Dissecting Pediatric Brain Tumor Microenvironment to Improve Treatment

 描述(申请人提供)：脑瘤--儿童时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)，这是最常见的儿童恶性肿瘤，标准的治疗方法是手术后再进行化疗。虽然治疗有可能治愈，但治疗往往会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，相当一部分患者经历了疾病复发，复发疾病的治疗选择有限。在其他脑肿瘤(室管膜瘤、胶质瘤、不典型畸胎/横纹肌样瘤)中，有效的治疗方法甚至更少。迫切需要在不影响疗效的情况下尽量减少或消除毒性治疗的更安全的治疗方法。在这个杰出研究者奖(OIA)的支持下，我将致力于改善儿童脑瘤患者的生存结果，减轻或消除这些儿童在治疗后遭受的毁灭性、永久性和危及生命的毒性。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。在这份OIA提案中，我们将针对儿童癌症的肿瘤微环境，以类似的方式改善患有脑瘤的儿童的预后。我们最近在儿科MB的微环境中发现了一个新的靶点-胎盘生长因子(PlGF)-它在MB的所有四个分子亚型中都有表达(细胞2013)。靶向PlGF可以阻止MB的生长和扩散，而不会在小鼠身上造成明显的副作用。鉴于PlGF在其他儿童脑肿瘤中的高水平表达，我们推测阻断PlGF对这些肿瘤也可能有效。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方面的集体经验和洞察力，制定一个全面的计划，进一步探索儿童脑肿瘤微环境特有的潜在机制和其他治疗机会，以改善化疗放射、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童脑瘤的创新治疗方法。为此，我们开发了功能强大的非侵入性高分辨率成像技术，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、2005、2009、2013)，并揭示了肿瘤进展的各个步骤(《自然修订癌症》2002年；《自然方法》2009、2010；《科学》2002年；《自然》2004年)。我们将使用这些技术和我们独特的专业知识，通过我们的合作者提供的各种儿科脑瘤的基因工程小鼠模型，揭示宿主-肿瘤相互作用在肿瘤进展和治疗中的作用。类似于我们在成人肿瘤中阻断血管内皮生长因子的发现(自然医学。2004年；癌症细胞2007；新英格兰医学杂志。2009年；PNAS 2013)，我们关于PlGF-BLOCKADE的发现将为未来的儿科肿瘤临床试验提供信息。

 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.