Transforming Neuroblastoma Therapy with a Metabolism-Driven Differentiation Program
Michael D. Hogarty, MD
Professor of Pediatrics
Perelman School of Medicine at the University of Pennsylvania
Attending Physician, Division of Oncology
Children’s Hospital of Philadelphia
This proposal focuses on high-risk neuroblastoma, a commonly fatal childhood cancer. Current treatment includes chemotherapy, surgery, stem cell transplant, radiation, immunotherapy, and biotherapy. Outcomes have improved over prior decades, but we still cure only half of these children and survivors suffer debilitating effects of their treatment. We are developing a novel therapy that depletes tumor cells of polyamines, targeting a specific metabolic need. Neuroblastomas behave aggressively due to genetic mistakes that activate MYC genes, and despite 40 years of effort, no drug has been developed to shut MYC off. We studied the building blocks created by MYC and identified polyamines as essential. MYC genes regulate each step of making polyamines, and the chance of a child dying of neuroblastoma is directly proportional to how strongly the polyamine system is turned up in their tumor cells. Our treatment goal is to reduce tumor polyamines and abolish MYC’s effects.
DFMO is an oral drug that turns-off the ODC enzyme that converts ornithine into polyamines. We have shown that the drug slows neuroblastoma growth in mouse models, and the FDA approved DFMO for neuroblastoma therapy in 2023. Notably, this approval is for low-dose DFMO while we only see antitumor activity with high-dose DFMO. We completed clinical trials testing high-dose DFMO with chemotherapy (Phase 1, NANT N1201) or chemoimmunotherapy (Phase 2, COG ANBL1821) in children with neuroblastoma. High-dose DFMO was well tolerated, and some children have remained tumor-free for >6 years despite receiving no additional therapy, which is exceedingly unusual. It is too soon to analyze survival in the Phase 2 trial, but we did not see a higher response rate with DFMO. Polyamines are lowered to about 50% of normal using high-dose DFMO alone and we reasoned that depleting polyamines further would enhance the treatment effect.
To do so, we used high-dose DFMO to turn off ODC while also depleting the nutrient ODC uses to make polyamines. We found it to be exceptionally effective. With no therapy or with low-dose DFMO, all mice die within 20 days. High-dose DFMO alone extends life ~40% but does not cure mice. With DFMO and nutrient depletion, 1/3rd of mice survived >300 days with complete tumor regressions and off therapy, with tumor polyamine reduction to <10% of normal. This activity was confirmed in human neuroblastoma PDX models. We now are using a drug called arginine deiminase (ADI-PEG20) to deplete the polyamine nutrient, this drug is in Phase 3 cancer trials in adults. Our goal is to position this non-genotoxic therapy for use in the maintenance phase of treatment, combined with retinoic acid and GD2-immunotherapy. We have industry partners invested in developing this for clinical use (Polaris/ADI: John Bomalaski, CSO; USWM/DFMO: Bob James, Medial Director) and clinical trials interest within NANT and internationally. Advocacy groups and clinician leaders have called for accelerated progress towards a future that removes routine use of transplant for neuroblastoma, and we foresee delivering a therapy that enhances survival and reduces toxicities to potentially enable that vision.