When combined, a new inhibitor and an existing therapy enhance each other’s antitumor effects | MUSK

A research team at the Medical University of South Carolina (MUSC) has developed new compounds that show initial promise in fighting the rare pediatric cancer neuroblastoma when paired with the existing cancer drug bortezomib (Velcade, Takeda Oncology). The new compounds block or inhibit an enzyme known as lysine-specific demethylase 1 (LSD1). The MUSC team, led by Patrick M. Woster, Ph.D., reports its findings in the European Journal of Medicinal Chemistry.

“Our compounds are a new chemical class of LSD1 inhibitors and are the first small molecules to produce a synergistic antitumor response in combination with bortezomib,” said Woster. Woster is the SmartState Endowed Chair in Drug Discovery and head of the Department of Drug Discovery and Biomedical Sciences at MUSC.

“Our studies are the first to show that LSD1 inhibition is a viable strategy to target high-risk MYCN-amplified neuroblastoma.” — Dr. Patrick Woster

Such combination therapies are the way of the future, said coauthor Yuri Peterson, Ph.D. Peterson is deputy director of the Drug Discovery Core and director of Bioenergetics Profiling at MUSC.

“Drug development in cancer therapy is shifting from single toxic agents to specific combinations tailored to the patient’s genetics,” said Peterson. “By using these combination therapies, we can increase the positive effect by limiting the negative effects of anticancer agents such as bortezomib.”

Such new treatment options are urgently needed for children with high-risk diseases. Current therapies are often ineffective and incredibly painful. Nearly half of these children die within five years of being diagnosed.

“We need treatments that are not only more effective against high-risk diseases, but are better tolerated by patients.” — Dr. Catherine Mills

Woster’s team is acutely aware of the challenges these children face and is motivated to provide them with new options.

“We need treatments that are not only more effective against high-risk diseases, but are better tolerated by patients,” said postdoctoral researcher Catherine Mills, Ph.D., first author of the paper.

Woster and the scientists in his lab are studying compounds that block the activity of LSD1. Previous work has shown that LSD1 serves as a scaffold to support and stabilize the protein factor MYCN. This scaffold helps tumors form and spread, so patients with increased MYCN tumors are considered to be at high risk for the disease. Woster lab wants to destroy that scaffolding with their new LSD1 inhibitors.

Research team members (left to right): Kathleen Garrabrant;  Patrick Woster, PhD;  Ivett Pina, PhD;  Yuri Peterson, PhD;  and Catherine Mills, Ph.D. Photos by Sarah Pack.
Research team members (left to right): Kathleen Garrabrant; Patrick Woster, PhD; Ivett Pina, PhD; Yuri Peterson, PhD; and Catherine Mills, Ph.D. Photos by Sarah Pack.

Using resources provided by the MUSC Drug Discovery Core, the team tested the new inhibitors alone and together with bortezomib in neuroblastoma cells with abnormally high levels of MYCN. When used together, the new inhibitor and bortezomib were much more potent killers of these cancer cells than when either was used alone.

“Our studies are the first to show that LSD1 inhibition is a viable strategy to target high-risk MYCN-amplified neuroblastoma,” Woster said.

“Drug development in anticancer therapies is shifting from single toxic agents to specific combinations customized according to patient genetics. By using these combination therapies, we can increase the positive effect while limiting the negative effects of anticancer agents such as bortezomib.”

— Dr. Yuri Peterson

Several LSD1 inhibitors are in clinical trials for solid tumors. However, few of them interact with LSD1 reversibly. Irreversible drugs bind to their targets and never separate, producing side effects related to toxicity.

“You can think of reversible and irreversible drugs and how they interact with a target protein in terms of a handshake,” Mills said.

“At the end of the handshake, reversible drugs allow both parties to take their hands off and go about their business. However, with irreversible drugs, their hands stay glued together,” he explained. “Can you imagine going about your day with your hand stuck to another person’s hand? You would lose the function of that hand. Likewise, you lose the function of the protein that is attached to the irreversible drug, causing toxic side effects.

The study findings suggest that the combination of a reversible, less toxic LSD1 inhibitor and bortezomib could pack an especially potent anti-cancer punch.

The next steps are to adjust the inhibitor to make it even more effective against high-risk neuroblastoma when combined with bortezomib.

“We plan to optimize the structure of our LSD1 inhibitor to increase its potency against LSD1 and hope it will produce an even greater synergistic effect,” Woster said. “We also hope to test this combined approach in many other cancer types with an increase in MYCN.”

Reference

Mills CM, Turner J, Pina IC, Garrabrant KA, Geerts D, Bachmann AS, Peterson YK, Woster PM. Synthesis and evaluation of small molecule inhibitors of LSD1 for use against MYCN-expressing neuroblastoma. Eur J Med Chem. 2022 Dec 15;244:114818. doi: 10.1016/j.ejmech.2022.114818.

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