Working to Improve Cure Rates for High-risk Neuroblastoma

After stunning improvements in patient outcomes for most childhood cancers in the latter half of the last century, cure rates have plateaued for many cancers. In particular, children with metastatic solid malignancies continue to have a less than 50 percent chance of survival despite being treated with highly intensive cytotoxic therapies.

Neuroblastoma is a diverse malignancy affecting very young children that arises from the developing sympathetic nervous system. Neuroblastoma is responsible for a disproportionate amount of morbidity and mortality attributable to childhood cancer and is the main focus of the translational research program run by John Maris, MD, a pediatric oncologist at Children’s Hospital of Philadelphia (CHOP) who holds the Giulio D'Angio Chair in Neuroblastoma Research and a National Cancer Institutes Outstanding Investigator Award.

Maris and his team of world-class clinicians and scientists are dedicated to rapidly translating research about childhood cancers from the laboratory to the patient. Their primary motivation is to improve patient outcomes for children with neuroblastoma. This tumor is also an outstanding model of cancer in general, such that discoveries of basic mechanisms of tumorigenesis in neuroblastoma are broadly applicable to other human malignancies.

The Maris Laboratory’s goal over the next several years is to substantively improve cure rates for patients — particularly those with high-risk neuroblastoma where the 5-year survival rate is less than 50 percent — through a multidisciplinary and collaborative research program. The broad goal is to discover the fundamental mechanisms that subvert normal neural development and orchestrate neuroblastoma tumorigenesis, and then to translate this knowledge into patient-specific therapies that will be more effective and less toxic. Their comprehensive approach involves five highly integrated major research efforts.

1. Genetic susceptibility to neuroblastoma. The lab has discovered the majority of neuroblastoma predisposition genes using genetic approaches. Team members will now define the mechanisms by which DNA variation causes malignant transformation, and this will better inform genetic counseling of patients who may have a genetic mutation.
2. Neuroblastoma genomics and clonal evolution. The lab has led the collaborative efforts to define the genomic landscape of diagnostic high-risk neuroblastoma, and now has several efforts to define how the cancer evolves during therapy and becomes resistant, leading to relapse.
3. Neuroblastoma drug development. The Maris Laboratory has utilized genomic data and genetic screens to define oncogenic vulnerabilities, and many of these have been translated to the clinic. The current focus is on defining mechanisms of therapy resistance to both standard-of-care agents and the targeted therapies that are developed. Maris leads the neuroblastoma program of the National Cancer Institute’s Pediatric Preclinical Testing Consortium (PPTC), which this year, along with the Alex’s Lemonade Stand Foundation, announced the release of genomic data for over 270 childhood cancer patient-derived xenograft (PDX) models to the childhood cancer research community. The project was a major collaborative effort among CHOP and nine other institutions. Maris and his team use the PPTC data to inform clinical trials uniquely available at CHOP.
4. Immunogenomics. The lab has used an integrative approach to discover several new immunotherapeutic targets in neuroblastoma and other childhood cancers. The next step is developing antibodies, antibody-drug conjugate and adoptive T-cell therapies to these targets designed to eradicate neuroblastoma safely.
5. Precision neuroblastoma therapies. The team has developed biomarker-directed clinical trials for children with relapsed neuroblastoma, and will continue their efforts in this area both in the relapse and newly diagnosed setting using clinical trials designed to enrich for patients most likely to benefit.

This research program proposes a variety of innovative experimental strategies to uncover basic mechanisms of oncogenesis, cancer evolution, epigenetic adaptation and immune evasion, and is steadfastly translational.