Sept. 13, 2024 – In his care of children with high-risk leukemia, the charge to “first, do no harm” weighs heavily on Jay Sarthy, MD, PhD. The overriding goal of the Seattle Children’s hematologist-oncologist is, of course, to cure kids. He knows, however, the lifesaving treatments often come with prolonged, toxic side effects. But, with the help of international collaborators, the drive of his lab team at Seattle Children’s Research Institute’s Ben Towne Center for Childhood Cancer Research and a bit of good luck, he’s poised to launch clinical studies with a less punishing chemotherapy still able to kill cancer.
Though cure rates for childhood cancers have risen significantly in recent decades, studies have found more than 95% of childhood cancer survivors will have a significant health-related issue by the time they are 45 years old.
Researchers are increasingly learning how cancer treatments reshape the growth and development of young bodies. For instance, the Childhood Cancer Survivor Study found young cancer survivors are 15 times likelier to develop congestive heart failure and are seven times more likely to die prematurely from cardiac causes, when compared with the general population.
“The potential impact of less-toxic therapies in pediatrics is huge because many children survive their cancer but then suffer the effects of long-term toxicities of the chemotherapy they've received,” said Dr. Sarthy, who is also an assistant professor in the Department of Pediatrics at the University of Washington School of Medicine and an affiliate investigator at Fred Hutchinson Cancer Center. “If we can reduce toxicity without reducing efficacy, we will impact decades of life in our population.”
‘A Promising Agent’
A class of compounds known as anthracyclines, which occur naturally in Streptomyces bacteria, are potent chemotherapies. Anthracyclines are used to treat 1 million cancer patients each year, particularly those with leukemia and breast cancer.
But one anthracycline, aclarubicin, has never been available in the U.S. due to medical economics, Dr. Sarthy said. As a natural product, it wasn’t patentable when the compounds were first identified and tested in the ‘70s and ‘80s.
In Asia, however, where patients buy prescribed chemotherapies directly from pharmacies and bring them to the hospital to be administered, aclarubicin is widely used because it’s inexpensive and is considered safe and effective.
“One thing we can do to really help patients with cancer is to make chemotherapy safer without reducing its effectiveness. I believe this therapy has the potential to keep children alive and healthy not only today but throughout adulthood, cancer free.”
“Our Chinese colleagues report aclarubicin is popular because patients see what it does. They know it’s effective and they're not going to be debilitated from the therapy,” Dr. Sarthy said.
Promising early work from Dr. Sarthy’s lab and colleagues supports that assessment. In unpublished findings in a small-animal model of high-risk leukemia, the researchers found aclarubicin kills cancer cells more effectively and safely than doxorubicin, a common chemotherapy in the U.S.
“We showed you can give this drug at the highest levels ever administered, and we had 100% survival in the model. It just shows how promising it could be,” he said.
Dr. Sarthy and others believe the drug may prove ideal for frontline treatment of pediatric cancers due to its reduced potential to cause long-term effects such as heart problems, infertility and secondary cancers.
Fruit Fly Molecular Insights
The early data, while exciting, have not surprised Dr. Sarthy. Over a decade ago, as a postdoctoral fellow in the Fred Hutchinson Cancer Center lab of molecular biologist Steven Henikoff, PhD, Dr. Sarthy studied variants of chemotherapies, including aclarubicin, in fruit fly cells to better understand the fundamental mechanisms of the drugs’ effects on DNA.
“When I saw what these drugs were doing in fruit flies, I asked, ‘Why don't we use these in patients?’ And Steve said, “I don't know why. We should.’”
Dr. Henikoff’s team published this research in 2013 explaining how, at a molecular level, these drugs disable cancer. Across the world, a team in the Netherlands led by immunologist Jacques Neefjes, PhD, was on the same quest and published similar findings.
They observed the drugs, as expected, killed rapidly dividing cancer cells by blocking an enzyme the cells need to untangle and repair DNA as they replicate. But surprisingly, both research groups found doxorubicin also kills cancer cells by dislodging histones, the spherical proteins that DNA coils around like a spool to form a structure known as chromatin. Chromatin controls how genes are switched on and off.
The cardiotoxic effects seen with doxorubicin were linked to DNA damage. But aclarubicin kills cancer cells by only damaging chromatin, not DNA. This suggests that anthracycline variants acting primarily through chromatin damage may allow successful treatment of cancer patients while improving the quality of life of cancer survivors.
The researchers recently published a review article in Trends in Cancer, outlining their ongoing research into chromatin and how to maximize the impact of chromatin-damaging drugs in cancer care.
