When combined, the new inhibitor and existing therapy enhance each other’s anti-cancer effects MUSC

A research team at the Medical University of South Carolina (MUSC) has developed new compounds that show early promise in the fight against 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 Ph.D. Patrick M. Woster, reports his findings in the European Journal of Medicinal Chemistry.

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

“Our studies are the first to demonstrate that LSD1 inhibition is a viable strategy for targeting MYCN-amplified high-risk neuroblastoma.” — Dr. Patrick Wooster

Such combination therapies are the way of the future, said co-author Yuri Peterson, Ph.D. Peterson is Associate Director of the Drug Discovery Core and Director of Bioenergetic Profiling at MUSC.

“Drug development in cancer therapy is moving away from single toxic agents toward specific combinations that are personalized to the patient’s genetics,” Peterson said. “Using these combination therapies, we can increase the positive effect while limiting the negative effects of cancer-killing agents like bortezomib.”

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

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

The Woster team is well aware of the challenges these children face and is motivated to provide them with new opportunities.

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

Woster and scientists in his lab are investigating compounds that block LSD1 activity. Previous work has shown that LSD1 acts as a scaffold to support and stabilize the protein factor MYCN. This scaffolding helps tumors form and spread, so patients with MYCN-amplified tumors are considered high-risk. The Woster lab wants to disrupt that scaffolding with its new LSD1 inhibitors.

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

Using resources provided by the MUSC Drug Discovery Core, the team tested the new inhibitors alone and in combination 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 used alone.

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

“Drug development in cancer therapy is moving away from single toxic agents toward specific combinations that are personalized to the patient’s genetics. By using these combination therapies, we can maximize the positive effect while limiting the negative effects of cancer-killing agents such as bortezomib.”

— Dr. Yuri Peterson

Several LSD1 inhibitors are in clinical trials for solid tumors. However, few interact with LSD1 in a reversible manner. Irreversible drugs bind to their targets and are never unbound, producing side effects associated with toxicity.

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

“At the end of the handshake, reversible drugs allow both parties to put their hands away and get on with their business. However, with irreversible drugs, their hands remain super-glued,” she explained. “Can you imagine spending your day with your hand glued to someone else’s? He would lose the function of that hand. Similarly, you lose the function of the protein that is irreversibly attached to the drug, causing toxic side effects.”

The study’s findings suggest that the combination of the reversible and less toxic LSD1 inhibitor and bortezomib could have a particularly potent effect against cancer.

The next steps are to adapt the inhibitor to be even more effective against high-risk neuroblastoma in combination with bortezomib.

“We plan to optimize the structure of our LSD1 inhibitor to increase its potency against LSD1 and hope that it can produce an even greater synergistic effect,” Woster said. “We also hope to test this combination approach in several other MYCN-amplified cancers.”

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. December 15, 2022; 244:114818. doi: 10.1016/j.ejmech.2022.114818.

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