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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：
8528740
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/8528740
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 public health relevance 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. PUBLIC HEALTH RELEVANCE: Malignant gliomas are an aggressive and common cancer in both children and adults. This research aims to improve therapy for these patients by understanding why current therapies fail and proposing novel strategies.

描述（由申请人提供）：我的医学生涯一直强烈关注神经肿瘤学。通过在医学院和住院医生期间的临床研究，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瘤的儿童的需求所驱使。最近完成了我在儿科血液学/肿瘤学的奖学金，我现在正在寻求通过指导临床医生科学家奖继续我的调查路线。我认为，加州大学旧金山分校弗朗西斯科提供了一个很好的环境，这样做。我的导师William韦斯医学博士有一个培养实验室，可以让我实现我的目标。[My共同导师Kevin Shannon在小鼠癌症模型方面具有专业知识，并指导了几位获得K 08奖项的儿科医生科学家。此外，通过与Kevan Shokat（酪氨酸激酶专家）和C。大卫詹姆斯（脑肿瘤模型专家），我相信我是独一无二的，以实现我的目标。我的研究重点是恶性胶质瘤。目前的治疗是不够的，大多数患者死于疾病，幸存者有显着的长期缺陷。表皮生长因子受体（EGFR）通过过度表达、扩增和突变在该疾病中具有突出特征。使用小分子抑制剂或单克隆抗体的EGFR靶向治疗仅在一小部分患者中显示出短暂的反应。我们认为，目前的靶向方法失败，因为目前的抑制剂导致EGFR的阻断和下游信号通路的恢复不足。我们的初步数据表明，不可逆的EGFR抑制剂和联合治疗方法可以显着提高治疗效果。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。公共卫生相关性：恶性神经胶质瘤是一种侵袭性和常见的癌症，在儿童和成人。这项研究旨在通过了解目前治疗失败的原因并提出新的策略来改善这些患者的治疗。