Kanita Chaudhry

Kanita Chaudhry.

Kanita Chaudhry

Kanita Chaudhry

Thesis Title

Novel Tumor-Promoting Functions of the Aryl Hydrocarbon Receptor

Research Publications Overview

Research Description

Neuroblastoma is the most common extracranial solid tumor in children. MYCN amplification is detected in almost half of neuroblastoma high-risk cases and is associated with poorly differentiated tumors, poor patient prognosis and poor response to standard-of-care therapies, including retinoic acid. Here, we identify the aryl hydrocarbon receptor (AhR) as a transcription factor that promotes the growth and aggressiveness, and suppresses the differentiation, of MYCN-amplified neuroblastoma. A neuroblastoma specific AhR transcriptional signature reveals an inverse correlation of AhR activity with outcome of neuroblastoma patients, suggesting that AhR activity is critical for disease progression. AhR modulates chromatin structures, reducing accessibility to regions known to be responsive to retinoic acid. Genetic and pharmacological inhibition of AhR results in induction of differentiation. Importantly, AhR antagonism with clofazimine, an FDA-approved drug that has been safely used in children, synergizes with retinoic acid in inducing differentiation both in vitro and in vivo. Thus, we propose AhR as a novel target in MYCN-amplified neuroblastoma and suggest that its antagonism, in combination with current standard-of-care, may result in a more durable response in patients.

Thesis Advisor