Blocking the Evil Messenger in MYCN-driven High-risk Neuroblastoma
MYCN is a potent cancer-causing gene, and its elevated activity drives the initiation, progression, and treatment resistance of a broad spectrum of childhood cancers. Neuroblastoma is the most common extracranial solid tumor among children, with approximately half of them characterized as high-risk, which spread to distant organs rapidly and result in less than 50% survival rates. Increased activity of MYCN, often resulting from excessive copy number of the gene (i.e., >100 copies instead of normally 2 copies), is a reliable predictor of disease aggression and poor prognosis in high-risk neuroblastoma. Given that MYCN is also needed for normal cell function and the toxicities associated with MYCN inhibition, identification of alternative key contributors that promote tumor aggressiveness could pinpoint therapeutic strategies with minimal toxicities. Through the combined analysis of human patient samples, in-vitro cell culture systems, and zebrafish models of MYCN-driven neuroblastoma that resemble human high-risk disease, we found that MYCN selectively increases the levels of a cellular messenger, referred to as chemokine in the scientific term, to attract T regulatory cells (a type of immune cells) into the tumor microenvironment to suppress anti-tumor immune responses and promote tumor aggression. Elevated expression of this chemokine predicts tumor aggression and poor prognosis among children with neuroblastoma, and its enhanced expression in zebrafish tumor cells promotes neuroblastoma development.
Project Goals:
This project has two major goals: 1) to understand how a newly identified MYCN-regulated chemokine contributes to the communications between tumor cells and their microenvironment to promote immunosuppression and tumor aggression in high-risk neuroblastoma; 2) to evaluate the ability of available drugs targeting this chemokine's function (including an FDA-approved drug for treating other diseases) to restore anti-tumor immune responses and thus serve as novel immunotherapies for high-risk neuroblastoma. The combined analysis of clinical patient samples and therapeutic testing using preclinical mouse and zebrafish models ensure that our studies are directed toward meeting the clinical needs. If successful, our study will uncover effective drug(s), which should be much less toxic than chemotherapy and radiotherapy, for treating high-risk neuroblastoma and perhaps other types of MYCN-driven childhood cancer as well.
Project Update 2024:
MYCN is a potent cancer-causing gene, and its elevated activity drives the initiation, progression, and treatment resistance of a broad spectrum of childhood cancers. Neuroblastoma is the most common extracranial solid tumor among children, with approximately half of them characterized as high-risk, which spread to distant organs rapidly and result in less than 50% survival rates. Increased activity of MYCN, often resulting from excessive copy number of the gene (i.e., >100 copies instead of normally 2 copies), is a reliable predictor of disease aggression and poor prognosis in high-risk neuroblastoma. Given that MYCN is also needed for normal cell function and the toxicities associated with MYCN inhibition, identification of alternative key contributors that promote tumor aggressiveness could pinpoint therapeutic strategies with minimal toxicities. Through the combined analysis of human patient samples, in-vitro cell culture systems, and zebrafish models of MYCN-driven neuroblastoma that resemble human high-risk disease, we found that MYCN selectively increases the levels of a cellular messenger, referred to as chemokine in the scientific term, to attract T regulatory cells (a type of immune cells) into the tumor microenvironment to suppress anti-tumor immune responses and promote tumor aggression. Elevated expression of this chemokine predicts tumor aggression and poor prognosis among children with neuroblastoma, and its enhanced expression in zebrafish tumor cells promotes neuroblastoma development. In the past one year, we have combined the analysis of clinical patient samples and preclinical zebrafish models, providing experimental evidence to support patient relevance and the potential of inhibiting the chemokine to treat high-risk neuroblastoma. For the coming year, we will continue to finish the experiments proposed and apply mouse models for preclinical studies. Our seeks to uncover effective therapeutics that are less toxic than chemotherapy and radiotherapy, for treating high-risk neuroblastoma and other types of MYCN-driven childhood cancer as well.
