When 9-year-old Aspen Tangonan was 22 months old, she was diagnosed with stage 4 high-risk neuroblastoma — an aggressive pediatric solid tumor arising from nerve tissues and cells.
At the time, her family had no idea Aspen would become the first pediatric patient successfully treated with a novel drug combination for high-risk refractory neuroblastoma.
Aspen underwent lengthy treatment at St. Luke’s Medical Center in Quezon City, using a protocol developed and shared by St. Jude Children’s Research Hospital doctors and researchers. But six months later, the cancer was spreading again.
Aspen’s care team wanted to try immunotherapy, but the treatment was unavailable in the Philippines. “We trusted our doctors back home; they were the best of the best,” says Stephanie Uy, Aspen’s mom. “But they told us it would be difficult to bring this treatment to the Philippines because they didn’t know if the facility could support it.”
Aspen’s oncologist, Maria Luz Del Rosario, MD, found an opportunity for treatment at St. Jude, located on the other side of the globe in Memphis, TN. St. Jude treats children with cancer and other life-threatening diseases regardless of their race, ethnicity, beliefs or ability to pay. Families never receive a bill from St. Jude for treatment, travel, housing or food, so they can focus on helping their child live, regardless of the duration or the cost of care.
“When they told us that everything will be free, it was like a thorn was taken away. At first it’s unbelievable. We didn’t expect anything like this. We were so grateful,” said her dad, Mark.
Connecting across Global borders to access care
Aspen, Stephanie and Mark flew to Memphis in September 2019. For the next three months, the rest of the family stayed in the Philippines while Maria and her parents met with pediatric oncologist Sara Federico, MD, Solid Tumor Division director, Department of Oncology, and other care team members at St. Jude.
By January 2020, Aspen, her parents and her two siblings had fully relocated from the Philippines to Memphis, and Aspen began treatment once again. Federico treated Aspen for relapsed neuroblastoma using different combinations of therapies that stabilized her disease. But she was still a long way from a cure.
Aspen’s best chance at a curative therapy lay in the genomics of her cancer, so Federico requested tumor tissue samples from Maria’s initial surgery in the Philippines for genetic sequencing. When the samples arrived in Memphis, St. Jude researchers identified a germline (inherited) mutation in the BARD1 gene, a finding that gave Federico a new focus point for identifying potential treatments.
A decade of collaborative research in clinical genomics led to the discovery of Aspen’s BARD1 mutation. In 2010, St. Jude and Washington University School of Medicine launched the Pediatric Cancer Genome Project (PCGP), a first-of-its-kind collaboration to analyze the genetic underpinnings of pediatric cancer. Their work resulted in a 2015 New England Journal of Medicine publication that compiled a list of 60 pediatric cancer predisposition gene mutations that became recognized by the oncology community. BARD1 was one of those genes.
Jinghui Zhang, PhD, Endowed Chair of Bioinformatics in the Department of Computational Biology, played a pivotal role in the PCGP by helping to place sequencing findings into a meaningful context. The mutation of the BARD1 gene caused a problem in how the cell repairs its DNA. Cells have mechanisms for repairing DNA damaged by disease or other factors, but when these mechanisms do not work correctly, damage can pile up. Cancer cells accumulate a lot of DNA damage as they grow. If someone with cancer has a DNA damage repair defect, the tumor will not be able to repair the damage, which can ultimately lead to cancer cell death.
Blocking DNA damage repair by targeting genetic variants that affect the process is a potential treatment strategy for some cancers. Poly (ADP-ribose) polymerase (PARP) inhibitors act on mechanisms in the homologous recombination deficiency pathway and were first used as treatment in adult breast cancer, targeting BRCA1/2 mutations.
But could PARP inhibitors also be used against pediatric cancers to target germline mutations, including BARD1, that introduce DNA damage repair defects?
Research sets Aspen’s next treatment in forward motion
At St. Jude, Elizabeth Stewart, MD, Department of Oncology, had spent years studying potential treatments for Ewing sarcoma, a pediatric solid tumor known to have DNA damage repair defects. In 2014, she published results that demonstrated an Ewing sarcoma preclinical model with a DNA defect had a better therapeutic response to PARP inhibitors when the PARP inhibitors were used in combination with chemotherapy.
Due to Stewart’s work, Federico recognized an opportunity to evaluate this combination therapy approach in other solid tumors with DNA damage repair vulnerabilities. Federico developed a phase 1 clinical trial, BMNIRN, to determine the safe and effective dose of PARP inhibitors to use when given in combination with chemotherapies for pediatric patients with recurrent or treatment-resistant solid tumors.
Federico wrote a new treatment protocol specifically for Aspen. She began treatment with the PARP inhibitor talazoparib and the chemotherapy irinotecan. The cancer in Aspen’s bone marrow quickly responded. She was able to stop chemotherapy after six cycles of treatment, but she continued to receive the PARP inhibitor. She also received radiation therapy for three bone lesions, all of which responded successfully.
When Aspen responded to treatment, she was the first child with refractory high-risk neuroblastoma to have a durable response to a PARP inhibitor and chemotherapy combination. She has been completely off therapy since October 2021.
The success of Aspen’s treatment shows the potential not only for PARP inhibitors as targeted treatments in pediatric refractory solid tumors but for the use of clinical genomics as part of regular clinical care.
Beyond Aspen’s success — moving forward, not stopping
“I’m thrilled by these results because it’s so rewarding for me to see Aspen cured of her disease due to the findings from clinical genomics,” says Zhang. “This is one of the most rewarding projects I’ve ever participated in.”
As data analysis capabilities continue developing, Zhang sees a future for clinical genomics that integrates germline and somatic variant data into therapeutic decision-making. Aspen’s case, published in 2024 by the New England Journal of Medicine, stands as a first-of-its-kind feat in pediatric oncology and clinical genomics. But it will not be the last.
Researchers continue to lead clinical trials of targeted therapies for difficult-to-treat solid tumors, using what they learned from clinical genomics and Aspen’s care to inform the next generation of studies.
While the science advances and research continues, Aspen and her family revel in a life without treatment. She has been healthy and off treatment for over three years. The family still comes to St. Jude for checkups every six months to monitor the disease and mitigate any treatment-related symptoms that may arise.
Aspen Tangonan wants to continue to be a girl “who travels the world.” For a family whose only direction was forward as they traversed the globe in search of a cure, anything seems possible.