Carolina. Innovations from MUSC, including medical devices, therapies and software, are positively impacting health care worldwide. Please visit us online at frd.musc.edu.

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