Dissecting Pediatric Brain Tumor Microenvironment to Improve Treatment

剖析小儿脑肿瘤微环境以改善治疗

• 批准号: 9334783
• 负责人: Rakesh K. Jain
• 金额: $ 104.4万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-14 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9334783
• 关键词: Adult; Adverse effects; Award; Brain; Brain Neoplasms; Cells; Child; Childhood Brain Neoplasm; Childhood Medulloblastomas; Clinical Trials; Collaborations; Ependymoma; Future; Genetically Engineered Mouse; Glioma; Goals; Growth; Imaging technology; Immunologist; Immunotherapy; Impaired cognition; Impairment; Life; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of brain; Methods; Molecular; Morbidity - disease rate; Mus; Nature; New England; Operative Surgical Procedures; Pathologist; Patients; Pediatric Neoplasm; Pediatric Oncologist; Placental Growth Factor; Recurrent disease; Relapse; Research Personnel; Rhabdoid Tumor; Role; Science; Scientist; Solid; Techniques; Theft; Therapeutic; Toxic effect; Translating; Vascular Endothelial Growth Factors; anticancer research; blocking factor; cancer cell; career; chemoradiation; clinical practice; curative treatments; design; effective therapy; experience; high resolution imaging; host neoplasm interaction; improved; improved outcome; innovation; insight; medulloblastoma; molecular subtypes; mouse model; multidisciplinary; novel strategies; programs; psychologic; public health relevance; standard care; survival outcome; targeted treatment; therapy outcome; tumor; tumor microenvironment; tumor progression

 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.

 描述（应用程序提供）：脑肿瘤 - 最常见的儿童期恶性肿瘤 - 治疗选择有限。对于髓母细胞瘤（MB），最普遍的小儿恶性肿瘤，标准治疗方法是手术，然后是化学辐射。尽管潜在的治疗方法，但治疗通常会导致毁灭性治疗引起的病因，包括严重的认知障碍和社会心理问题。此外，很大一部分患者会缓解疾病，并且复发性疾病的治疗选择有限。在其他脑肿瘤（室内膜瘤，神经胶质瘤，非典型Teratoid/buarbdoid肿瘤）中，有效疗法甚至更少。迫切需要最小化或消除有毒疗法而无需损害有效性的更安全的治疗方法。在这项杰出研究者奖（OIA）的支持下，我将自己致力于改善儿科脑肿瘤患者的生存结果，并减轻或消除这些儿童治疗后遭受的灾难，永久性和生命损害的毒性。在我从事癌症研究的三个十年的职业中，我研究了成人癌症肿瘤微环境的各个方面，以了解有效疗法的障碍并在临床实践中克服它们。在此OIA提案中，我们将针对小儿癌的肿瘤微环境，以类似地改善脑肿瘤儿童的预后。最近，我们发现了小儿MB-斑点生长因子（PLGF）微环境中的一个新靶标，该目标均在MB的所有四种分子亚型中表达（Cell 2013）。靶向PLGF会阻止MB的生长并扩散而不会引起小鼠的显着副作用。鉴于PLGF在其他小儿脑肿瘤中的表达水平高，我们假设阻断PLGF在这些肿瘤中也可能有效。与一个基础科学家，病理学家，免疫学家和儿科肿瘤学家组成的多学科团队，我将利用我们在成人肿瘤微环境中的集体经验和见解，以开发全面的计划，以进一步探索潜在的机制，以及其他对其他治疗机制以及其他治疗机会以及其他治疗方法的影响，以改善化学的预防措施。我们的最终目标是将我们的发现转化为针对小儿脑肿瘤的创新治疗方法。为此，我们开发了强大的，无创的，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，结构和功能洞察力（Nature Med 2001，2001，2003，2004，2004，2005，2009，2009，2009，2013）并揭示了肿瘤进展的各种步骤（Nature Rev. Cancer 2002; Nature Rev. 2002; Nature Match 2009 2009，2010; Science; Science 2002;自然2004年）。我们将使用这些技术和我们独特的专业知识来揭示宿主肿瘤相互作用在肿瘤进展和治疗中的作用，这在各种儿科脑肿瘤的一般工程小鼠模型中，可通过我们的合作者获得。与我们对成人肿瘤中VEGF阻滞的发现相似（NatureMed。2004; Cancer Cell 2007; New England J.Med。2009; PNAS 2013），我们对PLGF-Blockade的发现将为儿科肿瘤的未来临床试验提供信息。