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Optimizing EGFR Targeted Therapy in Malignant Glioma

优化恶性胶质瘤的 EGFR 靶向治疗

基本信息

批准号：
8730714
负责人：
Theodore Nicolaides
金额：
$ 16.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8730714
关键词：
Active Sites Address Adult Affinity Alleles Apoptotic Automobile Driving Award Basic Science Bioluminescence Brain Neoplasms California Cancer Patient Child Childhood Clinical Clinical Data Clinical Research Clinical Trials Collaborations Combined Modality Therapy Data Disease Doctor of Philosophy Environment Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Fellowship Firefly Luciferases Gefitinib Glioma Goals In Vitro Investigation Lead Ligands Luc Gene Malignant Glioma Malignant Neoplasms Malignant neoplasm of lung Medical Medical Residency Mentors Mitogen-Activated Protein Kinase Inhibitor Mitogen-Activated Protein Kinases Modeling Molecular Monoclonal Antibodies Mus Mutate Mutation Oncogenes Outcome PTEN gene Pathway interactions Patients Pediatric Hematology/Oncology Pharmaceutical Preparations Phosphotransferases Physicians Primary Brain Neoplasms Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Recovery Relapse Research Resistance San Francisco Scientist Signal Pathway Signal Transduction Survivors System Testing Translating Treatment Efficacy United States Universities Xenograft Model Xenograft procedure analog base career chemical genetics epidermal growth factor receptor VIII improved in vivo in vivo Model inhibitor/antagonist innovation medical schools mouse model mutant neuro-oncology novel novel strategies oncogene addiction optimism pre-clinical prevent response small molecule therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): My medical career has been strongly focused towards neuro-oncology. Through clinical research during medical school and residency, then moving on to basic science research during my fellowship, I have been driven by the need to cure children with brain tumors. Having recently completed my fellowship in Pediatric Hematology/Oncology, I am now seeking to continue my line of investigation through a Mentored Clinician Scientist Award. I feel that the University of California, San Francisco provides an excellent environment in which to do so. My mentor, William Weiss MD,PhD, has a nurturing lab that will allow me to reach my goals. [My co-mentor Kevin Shannon has expertise in mouse models of cancer and has mentored several pediatric physician scientists with K08 awards.] In addition, through productive collaborations with Kevan Shokat (an expert in tyrosine kinases) and C. David James (an expert in brain tumor models), I believe I am uniquely situated to achieve my goals. My research focus is on malignant gliomas. Current therapies are inadequate, with most patients succumbing to their disease and survivors having significant long-term deficits. The Epidermal Growth Factor Receptor (EGFR) features prominently in this disease, through over-expression, amplification and mutation. EGFR-targeted therapy using small molecule inhibitors or monoclonal antibodies have shown only brief responses in a small fraction of patients. We believe that current targeted approaches fail because current inhibitors result in inadequate blockade of EGFR and recovery of downstream signaling pathways. Our preliminary data argues that irreversible EGFR inhibitors and combination therapy approaches can significantly improve therapeutic efficacy. In our proposed studies, we seek to further study these mechanisms and to investigate these approaches in a highly relevant in vivo model.

描述（由申请人提供）：我的医学生涯一直专注于神经肿瘤学。通过在医学院和住院医生实习期间的临床研究，然后在我的奖学金期间转向基础科学研究，我一直被治愈患有脑肿瘤的儿童的需求所驱使。我最近完成了儿科血液学/肿瘤学的研究，现在我正在寻求通过指导临床医生科学家奖继续我的研究。我觉得加州大学旧金山分校提供了一个很好的学习环境。我的导师，威廉·韦斯医学博士，他有一个培养我的实验室，可以让我实现我的目标。我的共同导师凯文·香农（Kevin Shannon）在癌症小鼠模型方面具有专长，并指导了几位获得K08奖的儿科内科科学家。此外，通过与Kevan Shokat（酪氨酸激酶专家）和C. David James（脑肿瘤模型专家）的富有成效的合作，我相信我处于实现我的目标的独特位置。我的研究重点是恶性神经胶质瘤。目前的治疗方法是不充分的，大多数患者死于他们的疾病，幸存者有显著的长期缺陷。表皮生长因子受体（EGFR）通过过表达、扩增和突变在本病中表现突出。使用小分子抑制剂或单克隆抗体的egfr靶向治疗在一小部分患者中仅显示出短暂的反应。我们认为目前的靶向方法失败，因为目前的抑制剂导致EGFR的阻断不足和下游信号通路的恢复。我们的初步数据表明，不可逆EGFR抑制剂和联合治疗方法可以显著提高治疗效果。在我们提出的研究中，我们寻求进一步研究这些机制，并在高度相关的体内模型中研究这些方法。