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Taking Aim at AML: The Mission Continues

Discoveries emerging from a lab in Cell and Molecular Biology are now moving into the clinic to help children with an aggressive form of leukemia.

By Amy Wolff Sorter; Photos by Peter Barta and Seth Dixon

Patient Dylan

Gallant gamer

Video game ace Dylan Thomas participated in the VENAML clinical trial, which helped him achieve remission so that he could undergo a second bone marrow transplant for acute myeloid leukemia.

Thirteen-year-old Dylan Thomas used to spend hours executing secret missions, infiltrating enemy lines and proving his valor through action-adventure video games. When he wasn’t dashing through battlefields or vanquishing the forces of evil, he was embroiled in a battle with an even more insidious adversary: a particularly aggressive form of acute myeloid leukemia (AML).

Nearly two years ago, Dylan underwent two grueling rounds of chemotherapy and a bone marrow transplant at a North Carolina hospital. Eventually, his leukemia returned. A second transplant held his only hope for a cure.

Dylan’s doctor suggested that he consider a new clinical trial, called VENAML, at St. Jude Children’s Research Hospital. The study features a drug called venetoclax, which has shown promise in treating adults with leukemia.

A dramatic response

In August of 2017, Dylan enrolled in the clinical trial.

“When we arrived, Dylan had a tumor on his leg, and cancer had infiltrated into his sinuses,” explains his mom, Cloie Thomas, RN. “It was starting to spread down his throat. He could barely speak. But after the third day of taking venetoclax, he was talking again. Within a week, it was like the tumor in his leg completely melted away.”

Cloie says the treatment was much less traumatic than the chemotherapy Dylan had previously undergone.

“Venetoclax got his disease to the lowest point it had been since the day he was diagnosed,” she says.

By October, Dylan had been in remission long enough to undergo a second transplant.

Jeffrey Rubnitz, MD, and Joseph Opferman, PhD

Dynamic duo

Laboratory researcher Joe Opferman, PhD, has joined forces with clinician Jeffrey Rubnitz, MD, PhD, to find a way to cure AML that has relapsed or is difficult to treat.


Bold collaboration

The drug that helped Dylan achieve that remission has been a focus of the lab of Joe Opferman, PhD, of St. Jude Cell and Molecular Biology.

At St. Jude, the paths and goals of laboratory and clinic often merge to improve patient outcomes. Basic-science discoveries Opferman made in his lab have recently moved into the clinic through the VENAML study.

Opferman joined forces with Jeffrey Rubnitz, MD, PhD, of St. Jude Oncology, for the study, which launched in July 2017. It marks the first time Opferman and Rubnitz teamed up to bring lab results into the clinical setting.

Assessing the foe

Pediatric leukemia isn’t a singular disease. The most common is acute lymphoblastic leukemia, or ALL. This disease generally responds well to treatment.

But AML is different.

This leukemia has many different subtypes and is more difficult to treat. Fewer children are diagnosed with the disease, and fewer drugs are available to combat it.

“We’ve been stuck at a 70% survival rate for the past 10 to 15 years,” Rubnitz says, “so we need to find new therapies for AML.”

We’ve been stuck at a 70% survival rate for the past 10 to 15 years, so we need to find new therapies for AML.

Jeffrey Rubnitz, MD, PhD


Call of duty

For many years, Opferman has been studying how certain proteins enable cancer cells to evade death—and how to obstruct that process.

His particular interest is in the MCL1 protein and the BCL2 family of proteins. Expression of the BCL2 protein is often elevated in hard-to-treat leukemias, including AML. Opferman’s research has been instrumental in testing venetoclax, a BCL2 inhibitor.

To pinpoint which proteins boost cancer cells, he uses another technique, called BH3 profiling.

“It’s a rapid way to take a mixture of cancer cells and assess which pro-survival molecule it’s addicted to,” he says. “By knowing that, you could postulate that if you added an inhibitor of that specific family member, then you would get a therapeutic benefit.”

