项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

HILDESHEIM, JEFFREY

项目受资助机构

MASSACHUSETTS GENERAL HOSPITAL

项目编号

5R35CA197743-06

立项年度

2020

立项时间

未公开

项目级别

国家级

研究期限

未知 / 未知

受资助金额

1044000.00美元

学科

Brain Cancer; Brain Disorders; Cancer; Neurosciences; Orphan Drug; Pediatric; Pediatric Cancer; Radiation Oncology; Rare Diseases;

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

JAIN, RAKESH K.

参与机构

NATIONAL CANCER INSTITUTE

项目标书摘要：? 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.