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Alex’s Lemonade Stand Powers 20 Years of Pediatric Cancer Research at CHOP
Over the last two decades, Children’s Hospital of Philadelphia has worked proudly alongside Alex’s Lemonade Stand Foundation (ALSF) on high-risk, high-reward cancer research to save children’s lives.
CHOP’s relationship with the pediatric cancer charity began in 1999, when Liz and Jay Scott traveled from Connecticut to Philadelphia, so their 3-year-old daughter, Alex, could meet John Maris, MD, one of the country’s top pediatric oncologists. Alex joined a clinical trial to test an experimental liquid radiation to treat her high-risk neuroblastoma, an aggressive cancer that starts in the nerve cells and has a survival rate of around 50%.
“She came into that treatment on morphine,” said Dr. Maris, the Giulio D'Angio Chair in Neuroblastoma Research at CHOP. “A day into the therapy, she told her mom she knew the medicine was working, and by the time she left the hospital a few days later, she was out of pain and stopped to shop for the holidays on their way home.”
The family soon moved to Philadelphia, and Alex set a goal: to raise $1 million to help doctors and scientists find a cure for all childhood cancers.
“She was a dynamo,” said Michael Hogarty, MD, an oncologist who also treated Alex at CHOP and has received multiple research grants from ALSF, including funding to study how high doses of a drug called difluoromethylornithine could improve neuroblastoma therapy. “She was absolutely unwavering and always thinking big. She had a vision that’s hard to imagine in such a young package.”
After Alex’s initial experimental therapy at CHOP, she enjoyed a good quality of life for four years, allowing her to welcome a baby brother into the world. However, her disease eventually became resistant to all therapies. Alex died peacefully in August 2004, having reached her $1 million fundraising goal a few weeks earlier.
Today, Alex’s legacy lives on at CHOP and has inspired a nationwide fundraising movement that is celebrating its 20th anniversary this year. ALSF has funded more than 1,500 lifesaving research projects at nearly 150 institutions across North America and Europe.
Filling Research Gaps
CHOP has received approximately $17 million from the foundation through philanthropic support and research grants since its inception. In addition to funding more than 25 projects focused on neuroblastoma, ALSF has supported CHOP research — from basic science to clinical trials — related to finding new treatments for leukemia, gliomas, colorectal cancer, and other cancers.
The foundation has also established Centers of Excellence, such as CHOP’s Center of Excellence in Childhood Cancer Drug Development and Clinical Pharmacology, led by Frank Balis, MD, Director of Cancer Clinical Research, and Ted Laetsch, MD, a pediatric oncologist. The center’s mission is to provide training and research infrastructure to meet the current challenges of drug development.
For Dr. Maris — who is an inaugural member of the ALSF Scientific Advisory Board and helped to design its childhood cancer grant program — the impact of ALSF funding on CHOP research discoveries cannot be overstated.
“ALSF strongly supports high-risk, high-reward childhood cancer research,” Dr. Maris said. “Especially as government funding for research wanes, Alex’s is a huge lifeline to fund new, innovative projects.”
CHOP’s Cancer Center presented Dr. Maris with the foundation’s Pitcher of Hope Award during a ceremony held at CHOP earlier this year. The physician-scientist said he is most proud of the foundation’s commitment to investing in the next generation of physicians and scientists.
One of those early career scientists is Timothy Spear, MD, a Hematology/Oncology Fellow working with Dr. Maris who received an ALSF Young Investigator Award in 2024. His research goal is to test a vaccine that will boost chimeric antigen receptor (CAR) T-cell therapy in children with high-risk neuroblastoma.
“As a young investigator, it can be tough, because you're applying for grants without much of a track record,” Dr. Spear said. “It’s a ceiling that young investigators have to break through. Receiving this kind of funding, along with the incredible mentorship and resources here at CHOP, makes it much easier to apply for funding in the future.”
A Pivotal Discovery: ALK Mutations in Neuroblastoma
One question that Dr. Maris is often asked is whether Alex’s outcome would be different today than it was in 2004.
“For the majority of high-risk patients, unfortunately, the answer is ‘no.’ But for Alex, it is very likely that it would have been,” he said.