Global Collaborations for Cancer Breakthroughs
Dr. Sarthy, now directly collaborating with Dr. Neefjes’ team and colleagues in China, is planning to develop aclarubicin clinical trials for Seattle Children’s and Fred Hutchinson.
“My lab understands drug chemistry and with our basic biology focus, we understand how these drugs work in the body,” he said. “As a clinician who uses cancer medicines in the clinic and has seen the toxicities of current chemo, I also know which patients to prioritize for them.”
He is working to register the drug with the Food and Drug Administration; once approved — which is expected to happen quickly since aclarubicin was deemed safe in an earlier, unrelated U.S. clinical trial — he plans to import the drug from China for testing and use data from Chinese oncologists to illuminate dosing and cancer targets.
The biggest barrier to aclarubicin’s use in the U.S. is that it is not patentable. While this means that it costs pennies compared to newly developed agents, the lack of industry investment makes it harder to get funding for clinical trials. Dr. Sarthy said he’ll need philanthropic support to run the studies. “We’ll start with a small trial to show the drug is safe. And then we’ll want to do consortium trials to see if the way that the drug is dosed in China works well here, and if it works better combined with other agents,” he said.
Harnessing Diverse Expertise with Team Science
While waiting to clear regulatory requirements, Dr. Sarthy is working to further understand aclarubicin’s mechanism of action with the teams of Beth Lawlor, MD, PhD, and Mignon Loh, MD, in the Ben Towne Center, as well as with the Center for Developmental Biology and Regenerative Medicine’s Lisa Maves, PhD, and the Norcliffe Foundation Center for Integrative Brain Research’s Aaron Olson, MD.
“We're doing everything from testing aclarubicin in zebrafish to ultimately running clinical trials, and to me, that’s the most exciting thing — being able to study the basic mechanism and then seeing how the drug does in patients,” he said.
Dr. Sarthy credits his lab team for the rapid progress toward clinical trials in cancer patients. “When I joined Steve’s lab, I thought it would take me 20 years to find something that might impact somebody,” he said. “We’ve lucked into an area where we might have some bench-to-bedside impact very quickly.”
He particularly praises the work of lab technician Carli Newman, who tested the drugs in models of leukemia and lymphoma.
The Damon Runyon Cancer Research Foundation recently selected Newman for its highly selective four-person cohort of the Damon Runyon Scholars Program for Advancing Research and Knowledge (SPARK), a one-year, paid intensive cancer research internship program for post-baccalaureate students who have the potential to become leaders in cancer research.
Dr. Sarthy, himself a former Damon Runyon-Sohn Fellow, encouraged Newman to apply for the program and helped guide her application. This summer, she joined the Fred Hutchinson lab of Christina Termini, PhD, for her internship.
“Carli had lymphoma as a toddler and was treated at Children’s. She suffered toxicities from her treatment, so she was very inspired by this work and motivated to have so much success in the lab in just one year,” Dr. Sarthy said.
For Dr. Sarthy, mentoring others is both a way of paying forward the mentoring he’s received and an investment in the future. He agrees with the perspective of one of his Children’s mentors, Jim Olson, MD, PhD, director of Invent@SC: “Jim says we can make discoveries individually and move therapeutics forward, but the way to impact generations is through training the next set of individuals who are going to make the discoveries.”
Dr. Sarthy said he’s particularly passionate about recruiting young researchers because pediatric cancer research tends to be overlooked.
“We really need to advocate to get trainees to look at pediatric cancer research labs and see the cool things that are happening. When they do, they’ve really been blown away by what we're doing here,” he said. “They also get to meet patients and it just makes our work so much more impactful. Even when our experiments are difficult, you still know that you're working for a purpose.”
With that purpose in mind, Dr. Sarthy is both excited and impatient to drive more effective chemotherapies to the clinic.
“Nearly all cancer patients today receive chemotherapy, especially all children. Even new immunotherapy approaches, like CAR T cell therapy, are still used with chemotherapy,” Dr. Sarthy said. “One thing we can do to really help patients is to make chemotherapy safer without reducing its effectiveness. From understanding and looking at the data on aclarubicin, it’s safe and effective. Tens of thousands of patients in China have used it. I believe we could offer this therapy and keep children alive and healthy not only today but throughout adulthood, cancer free.”
— Colleen Steelquist
About the Ben Towne Center for Childhood Cancer Research
The physician-scientists at Seattle Children’s Ben Towne Center for Childhood Cancer Research are working hard to improve treatments and outcomes for children with cancer and blood disorders, offering patients the very latest treatments through clinical trials. In the lab, researchers are making advances that are leading to new ways of diagnosing and treating these illnesses. Learn more.