Inhibiting EGFR and ER pathways in NSCLC

抑制 NSCLC 中的 EGFR 和 ER 通路

• 批准号: 8302279
• 负责人: EDWARD B GARON
• 金额: $ 16.52万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302279
• 关键词: Antiestrogen Therapy; Area; Aromatase; Award; Basic Science; Biological Assay; Biological Markers; Biological Markers; Blood; Blood specimen; Breast; California; Cancer Etiology; Cancer Patient; Cessation of life; Chairperson; Chest; Clinic; Clinical; Clinical Data; Clinical Research; Clinical Research Curriculum Award; Clinical Sciences; Clinical Trials; Cohort Studies; Combined Modality Therapy; Comprehensive Cancer Center; Conduct Clinical Trials; Data; Databases; Development Plans; Disease; Doctor of Medicine; Doctor of Philosophy; Educational process of instructing; Enrollment; Environment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Estradiol; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptors; Estrogens; Etiology; European; Evaluation; Faculty; Fulvestrant; Funding; Gelatinase B; Goals; Grant; Growth; Growth Factor; Hematology; In Vitro; Incidence; Inpatients; Institutional Review Boards; International; Investigation; Jonsson Comprehensive Cancer Center of University of California Los Angeles; Journals; K-Series Research Career Programs; Laboratories; Lead; Learning; Letters; Los Angeles; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Manuscripts; Master of Science; Medical; Medical Oncology; Medicine; Mentors; Mentorship; Mutation; Non-Small-Cell Lung Carcinoma; Nurse Practitioners; Nursing Staff; Outcome; Pathway interactions; Patients; Peer Review; Phase; Phase II Clinical Trials; Physicians; Play; Positioning Attribute; Preparation; Progesterone; Progesterone Receptors; Progestins; Prognostic Marker; Progression-Free Survivals; Public Health; Randomized; Randomized Clinical Trials; Relative (related person); Replacement Therapy; Research; Research Personnel; Research Proposals; Research Training; Resistance; Resources; Risk; Role; Safety; Sampling; Scientist; Series; Signal Pathway; Signal Transduction; Site; Specimen; Staging; Structure; Subgroup; Telephone; Time; Tissue Sample; Tissues; Training; Training Programs; Translational Research; United States; United States National Institutes of Health; Universities; Woman; Work; Writing; anticancer research; arm; base; cancer research center director; carcinogenesis; career; career development; cigarette smoking; design; enzyme biosynthesis; improved; in vivo Model; inhibitor/antagonist; meetings; member; men; mortality; oncology; patient oriented; patient oriented research; pre-clinical; professor; prospective; research study; response; symposium; trial comparing; tumor

DESCRIPTION (provided by applicant): I, Edward B. Garon, M.D., am an Assistant Professor of Medicine in the Division of Hematology and Oncology at UCLA with a focus in lung cancer. My short term goals are to receive training in the conduct of clinical/translational research, to complete a clinical trial of erlotinib alone vs. erlotinib plus fulvestrant, and to evaluate clinical and correlative data generated as part of this trial. My career goals are: 1) Research- To develop investigator-initiated trials based on my laboratory work and develop into an independent scientist who can successfully compete for peer-reviewed funding. 2) Clinical- To become an academic leader in thoracic medical oncology, focused on patient-oriented research. In order to achieve these goals, I have designed a career development plan that includes extensive, highly structured mentorship and didactic training. The University of California, Los Angeles (UCLA) is one of the world's leading research and teaching universities, conducting a full spectrum of research in basic and clinical science. The UCLA Jonsson Comprehensive Cancer Center (JCCC) members include nearly 300 physicians and scientists. Clinical trials are conducted across a wide range of malignancies. The affiliated Translational Oncology Research International (TORI) Network encompasses 27 practices with 154 physicians in 67 offices. At least 80% of my overall time will be devoted to research related activities. I have been provided with personal office space, access to a call center for clinical calls, medical