Neuroblastoma is a pediatric extracranial solid malignancy that arises from the developing sympathetic nervous system. Patients with high risk neuroblastoma face five-year survival rates of only 50%, despite intensive intervention with chemotherapy, surgery, radiation, and immunotherapy. Development of new therapies for neuroblastoma has been challenging due to the paucity of targetable oncogenic mutations. However, recent approval of monoclonal antibody therapy targeting GD2 has credentialed immunotherapy as a new avenue of therapeutic development in neuroblastoma. Conversely anti-GD2 therapy causes significant on-target, off-tumor toxicity due to the presence of GD2 on nociceptive neurons, and relapse due to loss of GD2 expression remains common. To subvert antigen downregulation as a mechanism of resistance, our lab focuses on development of immunotherapy targets that are both differentially expressed and necessary for tumor survival. We recently identified the cell adhesion molecule ALCAM as a potential target for immunotherapy development. ALCAM is a cellular adhesion molecule involved in retinal ganglion development, and high ALCAM expression is a negative prognostic marker in a variety of cancers. Our RNA-sequencing data shows ALCAM is highly expressed in most patient neuroblastomas. Furthermore, an ALCAM-targeted antibody-drug conjugate, CX-2009, is currently in clinical trials for advanced metastatic or locally unresectable adult cancers. This project aims to discover the mechanism of ALCAM overexpression in neuroblastoma, as well as define the contribution of ALCAM overexpression to tumor growth and metastasis. Preliminary data suggests shRNA-mediated ALCAM knockdown induces neurite formation in vitro, a phenotype associated with differentiation. Additionally, ChIP- sequencing data from two neuroblastoma cell lines shows expression ALCAM may be regulated by a network of transcription factors termed the core regulatory circuit (CRC). The CRC is a feed-forward transcriptional regulatory circuit in which each transcription factor regulates the expression of itself and the others, together defining a noradrenergic phenotype characterized by expression of proteins such as tyrosine hydroxylase and dopamine beta hydroxylase. By integrating bioinformatics and molecular biology approaches, we will uncover the mechanism of ALCAM overexpression in neuroblastoma. More broadly, this project will credential ALCAM as a viable target of immunotherapy, as well as an oncoprotein necessary for tumor survival.
This project has to potential to impact public health because it investigates ALCAM, a potential target for immunotherapy in the pediatric cancer neuroblastoma ? importantly, a target for which therapies have already been developed and are undergoing early clinical testing. This research seeks to meet a critical unmet need for development of new therapeutic approaches in neuroblastoma, while also developing the translational research skills in young scientists.
