Defining Optimal Combination Drug Therapies in Neuroblastoma

Background

Neuroblastoma is a pediatric malignancy that arises from embryonic tissues of the autonomic nervous system. It is heterogeneous in its clinical presentation with a number of factors determining the likelihood of being cured. Half of all patients have high-risk disease and are treated with aggressive multi-modal therapy. Almost 50% of the high-risk tumors are resistant to treatment or cause relapse, both killing the child. Thus, there is a need to develop novel therapies that will effectively increase overall survival with less toxicity than chemotherapy. One promising option is to use targeted drugs in combination to treat high-risk neuroblastomas classified by druggable genomic alterations.

A number of potential drug targets in neuroblastoma tumor cells exist. It has been shown that the Cyclin D/CDK4/CDK6/Rb pathway is hyperactive in neuroblastoma. The Maris lab reported that treatment with a small molecule inhibitor of CDK4 and CDK6, LEE011, significantly reduces proliferation in neuroblastoma-derived cell lines via induction of cell cycle arrest. Sensitivity to CDK4/6 inhibition by LEE011 positively correlated with MYCN amplification. Patients with MYCN amplification usually have high-risk disease and suffer worse outcomes. While LEE011 significantly inhibits cell proliferation, there was still slow, steady growth of tumor in vivo. This indicates that single agent treatment is beneficial but not enough.

Project Goal

It remains a priority to identify pathways contributing to resistance to LEE011 to identify novel drug combination strategies. We hypothesize that a screen to identify and validate additional drug targets will yield novel drug combinations that induce synthetic lethality in relapsed neuroblastoma tumors.