assistants, nursing staff, and a nurse practitioner (25%). My clinical responsibilities will be limited to 1 month of inpatient responsibility per year and one half-day of clinic per week. The institutional commitment to my project and my career are described in a letter from Dennis J. Slamon, M.D., Ph.D., chairman of the Division of Hematology/Oncology. Judith Gasson, JCCC director, has also written a letter describing resources that will be available to me through the JCCC. I will receive primary mentorship from Steven M. Dubinett, M.D. Dr. Dubinett been a successful mentor for trainees at all levels for more than 20 years. His successful track record of mentorship in lung cancer research includes numerous junior faculty who have been career development award recipients. The majority of these awardees have gone on to successful careers as independent investigators. These trainees are noted in Dr. Dubinett's trainee list in this application. Dr. Dubinett has lead the UCLA Lung SPORE training program for the past ten years and is also the PI for two NIH T32 training grants. He served on the training committee for the TRWG. I will meet weekly with Dr. Dubinett during the award period. Topics covered in our meetings will include review of data and planning of experiments; manuscript and proposal preparation and career advice. I will also meet monthly with my Mentorship Committee consisting of Dennis J. Slamon, M.D., Ph.D., Robert Elashoff, Ph.D., and Richard J. Pietras M.D., Ph.D. Dr. Dubinett will also attend these meetings. In addition, I will have monthly phone calls and thrice yearly meetings with my external advisor, Jill Siegfried, Ph.D. I will be in a highly structured, protected and stimulating research environment devoted to translational research in lung cancer. I have enrolled in the UCLA K30 Graduate Training Program in Translational Investigation to receive a Master of Science Degree in Clinical Research. Timing of the coursework has been tailored in order to optimally benefit my proposed research plan. Additional focus during the training program will be directed to manuscript and grant writing. In addition, I will attend departmental and divisional research conferences, weekly laboratory meetings, clinical research meetings, and journal clubs. I will continue to attend the JCCC seminar series which includes a monthly seminar focused on lung cancer. My research proposal entails evaluation of the role of the estrogen receptor (ER) pathway in combination with the epidermal growth factor receptor (EGFR) pathway in non-small cell lung cancer (NSCLC). 1) I will complete a clinical trial of erlotinib alone or in combination with fulvestrant. 102 Patients with Stage IIIB or IV NSCLC and at least one prior line of therapy (unless patient refuses other therapy) will be enrolled on this phase II, randomized clinical trial conducted at UCLA and through the TORI Network. The project received approval from the UCLA IRB, WIRB (for TORI sites), UCLA ISPRC, and it received IND approval from the FDA. 51 of the projected 102 patients have been enrolled. The primary objective of the study is to determine the response rate in each arm. Secondary objectives include progression-free survival, overall survival and safety. 2) I will evaluate blood samples collected as part of the clinical trial for biologic markers, including estradiol and investigational biomarkers NGAL and MMP-9, and 3) I will evaluate tissue collected as part of the clinical trial for correlative secondary endpoints, including tumor levels of ER, ER, progesterone receptor, aromatase and EGFR as well as EGFR mutations and other selected biologic markers. At the conclusion of this project, I will be able to conduct investigator-initiated clinical trials with extensive correlative analysis. This will be accomplished by conducting the proposed research, receiving mentorship during the course of this project, and didactic learning through the UCLA Masters of Science in Clinical Research (K30) Program. At the conclusion of this research training, I will be well positioned to function as an independent physician scientist in patient-oriented lung cancer research, and I anticipate competing for independent research funding.

