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: 9766197
• 负责人: Rakesh K. Jain
• 金额: $ 101.27万
• 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/9766197
• 关键词: Adult; Adverse effects; Award; Brain; Brain Neoplasms; Cells; Cellular Structures; 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; multidisciplinary; novel strategies; programs; psychologic; public health relevance; side effect; 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（由申请人提供）：脑肿瘤 - 儿童期最常见的实体恶性肿瘤 - 对于最常见的儿科恶性肿瘤 - 髓母细胞瘤 (MB) 来说，标准治疗方法是手术后进行化疗，尽管有可能治愈。治疗通常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，而且很大一部分患者会出现疾病复发，而其他脑肿瘤的复发性疾病的治疗选择有限。 （室管膜瘤、神经胶质瘤、非典型畸胎瘤/横纹肌瘤），迫切需要在不影响疗效的情况下最大限度地减少或消除毒性疗法的更安全的治疗方法，在杰出研究者奖（OIA）的支持下，我将全力以赴。为了改善儿科脑肿瘤患者的生存结果，并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，我进行了研究。成人癌症的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，以类似地改善脑肿瘤儿童的治疗结果。儿科 MB 微环境中的一个新靶点 - 胎盘生长因子 (PlGF) - 在所有四种 MB 分子亚型中表达（Cell 2013），靶向 PlGF 可阻止 MB 生长和扩散，而不会引起明显的副作用。鉴于 PlGF 在其他儿科脑肿瘤中的高表达水平，我们与基础科学家、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，探索阻断 PlGF 也可能对这些肿瘤有效。结合成人肿瘤微环境的集体经验和洞察力，制定一项综合计划，进一步探索儿科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、靶向治疗和免疫疗法的效果。我们的发现为此，我们开发了强大的、非侵入性的高分辨率成像技术，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）并揭示肿瘤进展的各个步骤（Nature Rev. Cancer 2002；NatureMethods 2009、2010；Science 2002 年；《自然》2004 年），我们将利用这些技术和我们独特的专业知识来揭示宿主-肿瘤相互作用在各种儿童脑肿瘤的基因工程小鼠模型中的作用，这与我们的合作者的研究结果类似。成人肿瘤中的 VEGF 阻断（Nature Med. 2004；Cancer Cell 2007；New England J. Med. 2009；PNAS 2013），我们的研究结果PlGF 阻断将为未来的儿科肿瘤临床试验提供信息。