Exploiting Aryl Hydrocarbon Receptor (AhR) as a Novel Therapeutic Strategy in MYCN-Amplified Neuroblastoma
Project Goal: Our studies are expected to identify AhR antagonists as a novel treatment option for high-risk neuroblastoma patients with MYCN amplification.
Institution: University of Buffalo and Roswell Park Comprehensive Cancer Center
Researchers: Kanita Chaudry
Year Awarded: 2022
Type of Childhood Cancer: Neuroblastoma
Neuroblastoma is a deadly childhood cancer affecting cells of the developing nervous system. Despite intensive therapies, roughly 50% of patients with high-risk neuroblastoma die from progressive disease. Therefore, new treatment options are urgently needed. MYCN is a major driver of neuroblastoma disease progression and is genetically amplified in approximately 40- 50% of high-risk neuroblastoma patients. However, there are no current drugs that can inhibit MycN directly. Research efforts are therefore focused towards developing strategies to indirectly inhibit MycN expression and function. Targeting the metabolic function of MYCN-amplified neuroblastoma cells is a promising therapeutic approach. We have identified the aryl hydrocarbon receptor (AhR), a transcription factor, as a novel therapeutic target in MYCN-amplified neuroblastoma. Our preliminary findings show that AhR promotes tumor growth and changes the metabolic function of MYCN-amplified neuroblastoma cells. We found that treatment with an FDA-approved AhR antagonist, clofazimine (CLF), inhibits neuroblastoma growth and lowers MycN expression. CLF is orally given, is safe with minimal toxicity, and already approved for use in children, thus representing a potential and promising new therapy for high-risk neuroblastoma patients. In this proposal, we plan to test a panel of clinically translatable AhR antagonists in pre-clinical models that can be easily repurposed for the treatment of MYCNamplified neuroblastoma. We will also study how AhR alters the metabolic function of cells, with the goal of developing new combination therapies for the disease. Our studies are expected to identify AhR antagonists as a novel treatment option for high-risk neuroblastoma patients with MYCN amplification. If successful, these agents will be tested further in human clinical trials. We will also gain a better understanding of how AhR drives MYCN-amplified neuroblastoma disease progression by altering metabolic function and how this can be exploited therapeutically in novel combination treatments.