This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Murray JohnstonProteomic Analysis of Apoptotic Mechanisms in CancerNeuroblastoma is the major solid tumor found in infants and is a unique cancer of children. Although tumors that are detected early often regress, the disease is often not detected until the patient is older (above 2 years), and the disease presents as stage 3 or 4 and the prognosis for the patient is poor. These patients are typically treated with aggressive surgery, radiation and chemotherapy in attempts to eradicate the cancer. However, side effects of general cytotoxic chemotherapy are particularly severe for children, and the success rate for treatment of these patients remains poor. Clearly better therapies need to be developed to treat this cancer.We have developed a hypothesis that lysosomal proteases are potentially unique therapeutic targets that can be inhibited to regulate progression of neuroblastoma with limited side effects. We found that inhibition of both cathepsins B and L results in death of neuroblastoma cells by inducing apoptosis. We discovered that the induction of apoptosis is unique to neuroblastoma cells and consequently are pursuing inhibitors of these proteases as potential therapeutic compounds in an animal model of neuroblastoma (a study supported by Nemours). In the present study we propose to determine the mechanism by which this protease inhibition causes selective apoptosis of neuroblastoma cells. These mechanistic studies, coupled with our translational therapeutic studies, are essential to development of a project suitable for NIH R01 funding. We will also use this project to develop novel proteomic technologies and anticipate that this will lead to additional funding opportunities and significantly enhance proteomic capabilities in the State of Delaware.
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