Synergistic Differentiation Therapy in Neuroblastoma
Neuroblastoma is the most common cancer in infancy, with advanced-stage patients having a low survival rate. Patients with neuroblastoma cells that more closely resemble normal cells (i.e. differentiated) and with tumors with more connective tissue (i.e. stroma) have a better survival rate. Treatment with the drug retinoic acid, which promotes differentiation, is used clinically in neuroblastoma, but additional differentiation therapies are needed. The neuroblastoma tumor stroma is thought to suppress neuroblast growth by releasing soluble differentiating factors. Here we have provided evidence that a number of proteins, termed proteoglycan co-receptors, are highly expressed in neuroblastoma stroma, and when secreted from these stroma cells can induce differentiation. The clinical drug, heparin, which is used as an anti-coagulation agent in patients, can mimic the effects of these proteoglycan co-receptors, and other agents that modify gene expression can restore expression of these receptors.
Here we propose to investigate whether heparin and its derivatives, as well as agents that increase the expression of these receptors can work together to promote neuroblast differentiation, suppress proliferation and tumor growth in neuroblastoma cells and animal models of neuroblastoma. These studies will define the role of proteoglycan co-receptors in neuroblastoma pathogenesis while investigating the use of heparin derivatives, and agents that increase the expression of proteoglycan co-receptors as novel differentiating agents.