描述（由申请人提供）：我，爱德华B。Garon，医学博士，我是加州大学洛杉矶分校血液学和肿瘤学系的医学助理教授，主要研究肺癌。我的短期目标是接受开展临床/转化研究的培训，完成厄洛替尼单药与厄洛替尼+氟维司群的临床试验，并评价作为本试验一部分生成的临床和相关数据。我的职业目标是：1）研究-根据我的实验室工作开发委托人发起的试验，并发展成为能够成功竞争同行评审资金的独立科学家。2)临床-成为胸内科肿瘤学的学术领导者，专注于以患者为导向的研究。为了实现这些目标，我设计了一个职业发展计划，其中包括广泛的，高度结构化的指导和教学培训。 加州大学洛杉矶分校（UCLA）是世界领先的研究和教学大学之一，在基础和临床科学方面进行全方位的研究。加州大学洛杉矶分校琼森综合癌症中心（JCCC）的成员包括近300名医生和科学家。临床试验在广泛的恶性肿瘤中进行。附属的转化肿瘤学研究国际（TORI）网络包括27个诊所，67个办公室的154名医生。 至少80%的时间将用于研究相关的活动。我被提供了个人办公空间，可以使用呼叫中心进行临床呼叫，医疗助理，护理人员和执业护士（25%）。我的临床责任将限于每年1个月的住院责任和每周半天的门诊。丹尼斯·J·斯拉蒙医学博士在一封信中描述了对我的项目和我的职业生涯的机构承诺，哲学博士、血液学/肿瘤学分部主席JCCC主任Judith Gasson也写了一封信，描述了我可以通过JCCC获得的资源。我将接受史蒂文·M的主要指导。Dubinett，医学博士Dubinett博士20多年来一直是各级学员的成功导师。他在肺癌研究方面的成功指导记录包括许多获得职业发展奖的初级教师。这些获奖者中的大多数都作为独立调查员取得了成功。这些受训人员在本申请中的Dubinett博士的受训人员名单中注明。Dubinett博士在过去十年中领导了UCLA肺孢子培训计划，也是两个NIH T32培训赠款的PI。他曾在TRWG的培训委员会任职。在获奖期间，我将每周与杜比内特博士会面。我们会议的主题将包括数据审查和实验计划;手稿和提案准备以及职业建议。我还将每月与我的导师委员会会面，该委员会由丹尼斯·J·斯拉蒙医学博士组成，哲学博士、Robert Elashoff博士，和理查德·J·皮特拉医学博士，博士杜比内特博士也将出席这些会议。此外，我将与我的外部顾问吉尔齐格弗里德博士每月通一次电话，每年开三次会。 我将在一个高度结构化，保护和刺激的研究环境，致力于肺癌的转化研究。我已经报名参加了加州大学洛杉矶分校的K30研究生培训计划在转化调查，以获得科学学位的临床研究硕士学位。课程的时间安排已经过调整，以最大限度地有利于我提出的研究计划。培训计划期间的其他重点将针对手稿和赠款写作。此外，我将参加部门和部门的研究会议，每周的实验室会议，临床研究会议和期刊俱乐部。我将继续参加JCCC系列研讨会，其中包括每月一次的肺癌研讨会。我的研究计划需要评估雌激素受体（ER）通路与表皮生长因子受体（EGFR）通路在非小细胞肺癌（NSCLC）中的作用。 1)我将完成厄洛替尼单药或与氟维司群联合用药的临床试验。102例IIIB或IV期NSCLC患者和至少一种既往治疗（除非患者拒绝其他治疗）将入组在UCLA通过TORI网络进行的II期随机临床试验。该项目获得了UCLA IRB、WIRB（针对TORI研究中心）、UCLA ISPRC的批准，并获得了FDA的IND批准。预计102名患者中有51名已入组。研究的主要目的是确定各组的反应率，次要目的包括无进展生存期、总生存期和安全性。2)我将评估作为临床试验的一部分收集的血液样本的生物标志物，包括雌二醇和研究性生物标志物NGAL和MMP-9，和3）我将评估作为临床试验的一部分收集的组织的相关次要终点，包括ER、ER、孕酮受体、芳香酶和EGFR的肿瘤水平以及EGFR突变和其他选定的生物标志物。 在这个项目结束时，我将能够进行广泛的相关分析的临床试验。这将通过进行拟议的研究，在本项目的过程中接受指导，并通过加州大学洛杉矶分校临床研究科学硕士（K30）计划的教学学习来实现。在这项研究培训结束时，我将很好地定位为一个独立的医生科学家在以患者为导向的肺癌研究，我预计竞争独立的研究资金。