The overall objective of these studies is to validate and target the urokinase plasminogen activator system for the treatment of neuroblastoma. The urokinase plasminogen activator (uPA) system has been linked to tumor progression and metastasis in a variety of adult cancers including glioma, breast, prostate, colon, lung, pancreatic, and ovarian cancer as well as myeloma and acute myeloid leukemia. The uPA system is comprised of several proteins that have already proven to be good therapeutic targets in these different tumor types. However, very little is known about the expression of this system in pediatric neuroblastoma. A small study published almost a decade ago demonstrated that uPA and its receptor, uPAR, were frequently found in high-grade neuroblastoma and their presence was associated with poor prognosis in this pediatric patient population. Results from that study and others suggest that uPA and uPAR have the potential to be new therapeutic targets for the treatment of high-grade and recurrent neuroblastoma. Dr. Mazar’s research group has studied the role of uPA and uPAR in tumor progression for almost 24 years with a focus on developing new drugs that target the uPA system for the treatment of cancer. Over the past decade, Dr. Hendrix’s lab has identified biologics and monoclonal antibodies (antibodies designed specifically to only target a certain antigen) that target the Lefty/Nodal members of the TGF-superfamily with unique attributes that allow them to be used in a variety of therapeutic strategies. For example, one of these monoclonal antibodies can hinder tumor cell proliferation and cause cell death in tumor cells and an animal model of melanoma, effects that are further enhanced in combination with chemotherapy. Another can be used for chemotherapy drug delivery directly to tumor cells. Using this portfolio of novel targeted agents from the Hendrix and Mazar laboratories that can potentially combat neuroblastoma, they now plan to evaluate them for neuroblastoma inhibiting activity in vitro and in vivo. Initial studies will involve obtaining neuroblastoma clinical samples for target validation studies to confirm the expression of uPA and uPAR as previously described in the literature. If these results are confirmed, the targeted agents will be evaluated for antitumor activity against several neuroblastoma cell lines in vitro and in several neuroblastoma animal models including patient-derived tumorgrafts that are being developed in vivo. The goal at the end of these studies will be to identify one or more uPA or uPAR targeted agents to advance toward clinical trials for the treatment of high-grade or recurrent neuroblastoma.
|Effective start/end date||11/1/13 → 2/28/16|
- Ann & Robert H. Lurie Children's Hospital of Chicago (#955660 - NU)
- Little Heroes Pediatric Cancer Research Foundation (#955660 - NU)
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