by Dr. C.H. Weaver M.D. ASCO 2021 Update
When combined with an already FDA-approved chemotherapy, a novel agent developed by researchers at Georgetown Lombardi Comprehensive Cancer Center, appears to halt the ability of Ewing sarcoma to grow and progress.
The agent, known as TX216 targets the most common cancer causing mutation in Ewings, a fusion of two genes called EWSR1 and FLI1. FLI1 is part of a group called ETS genes, and when EWSR1 fuses with FLI1, an abnormal transcription factor protein is created that interacts with DNA in a way that causes cells to grow abnormally and develop cancer in the bone or soft tissue. TK216 is a novel inhibitor of ETS proteins and work by interrupting the interactions between this abnormal protein and the genes that drive the cancer’s growth.
Reports released at ASCO 2021 suggest that almost half of the patients treated with TK216 experienced clinical benefits – either complete response or stable disease – and two patients achieved a complete remission with no evidence of recurrence for over one and two years.
The initial findings on TK216 were, published October 2018 in the journal Science Signaling (Inhibition of the oncogenic fusion protein EWS-FLI1 causes G2-M cell cycle arrest and enhanced vincristine sensitivity in Ewing’s sarcoma), tests a combination of YK-4-279, the compound developed at Georgetown, with vincristine in laboratory and mice studies. Vincristine is one of the chemotherapy drugs now used to treat Ewing sarcoma.
“Each of the two drugs impacts the cancer cell’s ability to survive, but they do it in a way that magnifies their effectiveness compared to if they were used alone. It’s like a left hook followed by an uppercut,” says the study’s senior investigator, Jeffrey Toretsky, MD, a pediatric oncologist and researcher at Georgetown Lombardi.
In the United States, about 500 children and young adults are diagnosed with Ewing sarcoma annually. Between 60 to 70 percent of patients survive more than five years, but with many late effects from treatment. Patients with Ewing sarcoma are currently treated with a combination of five different chemotherapy drugs, which often damages nerves and few treatments lead to a cure when the cancer progresses, Toretsky says.
Ewing sarcoma is caused by the exchange of DNA between two chromosomes. The resulting EWSR1-FLI1 gene produces a fusion protein, EWS-FLI1, responsible for cancer’s growth. In 2006, Toretsky and his team discovered that the fusion protein binds to another protein, RNA helicase A (RHA), which is important for cancer progression.
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YK-4-279 directly inhibits EWS-FLI1. Toretsky’s work on YK-4-279 led to the eventual development of TK216, a first-in-class small molecule that is now being studied by Oncternal Therapeutics in patients with relapsed or refractory Ewing sarcoma.
In this study, Toretsky led a team of researchers that tested 69 different anti-cancer drugs to find an agent that would work synergistically with YK-4-279. They discovered that together, the drugs produce a “microtubule catastrophe” in Ewing sarcoma cancer cells.
Microtubules are tube-like structures that help cells keep their shape and act like highways that transport cellular proteins. They also pull apart chromosomes when they divide, and it is this action that is particularly affected by the drug combo, Toretsky says.
“Cancer needs to grow, and to do that, the cells need to divide and multiply. This is the step both drugs target, but in different ways,” he says.
- Zöllner S, Selvanathan S, Graham G, et al. Inhibition of the oncogenic fusion protein EWS-FLI1 causes G2-M cell cycle arrest and enhanced vincristine sensitivity in Ewing’s sarcoma. Sci. Signal. 03 Oct 2017:Vol. 10, Issue 499, eaam8429. DOI: 10.1126/scisignal.aam8429