Using this method, it’s possible to find out whether a certain cancer depends on BCL2 for survival.

“If you find that a cancer cell is supported by BCL2,” Opferman says, “you can predict that it would respond well to something like venetoclax.”

Joseph Opferman, PhD

Triumphs in the lab

Joe Opferman, PhD, of St. Jude Cell and Molecular Biology, has spent years studying how certain proteins enable cancer cells to evade death—and how to obstruct that process. Discoveries he made have recently moved into the clinic.

The one-two punch

Another important aspect of Opferman’s research involves combining new therapies with existing chemotherapy. Many cancer treatments rely on combination therapies. The benefits are that different agents attack various pathways in the same cancer cell.

“The more stress you put on cells from different pathways, the less chance that the patient ends up resistant to a single drug,” he says.

Venetoclax is the first FDA-approved drug targeting the BCL2 protein in cancer cells. Because the drug had not yet been approved for use in childhood leukemia, the next logical step was to introduce venetoclax to children who have undergone standard chemotherapies for AML and have relapsed.

That’s where the clinician stepped in.

Joining forces

Rubnitz learned about Opferman’s research when the latter made a presentation about how inhibiting the BCL2 protein might reduce cancer development. Rubnitz knew there had been long-term efforts to inhibit BCL2 and related proteins. He thought the relatively new drug venetoclax might be useful in targeting AML among children.

The resulting clinical trial, VENAML, is a two-phase trial. The first phase tests the safety of venetoclax, when combined with a standard chemotherapy regimen.

Patients in the study have AML that never responded to treatment or that returned after receiving standard therapy. Rubnitz expects up to 30 children to participate in the first phase. The study’s second phase will roll the drug out to a larger group of children.

But Rubnitz and Opferman have even higher aspirations.

Inspiration and determination

The eventual plan is to collect a sample from a patient with relapsed AML and send it to Opferman and his lab.

“He can then tell us, ‘This patient is likely to respond to venetoclax,’ or ‘This patient would not,’” Rubnitz says. “We’d use venetoclax in patients Joe predicts would respond well to it.”

The hope, Rubnitz goes on to say, is that venetoclax, or a similar drug, could one day be used in patients newly diagnosed with AML, rather than only for those who relapse.

The VENAML trial helped Dylan achieve remission so he could undergo a second bone marrow transplant. But sadly, the cancer cells returned a few months after transplant, and Dylan eventually lost his valiant battle.

Heartbreaking losses like these make Opferman and Rubnitz even more determined to find a cure for this insidious disease.

The ultimate goal

Opferman says he envisions a rapid screening system that would allow clinicians to predict responsiveness to specific drugs.

“I think in the next five to 10 years, we’ll have a broader palette of drugs to use, so that you could tailor a given therapy based upon how the cells are in the patient,” he says. “You could say, ‘Aha, this patient is very MCL-1 dependent, so we’ll add this drug to the standard chemo versus that drug.’”

The long-term goal is to be agile in tailoring that treatment.

“If the patient initially responded well to the venetoclax and had a BCL2-dependent BH3 profile, but then had a recurrence later, we could check to see if the cells that recurred had changed their addiction,” Opferman explains. “Are they now dependent on a different protein for their survival? Then we could plug in other drugs as necessary.”

One of the cool things about St. Jude is that you are here to improve treatments and cures for patients. For a basic scientist like me, being involved in a clinical trial is as close as you can get to doing that.

Joe Opferman, PhD


Making a difference

Both researcher and clinician emphasize that the trial is in its early days. Still, the first step is to proceed with VENAML, centered on the only approved BCL2 drug.

“One of the cool things about St. Jude is that you are here to improve treatments and cures for patients,” Opferman says. “For a basic scientist like me, being involved in a clinical trial is as close as you can get to doing that. I’m excited about it, because it obviously brings us that much closer to making a difference.”

Learn more about the VENAML clinical study

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