Role of PLGF in Medulloblastoma Progression and Treatment

描述（申请人提供）：髓母细胞瘤（Medulloblastoma， MB）是儿童最常见的恶性脑肿瘤。尽管放化疗具有治疗潜力，但仍有三分之一的患者复发，许多患者发展为治疗引起的毁灭性疾病。因此，迫切需要新的治疗靶点。我们最近发现胎盘生长因子（PlGF）在mb癌细胞和mb相关基质细胞中高表达。此外，我们的初步数据表明，MB细胞分泌的sonic hedgehog （Shh）以旁分泌的方式诱导基质PlGF的表达。最后，我们发现PlGF阻断显著抑制MB的生长和向脊髓的扩散。基于这些令人兴奋的初步发现，我们现在建议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揭示多种亚型MB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Aim 1中，我们将分析Shh通路在MB中调控PlGF表达的机制，Shh通路是MB中肿瘤发生的主要驱动因素。在Aim 2中，通过分析MB细胞中的PlGF信号转导轴，我们将确定PlGF如何控制MB细胞的存活和生长。最后，在Aim 3中，我们将确定抗plgf治疗是否能改善GEMMs和基因定义的MBs原位模型中的肿瘤控制和小鼠存活率。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，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）。我们将利用这些技术和我们多学科团队独特的集体专业知识，通过我们的合作者提供的GEMMs来揭示PlGF通路在MB中的作用。与我们在其他实体肿瘤中对VEGF阻断的研究结果类似，我们对plgf阻断的研究结果将为未来MB的临床试验提供信息（Nature Medicine 2004; New England 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). PUBLIC HEALTH RELEVANCE: The current treatment options for medulloblastoma-the most prevalent form of pediatric brain cancer-cause devastating morbidities and result in tumor relapse in a significant fraction of patients. By revealing its mechanism of action, the proposed study aims to demonstrate PlGF as a novel therapeutic target for medulloblastoma. Our findings will directly inform the design and help interpret the results of potential clinical trials of antiPlGF therapy in medulloblastoma patients.