Osteopontin-mediated invasion and dissemination in central nervous system lymphom

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DESCRIPTION (provided by applicant): Primary central nervous system lymphoma (PCNSL) is an aggressive brain tumor characterized by invasion and widespread dissemination of lymphoma cells in the CNS. Autopsy studies have shown the presence of lymphoma cells throughout the brain, even in areas which appear normal on imaging scans: hence the term "whole brain disease". The 'whole brain' nature of PCNSL makes it difficult to cure. Our gene expression analysis has shown that osteopontin (OPN) is the most upregulated gene (about tenfold upregulation) in PCNSL compared to non-CNS lymphoma. We have developed excellent in vitro cell models, ex vivo brain slice assay, and novel orthotopic murine CNS lymphoma models to further study the role of OPN in CNS lymphoma. Our preliminary data indicate that OPN mediates proliferation, invasion, and dissemination of B lymphoma cells. We have also identified a novel CNS-penetrating, anti-osteopontin agent, Agelastatin A, with anti- lymphoma activity. Treatment of the B lymphoma cells in vitro with Agelastatin A (AA) significantly diminished cell proliferation and invasion. We have shown that OPN can activate NF?B signaling and interfere with its regulation. Our overarching hypothesis is that OPN mediates CNS tumor growth, invasion and dissemination in PCNSL, and is a molecular target for therapeutic development in PCNSL. We have three specific aims- 1) Test whether OPN mediates growth, invasion and dissemination of B cell lymphoma cells via NF?B signaling. We will elucidate the pathway OPNNF?BB lymphoma cell proliferation and invasion and how OPN activates NF?B signaling 2) Test whether anti-OPN therapy with Agelastatin A reduces tumor growth, invasion and dissemination of B lymphoma in the CNS. We will be testing a novel anti-osteopontin therapy for the first time against a brain tumor in orthotopic CNS lymphoma models. 3) Determine the mechanism by which Agelastatin A downregulates OPN. We will find out if downregulation of OPN by Agelastatin A is through modifications of OPN transcription. In summary, we will be employing state of the art models to study the role of the most upregulated gene (OPN) in PCNSL. Our findings should greatly contribute to better understanding of biology of PCNSL. Positive results will have great implications for other OPN- expressing primary brain tumors such as glioblastoma and astrocytoma. Moreover, there will be many implications for cancer treatment in general as OPN is ubiquitously expressed by many cancers, especially aggressive metastatic cancers. We plan to undertake detailed toxicologic study and development of phase 1/2 clinical trials for PCNSL.