Based on postmortem testing of her tumor, CHOP researchers know that Alex’s cancer was driven by a mutation in the anaplastic lymphoma kinase (ALK) gene. Thanks to CHOP-led research discoveries — funded in part by the foundation she founded — Alex’s cancer may have been treated with ALK-inhibitor medication that is available today.
It was Yael Mossé, MD, the Patricia Brophy Endowed Chair in Neuroblastoma Research at CHOP that is co-sponsored by ALSF, who, alongside Dr. Maris, first identified ALK mutations as a major driver of neuroblastoma in 2008. Subsequent research has shown that abnormal ALK changes are present in approximately 25% of newly diagnosed high-risk patients, and that this frequency is higher among patients who relapse.
The discovery in 2008 led Dr. Mossé to receive her first ALSF award, a Reach Grant to study how combinations of ALK inhibitors could stop cancer growth in animal models with neuroblastoma.
“Many foundations don’t see the excitement in funding research conducted in the lab,” Dr. Mossé said. “They want to fund the clinical trial, because that’s where they feel the impact will be. But to get to the clinical trial, you need preclinical research. ALSF has bridged that gap.”
The Reach project paved the way for Dr. Mossé to launch a phase 1 clinical trial in 2015 (the NEPENTHE trial), funded by a $1.5 million Bio-Therapeutic Impact Award. The first part of the project was to show the benefit of performing noninvasive biopsies on every pediatric neuroblastoma patient to determine whether that child had an ALK mutation.
The findings from that research have changed the paradigm of care for neuroblastoma patients around the country, Dr. Mossé said.
“When a child with neuroblastoma suffers a relapse, it is likely that they will have acquired new mutations that would make them eligible to get newer, targeted therapies,” Dr. Mossé said. “We showed that fairly non-invasive, image-guided bone biopsies on children are not only feasible, but necessary to make treatment recommendations and provide children with novel therapeutic options.”
The next phase of the project was to test a second-generation ALK inhibitor in combination with another novel drug in patients with high-risk neuroblastoma who had relapsed or not responded to standard treatment. However, while the trial was in progress, a different ALK inhibitor — a third-generation drug named lorlatinib — was showing significant promise in separate research studies. Dr. Mossé and her team decided to halt the NEPENTHE trial and focus their attention on lorlatinib.
In 2023, a CHOP-led study showed that lorlatinib is safe and demonstrated promising anti-tumor responses in children who were previously destined to die. The findings were published in Nature Medicine and co-authored by researchers at the Winship Cancer Institute of Emory University and the New Approaches to Neuroblastoma Therapy (NANT) Consortium. The trial was funded by the National Cancer Institute and Pfizer Inc., with additional support from ALSF.
In March 2021, Dr. Mossé hit another milestone. She received a $5 million Crazy 8 Award from ALSF to develop new drugs for neuroblastoma and other cancers driven by the oncoprotein MYCN, which has been historically deemed “undruggable.”
“It’s a dominant driver of about half of patients with high-risk neuroblastoma, so this project has really been going after a true cancer therapeutic Holy Grail,” Dr. Mossé said. “This ‘crazy’ idea is what excited Liz and Jay — the potential for big impact.”
One mission of the Crazy 8 projects is to connect “researchers across the globe,” which is why Dr. Mossé teamed up with researchers from around the world, including partners at the San Francisco-based pharmaceutical company, Nurix. The Crazy 8 team has been testing a series of targeted protein drugs called "degraders,” which selectively remove essential oncoproteins, like MYCN, from cancer cells.
As the Crazy 8 project was approaching its final year, Dr. Mossé was inspired to continue this line of research by submitting a proposal for a $25 million Cancer Grand Challenges award from the National Cancer Institute and Cancer Research UK. Liz Scott joined the study team in London as a patient advocate during the in-person interview portion of the Cancer Grand Challenges application process.
In March 2024, Cancer Grand Challenges announced Dr. Mossé’s team as one of five groups chosen to receive funding for their project. They plan to develop targeted protein degraders against five essential oncogenes implicated in the most common, and often lethal, childhood cancers to build evidence for future biomarker-driven clinical trials.
“The fact that we were awarded this grant is both humbling and truly exciting as we expect to impact many children with cancer across the globe,” Dr. Mossé said. “It would not have been possible without ALSF, Alex, Liz, and Jay.”