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Physician Resource

Drug Discovery: A Safer, More Accessible Treatment for Recurrent Pediatric T-ALL

Close to 90% of pediatric patients with acute lymphoblastic leukemia (ALL) — the most common pediatric malignancy — recover after receiving conventional therapy. However, refractory or relapsed ALL is the second most common cause of cancer-related death among children in the U.S. This is why UVA Children’s pediatric oncology physicians and researchers have dedicated themselves to finding better options to treat this disease. The good news: they’re making headway. One treatment showing promise is a new drug designed to block a key determinant of T-ALL cell survival. 

Recurrent ALL: A Formidable Foe

Although B-cell ALL and the more aggressive and higher-risk T-cell ALL are both highly treatable today, problems arise when these cancers don’t respond to initial treatment or recur after what appeared to be successful treatment, says Michael Engel, MD, PhD, division chief for UVA Pediatric Hematology/Oncology, professor of biochemistry and molecular genetics and vice-chair for pediatric research at UVA Children’s. 

Survival stats are improving, but remain pretty dismal after ALL recurrence. Only around 25% of pediatric patients survive with modern therapy, according to Engel. 

“Patients with recurrent T-ALL are really fighting an uphill battle, and we shouldn’t be surprised, really," says Engel. "These leukemia cells arise from cells destined to form our adaptive immune system. Under normal circumstances, these cells are designed to learn about the outside world through their interactions with it, then to protect us from it for the rest of our lives. They are hard-wired to survive and adapt, which makes them a formidable foe. It’s actually amazing we’re able to treat lymphoid leukemias at all.” 

Yet, we are making progress. Engel and his team are leading the charge to advance a new drug that aims to make the treatment of T-ALL even safer, more effective and more accessible worldwide.

“Commonly, recurrent lymphoid leukemias like T-ALL are treated with stem cell transplant or other forms of cellular therapy. Those complex treatments require highly advanced medical knowledge and technologies like we have here at UVA, but are not necessarily available to all children around the world,” says Engel.

Medications, on the other hand are portable, and can reach children everywhere. "When we understand what cancer cells need at the molecular level to stay alive, we believe we can target those Achille’s heels to make cancer treatment just as effective, but with fewer side effects,” says Engel.

UVA Discovers Key Target for T-ALL

As you’re aware, we’re long past the days of grind-and-find or randomly testing things to determine whether they have anti-cancer properties. Today, the process of drug development begins with deep knowledge of the underlying biology of a cancer, which informs the identification of druggable targets.

“Cancer cells are clever, but so are we," says Engel. "Technology has advanced to the point where what we can discover about a cancer is truly extraordinary. Cancer cells no longer can hide. We have ways of revealing their secrets.”

For pediatric T-ALL, one of the secrets appears to be a dependence upon an enzyme called lysine-specific demethylase 1 (LSD1). LSD1 is an epigenetic effector, which controls the context in which genes are expressed.

“Try to imagine reading a book without any punctuation marks or capitalization, or where I wrote all the words backwards. All the information is there, but there’s no context, so you could never understand it," explains Engel. "Our genome is composed of approximately 3 billion letters arranged into about 20,000 words. Without context, we have no way to read the words. LSD1 and its partners provide context to our genome so that its genes can be read and the combinations understood."

One of LSD1’s partners, according to Engel, is growth factor independence 1 (GFI1), which regulates expression of a subset of genes that control cell survival. When GFI1 and LSD1 normally partner, they inhibit expression of genes that can trigger cell death. “Blocking LSD1 function at GFI1-regulated genes overcomes this inhibition to trigger T-ALL cell death,” he says.

This is, of course, an abbreviated explanation of a complex discovery years in the making. It is a discovery that allowed Engel and a team of colleagues to develop a small molecule that interferes with the functions of LSD1. This molecule, called SP2577, is being tested as an anti-cancer drug under the trade name Seclidemstat.

“Seclidemstat is a clinical lead compound that came from a computational discovery process, perfected in the laboratory, tested for its ability to kill T-ALL cells and how it does so,” says Engel. “It’s Star Trek kind of stuff.”

A Promising Start for New Cancer Drug

Seclidemstat is currently being studied in patients with solid tumors, which is typical for assessing new cancer drugs for clinical use.

“Leukemia trials tend to follow solid tumor trials,” says Engel. “This way, we get to discover how a drug is metabolized, what its toxicity profile is, and gauge its effectiveness without the confounding influence of other drugs administered concurrently. Those are questions we can answer more readily in monotherapy trials for solid tumors.”

The effect of a drug can be more easily measured when treating solid tumors. Also, the process of testing one drug at a time is simpler and safer for solid tumors, which may be multifocal, but still discreetly localized. 

“Pediatric leukemias are, by definition, systemic. So if a new drug lacks efficacy, using it alone might have immediate negative consequences for a patient. Plus, in pediatric leukemias, no drug has ever been shown to be curative as a single agent,” says Engel.

Doctors who have a patient with recurrent leukemia are not likely to seek out a trial to help them that involves only one drug. "History suggests this would not be in the patient’s best interests," says Engel. "However, by understanding the mechanism of action, efficacy, and toxicity profile of a drug in monotherapy, we can develop plans for using it in combination with other drugs to treat leukemias.”

After the solid tumor trial is complete, a future study at UVA Children’s will involve layering Seclidemstat on top of well-accepted reinduction platforms comprised of conventional chemotherapy drugs.

“A clinical trial has been under development for some time so we can test our drug in children at UVA and at other centers around the country as soon as the data supporting this is available,” says Engel. “We’re hoping that by this time next year, we’ll be enrolling patients. We’d like to have around 30 to 50 patients total across multiple participating centers.”

Not How We Treat, How We Care

Ongoing efforts like this by our dedicated team of researchers, doctors, nurses, and specially trained support staff, as well as our partnership with the Children's Oncology Group, allow us to offer the most advanced treatments available to kids with cancer.

“We have several physician-scientists on our team engaged in research informed by our experience with patients. Everyone’s efforts are geared toward improving cancer treatment for kids, both today and in the future,” says Engel. 

However, what makes the pediatric oncology program at UVA Children’s unique goes beyond providing the latest cancer treatments.

“What distinguishes our institution is not the therapy itself," Engel says. "It’s the manner in which it is delivered. We want our patients to feel embraced by our program. We are here to shepherd them through something really hard and come out the other side to have an awesome life with cancer in their rearview mirror. That’s who we are. That’s what distinguishes us at UVA.”

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