Osteopontin-mediated invasion and dissemination in central nervous system lymphom

描述（由申请人提供）：原发性中枢神经系统淋巴瘤（PCNSL）是一种侵袭性脑肿瘤，其特征是淋巴瘤细胞在中枢神经系统的侵袭和广泛传播。尸检研究表明，淋巴瘤细胞遍布整个大脑，甚至在成像扫描中显示正常的区域也存在淋巴瘤细胞：因此称为“全脑疾病”。PCNSL的“全脑”特性使其难以治愈。我们的基因表达分析表明，与非中枢神经系统淋巴瘤相比，骨桥蛋白（OPN）是PCNSL中上调最多的基因（上调约10倍）。为了进一步研究OPN在中枢神经系统淋巴瘤中的作用，我们建立了优秀的体外细胞模型、离体脑切片实验和新型原位小鼠中枢神经系统淋巴瘤模型。我们的初步数据表明，OPN介导B淋巴瘤细胞的增殖、侵袭和传播。我们还发现了一种新的穿透中枢神经系统的抗骨桥蛋白药物，Agelastatin a，具有抗淋巴瘤活性。体外用Agelastatin A （AA）处理B淋巴瘤细胞可显著降低细胞增殖和侵袭。我们已经证明OPN可以激活NF？B信号并干扰其调节。我们的总体假设是，OPN介导PCNSL中中枢神经系统肿瘤的生长、侵袭和传播，并且是PCNSL治疗发展的分子靶点。我们有三个具体目的：1)测试OPN是否通过NF介导B细胞淋巴瘤细胞的生长、侵袭和播散？B信号。我们将阐明通路OPNNF？BB淋巴瘤细胞的增殖和侵袭以及OPN如何激活NF？2)检测Agelastatin A抗opn治疗是否能抑制B淋巴瘤在中枢神经系统的肿瘤生长、侵袭和传播。我们将首次在原位中枢神经系统淋巴瘤模型中测试一种新的抗骨桥蛋白治疗脑肿瘤的方法。3)确定Agelastatin A下调OPN的机制。我们将发现Agelastatin A下调OPN是否通过修改OPN转录。总之，我们将采用最先进的模型来研究最上调基因（OPN）在PCNSL中的作用。我们的研究结果将有助于更好地了解PCNSL的生物学。阳性结果将对其他表达OPN的原发性脑肿瘤如胶质母细胞瘤和星形细胞瘤具有重要意义。此外，由于OPN在许多癌症，特别是侵袭性转移性癌症中普遍表达，因此这将对癌症治疗产生许多影响。我们计划对PCNSL进行详细的毒理学研究和1/2期临床试验的开发。

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.