Role of PLGF in Medulloblastoma Progression and Treatment

描述（由申请人提供）：髓母细胞瘤（MB）是最常见的儿童恶性脑肿瘤。尽管化疗-放疗具有治愈潜力，但三分之一的患者会复发，许多患者会出现毁灭性的治疗诱发的疾病。因此，迫切需要新的治疗目标。我们最近发现，胎盘生长因子（PlGF）是高表达的MB-癌细胞和MB-相关的基质细胞。此外，我们的初步数据表明，分泌音刺猬（Shh）MB细胞诱导基质PlGF的表达在旁分泌的方式。最后，我们发现PlGF阻断显著抑制MB的原位人异种移植物中MB生长和扩散到脊髓。基于这些令人兴奋的初步发现，我们现在提出使用基因工程小鼠模型（GEMM）、人MB细胞系和最先进的成像技术来阐明MB的多种亚型中对抗PlGF治疗的应答机制。我们的长期目标是将这些发现转化为临床治疗MB。在目的1中，我们将剖析通过Shh途径调节MB中PlGF表达的机制，Shh途径是MB中肿瘤发生的主要驱动力。目的2：通过分析MB细胞中PlGF信号转导轴，我们将确定PlGF如何调控MB细胞的存活和生长。最后，在目的3中，我们将确定抗PlGF治疗是否导致GEMM和遗传定义的MB的原位模型中的肿瘤控制和小鼠存活的改善。为了实现这些目标，我们开发了强大的、非侵入性的、高分辨率的成像技术，这些技术提供了前所未有的分子、细胞、结构和功能洞察（Nature Medicine 2001，2003，2004，2009），并揭示了肿瘤进展的各个步骤（Nature Reviews Cancer 202; Nature Methods 209，2010）。我们将使用这些技术和我们的多学科团队的独特集体专业知识，通过我们的合作者使用GEMM揭示PlGF途径在MB中的作用。与我们在其他实体瘤中对VEGF阻断的发现类似，我们对PlGF阻断的发现将为MB的未来临床试验提供信息（Nature Medicine 2004;新英格兰Journal of Medicine 2009）。

DESCRIPTION (provided by applicant): Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the curative potential of chemo-radiation, one third of patients relapse and many develop devastating treatment-induced morbidities. Thus, new targets for treatment are urgently needed. We recently discovered that placental growth factor (PlGF) is highly expressed in the MB-cancer cels and MB-associated stromal cells. Furthermore, our preliminary data suggest that secretion of sonic hedgehog (Shh) by MB cells induces stromal PlGF expression in a paracrine manner. Finally, we found that PlGF blockade significantly inhibits MB growth and spread to the spinal cord in orthotopic human xenografts of MB. Building on these exciting preliminary findings, we now propose to unravel the mechanisms of response to anti-PlGF therapy in multiple subtypes of MBs using genetically engineered mouse models (GEMM), human MB cell lines and state-of-the-art imaging. Our long- term goal is to translate these findings to the clinic to treat MB. In Aim 1, we will dissect the mechanism o regulation of PlGF expression in MB by the Shh pathway, a major driver of tumorigenesis in MB. In Aim 2, by analyzing the PlGF signal transduction axis in MB cells, we will determine how PlGF governs MB cell survival and growth. Lastly, in Aim 3 we will determine whether anti-PlGF therapy leads to improved tumor control and mouse survival in GEMMs and orthotopic models of genetically defined MBs. To realize these aims, we have developed powerful, non-invasive, high-resolution imaging technologies that provide unprecedented molecular, cellular, structural and functional insight (Nature Medicine 2001, 2003, 2004, 2009) and reveal various steps of tumor progression (Nature Reviews Cancer 202; Nature Methods 209, 2010). We will use these techniques and the unique collective expertise of our multi-disciplinary team to uncover the role of PlGF pathway in MB using GEMMs, available through our collaborators. Similar to our findings on VEGF blockade in other solid tumors, our findings on PlGF-blockade will inform future clinical trials in MB (Nature Medicine 2004; New England Journal of Medicine 2009).