Role of PLGF in Medulloblastoma Progression and Treatment

描述(申请人提供)：髓母细胞瘤(MB)是最常见的儿童恶性脑肿瘤。尽管化疗具有治愈潜力，但三分之一的患者复发，许多人患上了毁灭性的治疗引发的疾病。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)在MB癌细胞和MB相关间质细胞中高表达。此外，我们的初步数据表明，MB细胞分泌Sonic Hedgehog(Shh)以旁分泌方式诱导间质PlGF的表达。最后，我们发现PlGF阻断剂显著抑制了MB的生长，并在人MB原位异种移植中扩散到脊髓。在这些令人兴奋的初步发现的基础上，我们现在提议利用基因工程小鼠模型(GEMM)、人类MB细胞系和最先进的成像技术来揭示多个亚型MBS对抗PlGF治疗的反应机制。我们的长期目标是将这些发现转化为临床治疗MB。在目标1中，我们将剖析Shh通路调节MB中PlGF表达的机制，Shh通路是MB肿瘤发生的主要驱动因素。在目标2中，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细胞的生存和生长。最后，在目标3中，我们将确定在GEMM和基因定义的MBS的原位模型中，抗PlGF治疗是否能够改善肿瘤控制和小鼠存活。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成像技术，提供了前所未有的分子、细胞、结构和功能洞察(《自然医学》2001、2003、2004、2009)，并揭示了肿瘤进展的各个步骤(《自然评论癌症202》；《自然方法209》，2010)。我们将使用这些技术和我们多学科团队的独特集体专业知识，通过我们的合作者提供的GEMM来揭示PlGF途径在MB中的作用。与我们在其他实体肿瘤中阻断血管内皮生长因子的发现类似，我们关于PlGF-阻断的发现将为未来MB的临床试验提供信息(自然医学2004年；新英格兰医学杂志2009年)。

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).