Dissecting Pediatric Brain Tumor Microenvironment to Improve Treatment

 描述（由申请人提供）：脑肿瘤-儿童期最常见的实体恶性肿瘤-治疗选择有限。对于髓母细胞瘤（MB），最常见的儿科恶性肿瘤，标准的治疗是手术，然后化疗-放疗。虽然有治愈的潜力，但治疗往往导致毁灭性的治疗引起的疾病，包括严重的认知障碍和社会心理问题。此外，很大一部分患者经历疾病复发，并且复发性疾病的治疗选择有限。在其他脑肿瘤（室管膜瘤、神经胶质瘤、非典型畸胎瘤/横纹肌样瘤）中，有效的治疗方法甚至更少。迫切需要更安全的治疗方法，最大限度地减少或消除毒性治疗而不影响疗效。在杰出研究者奖（OIA）的支持下，我将致力于改善儿童脑肿瘤患者的生存结局，减轻或消除这些儿童在治疗后遭受的破坏性，永久性和损害生命的毒性。在我三十年的癌症研究生涯中，我调查了成人癌症肿瘤微环境的各个方面，以了解有效治疗的障碍并在临床实践中克服它们。在这项OIA提案中，我们将针对儿童癌症的肿瘤微环境，以类似的方式改善脑肿瘤儿童的预后。我们最近在儿科MB的微环境中发现了一种新的靶点-胎盘生长因子（PlGF）-其在MB的所有四种分子亚型中表达（Cell 2013）。靶向PlGF阻断MB生长和扩散，而不会在小鼠中引起显著的副作用。鉴于PlGF在其他儿科脑肿瘤中的高水平表达，我们假设阻断PlGF在这些肿瘤中也可能有效。与基础科学家，病理学家，免疫学家和儿科肿瘤学家组成的多学科团队合作，我将利用我们在成人肿瘤微环境中的集体经验和洞察力，制定一项全面的计划，进一步探索儿童脑肿瘤微环境独特的潜在机制以及其他治疗机会，以改善化疗，放疗，靶向治疗和免疫治疗的结果。我们的最终目标是将我们的发现转化为儿科脑肿瘤的创新治疗方法。为此，我们开发了强大的、非侵入性的、高分辨率的成像技术，提供前所未有的分子、细胞、结构和功能洞察（Nature Med 2001，2003，2004，2005，2009，2013），并揭示了肿瘤进展的各个步骤（Nature Rev. Cancer 2002; Nature Methods 2009，2010; Science 2002; Nature 2004）。我们将利用这些技术和我们独特的专业知识，揭示宿主-肿瘤相互作用在肿瘤进展中的作用，并通过我们的合作者在各种儿科脑肿瘤的基因工程小鼠模型中进行治疗。类似于我们在成人肿瘤中VEGF阻断的发现（Nature Med.2004; Cancer Cell 2007;新英格兰J.Med.2009; PNAS 2013），我们在PlGF阻断上的发现将为儿科肿瘤的未来临床试验提供信息。

 DESCRIPTION (provided by applicant): Brain tumors - the most common solid malignancies of childhood - have limited therapeutic options. For medulloblastoma (MB), the most prevalent pediatric malignancy, the standard treatment is surgery followed by chemo-radiation. Although potentially curative, treatment often leads to devastating treatment-induced morbidities, including severe cognitive impairment and socio-psychological problems. Moreover, a significant fraction of patients experience disease relapse, and there are limited therapeutic options for recurrent disease. In other brain tumors (ependymoma, glioma, atypical teratoid/rhabdoid tumor), there are even fewer efficacious therapies. Safer treatments that minimize or eliminate toxic therapies without compromising efficacy are urgently needed. With the support of this Outstanding Investigator Award (OIA), I will dedicate myself to improving survival outcomes of pediatric brain tumor patients and to alleviate or eliminate the devastating, permanent and life-impairing toxicities suffered by these children after therapy. Over my three- decade career in cancer research, I have investigated various aspects of the tumor microenvironment of adult cancers to understand barriers to effective therapies and overcome them in clinical practice. In this OIA proposal, we will target the tumor microenvironment of pediatric cancers to similarly improve outcomes in children with brain tumors. We have recently discovered a new target in the microenvironment of pediatric MB - placental growth factor (PlGF) - that is expressed across all four molecular subtypes of MB (Cell 2013). Targeting PlGF blocks MB growth and spread without causing significant side effects in mice. Given the high levels of expression of PlGF in other pediatric brain tumors, we hypothesize that blocking PlGF may also be effective in these tumors. In collaboration with a multidisciplinary team of basic scientists, pathologists, immunologists and pediatric oncologists, I will leverage our collective experience and insight in adult tumor microenvironment to develop a comprehensive program to further explore underlying mechanisms as well as other therapeutic opportunities unique to pediatric brain tumor microenvironment to improve the outcome of chemo-radiation, targeted therapies and immunotherapies. Our ultimate goal is to translate our findings into innovative treatments for pediatric brain tumors. To this end, we have developed powerful, non-invasive, high-resolution imaging technologies that provide unprecedented molecular, cellular, structural and functional insight (Nature Med 2001, 2003, 2004, 2005, 2009, 2013) and reveal various steps of tumor progression (Nature Rev. Cancer 2002; Nature Methods 2009, 2010; Science 2002; Nature 2004). We will use these techniques and our unique expertise to uncover the role of host-tumor interactions in tumor progression and treatment in genetically engineered mouse models of various pediatric brain tumors, available through our collaborators. Similar to our findings on VEGF blockade in adult tumors (Nature Med. 2004; Cancer Cell 2007; New England J. Med. 2009; PNAS 2013), our findings on PlGF-blockade will inform future clinical trials in pediatric tumors.