Targeting MYCN-amplified Neuroblastoma Through RORalpha Activation
Cell metabolism is a key aspect of cell biology. Tumors frequently have significant alterations in the specific types of nutrients they require and the way in which they use these nutrients. Certain genes are often associated with driving these critical changes in tumor cell metabolism, which in turn define their aggressive nature. In particular, MYCN, a potent gene that is altered in several pediatric cancers, such as neuroblastoma, is capable of driving defined changes in tumor metabolism.
We have recently discovered a novel approach to oppose these metabolic changes driven by MYCN in neuroblastoma. Our method relies on restoring RORalpha signaling in order to block tumor progression and enhance sensitivity to current therapies. RORalpha is both an important player of numerous metabolic functions and also a key regulator of the circadian rhythm. We propose to: a) further identify and characterize these key molecular MYCN-induced metabolic changes, and b) therapeutically target them with novel RORalpha synthetic agonist ligands, which are under clinical development for metabolic diseases. These studies will enable us to deepen our understanding of neuroblastoma biology and offer new avenues for treating this aggressive and deadly disease.
"The focus of my research is to contribute to a better comprehension of the oncogenic signals that drive neuroblastoma tumorigenesis and to develop tumor-selective and possibly less toxic targeted therapies for high-risk patients. The ALSF Innovation Award will provide crucial support for this important phase of my career development. Importantly, the proposed study will provide critical information to the molecular basis of neuroblastoma, and will advance a deeper and broader understanding of the molecular mechanisms through which MYCN cooperates with the components of the circadian clock in promoting neuroblastoma tumor growth." - Dr. Eveline Barbieri