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A team effort delivers a new tool for fighting neuroblastoma

Sholler founded the Beat Childhood Cancer Research Consortium, a worldwide network of more than 50 hospitals dedicated to discovering new therapies for children with cancer.Credit: Penn State College of Medicine

The first time that paediatric oncologist Giselle Sholler met Will Lacey’s family, they grappled with a painful decision. Despite extensive treatment, Will’s neuroblastoma — an aggressive tumour affecting the peripheral nervous system — had relapsed. His father, Pat, was told they were out of options and needed to consider hospice and palliative care for their toddler son.

But Pat Lacey glimpsed hope in the work that Sholler was conducting to treat neuroblastoma, and enquired about the possibility of getting Will into one of her clinical trials. “He said, ‘I just want to see if there are any other possibilities’,” recalls Sholler. This encounter back in 2007 set into motion a remarkable collaboration between patients, their families, physicians and researchers that would propel a promising drug known as difluoromethylornithine (DFMO) through the clinical trial process and into the hands of paediatricians worldwide.

As of December 2023, DFMO won approval from the US Food and Drug Administration (FDA) for high-risk neuroblastoma as a maintenance therapy, and former patient Will Lacey is now a healthy college student. To continue her research, Sholler brought her team to Penn State College of Medicine, Hershey, Pennsylvania, in September 2023. There, and in her new role as chief of paediatric haematology/oncology at Penn State Health Children’s Hospital, she sees opportunities to replicate this success story for other rare and challenging paediatric malignancies. “This just opened the door for us to do so many more clinical trials,” she says.

A lingering menace

The earliest signs of neuroblastoma vary widely and can be hard to differentiate from more mundane childhood grievances — for example, constipation, limb pain or sporadic breathing problems.

Some cases can readily be addressed by surgery, but Sholler estimates that 400 out of the 700 children who develop this cancer each year in the United States will be diagnosed with advanced, ‘high-risk’ neuroblastoma — an aggressive, metastatic form of the disease. Yatin M. Vyas, chair of the Department of Pediatrics at Penn State College of Medicine, and vice president at Penn State Health Children’s, notes that this malignancy has historically been exceedingly difficult to treat. “You had a small chance of survival for metastatic stage 4 neuroblastoma, even in the late 1980s and early 1990s,” he says, adding that stronger doses of chemotherapy were essentially the only tools available.

A great deal has changed since then, and oncologists now employ a multi-pronged attack against neuroblastoma, combining chemotherapy with surgery, radiation and bone-marrow transplantation. The most recent addition to this armamentarium is an antibody drug, dinutuximab, which recognizes a specific protein on neuroblastoma cells and marks them for destruction by the immune system. This regimen can help extend life but is gruelling for young patients. Sholler mentions that dinutuximab also targets healthy neurons, causing severe pain. “They’re usually on a morphine or hydromorphone drip because it’s excruciating,” she says. “And then, even though they go through all of that treatment, about 40% of kids eventually relapse.”

The prognosis is poor for relapsed patients, and developing new treatment strategies for these children has been a primary focus of Sholler’s neuroblastoma research. In particular, she was interested in mechanisms for going after cancer stem cells. This small but important cell subpopulation is highly treatment-resistant and can single-handedly regenerate entire tumours, even after the remaining malignancy has been eradicated.

Banding together

DFMO can selectively target these stem cells, acting on molecular pathways that drive them into an exhausted ‘senescent’ state in which they can no longer replicate. Sholler has performed animal experiments1 confirming that DFMO can effectively block tumour formation in mice transplanted with neuroblastoma cancer stem cells.

Sholler's research team focuses on the study of DFMO targeting cancer stem cells in neuroblastoma and brain cancers for maintenance therapy.Credit: Penn State College of Medicine

Sholler’s past work garnered support from families, notably the Laceys, who single-handedly funded a 2010 phase I trial for DFMO in children with high-risk neuroblastoma. Despite such trials normally focusing on safety, early evidence of efficacy emerged. And now, three of the 18 children, including Will Lacey, have reached college age.

With the help of a nonprofit — the Beat Childhood Cancer Foundation — founded by the Laceys and three other families, Sholler worked with the FDA to find a way to conduct the necessary trials for approval. But the process was not smooth. Though initial trial results were positive, they did not meet the rigorous standards of the large, randomized controlled trials usually required to win FDA backing.

Given neuroblastoma’s rarity and high mortality rate2, this presented serious logistical and ethical challenges. Sholler recognized that a formal placebo-controlled trial would take far too long to complete. “A lot of kids were going to die,” she says. However, despite initial setbacks, Sholler’s team, in collaboration with US WorldMeds, performed a novel analysis of phase II data compared to an immunotherapy trial3, which gave them the statistical power they needed.

Setting a good example

DFMO is now entering the market as IWILFIN, a product of US WorldMeds. Sholler first connected with this company through its vice president Kristen Gullo, who is also a family member of a paediatric cancer patient. Any patient with high-risk neuroblastoma who partially responds to certain prior therapies, including antibody treatment, will be eligible for this drug to decrease the risk of relapse.

Sholler sees IWILFIN’s approval as a watershed moment for paediatric oncology trials generally. “It was the first time the FDA has ever relied on a single external control,” she says, and this in turn offers a roadmap for other drug-development efforts focused on rare but deadly paediatric diseases.

Fortunately, Penn State Health and Penn State College of Medicine have abundant resources to support such efforts, and Vyas is enthusiastic about building out the hospital’s capacity to develop and conduct innovative oncology clinical trials. “It is urgent for us in paediatric cancer to think outside the box,” he says. “This particular discovery of DFMO ushers in this new era.”

Equipped with funding from Four Diamonds, Vyas has spearheaded the US$24 million Four Diamonds Childhood Cancer Innovation Initiative to support translational research programmes like Sholler’s. He says that recruiting Sholler to Penn State Health and Penn State College of Medicine, and housing the Beat Childhood Cancer Research Consortium within the College of Medicine, was an important step for this initiative. Sholler is already working with colleagues at Penn State Health to move two additional paediatric drug programmes into clinical testing, alongside her own research into novel treatments for other rare cancers.

But the book isn’t closed on neuroblastoma just yet. Even with DFMO, 15% of patients will still relapse4. Sholler is preparing to launch a new trial that combines this drug with a second agent that closes an ‘escape hatch’ that cancer stem cells can potentially use to survive treatment. Sholler concludes: “Until we have no kids relapsing, we can’t stop.”

For more information on Penn State College of Medicine’s research efforts in paediatric cancer, visit their website here


  1. Avequin, T. et al. Cancer Res. 76, 2474 (2016).

  2. Park, J. et al. Pediatr. Clin. North Am. 55, 97–120 (2008).

  3. Oesterheld, J. et al. J. Clin. Oncol. 42, 90–102 (2024).

  4. Sholler, G. et al. Sci. Rep. 8, 14445 (2018).

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