Inhibiting EGFR and ER pathways in NSCLC

描述(由申请人提供)：我，Edward B.Garon，医学博士，加州大学洛杉矶分校血液和肿瘤科医学助理教授，主要研究肺癌。我的短期目标是接受临床/转化性研究指导方面的培训，完成厄洛替尼单独与厄洛替尼加富维斯特朗的临床试验，并评估作为试验一部分产生的临床和相关数据。我的职业目标是：1)研究--在我的实验室工作的基础上，开发由研究人员发起的试验，并发展成为一名独立的科学家，能够成功地竞争同行评审的资金。2)临床-成为胸科医学肿瘤学的学术领先者，专注于以患者为中心的研究。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指导性培训。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，从事基础和临床科学的全方位研究。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。临床试验针对范围广泛的恶性肿瘤进行。附属的转译肿瘤学研究国际(TORI)网络包括27个诊所，67个办事处的154名医生。 我总时间中至少有80%会投入到与研究相关的活动中。我已经获得了个人办公空间、临床呼叫中心的接入、医疗助理、护理人员和一名护士(25%)。我的临床责任将被限制在每年1个月的住院责任和每周半天的门诊时间。血液科/肿瘤科主任、医学博士丹尼斯·J·斯莱蒙在一封信中描述了机构对我的项目和我的职业生涯的承诺。JCCC主任朱迪思·加森(Judith Gasson)也写了一封信，描述了我将通过JCCC获得的资源。我将接受史蒂文·M·杜比奈特医学博士的主要指导。20多年来，杜比奈特博士一直是各级学员的成功导师。他在肺癌研究方面的成功导师记录包括许多获得职业发展奖的初级教员。这些获奖者中的大多数都以独立调查人员的身份成功地从事着职业生涯。在本申请表中，这些受训人员被记录在Dubinett博士的受训人员名单中。在过去的十年里，杜比内特博士一直领导着加州大学洛杉矶分校的肺孢子培训计划，同时也是两项NIH T32培训拨款的PI。他曾在TRWG的训练委员会任职。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回顾和实验规划；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Dennis J.Slamon，M.D.，Ph.D.，Robert Elashoff，Ph.D.和Richard J.Pietras M.D.，Ph.D.组成。Dubinett博士也将参加这些会议。此外，我将每月打电话，每年与我的外部顾问吉尔·西格弗里德博士会面三次。我将处于一个高度结构化、受保护和激励的研究环境中，致力于肺癌的转化研究。我已经参加了加州大学洛杉矶分校的K30翻译调查研究生培训计划，以获得临床研究的理学硕士学位。课程的时间安排已经过量身定做，以便最大限度地有利于我提出的研究计划。培训期间的其他重点将放在手稿和补助金的撰写上。此外，我还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以肺癌为主题的研讨会。我的研究建议需要评估雌激素受体(ER)途径和表皮生长因子受体(EGFR)途径在非小细胞肺癌(NSCLC)中的作用。1)我将完成厄洛替尼单独或与富维司琼联合使用的临床试验。102名IIIB期或IV期非小细胞肺癌患者和至少一种先前的治疗方法(除非患者拒绝其他治疗)将参加在加州大学洛杉矶分校和TORI网络进行的这项II期随机临床试验。该项目获得了加州大学洛杉矶分校IRB、WIRB(用于Tori站点)、UCLA ISPRC的批准，并获得了FDA的IND批准。预计102名患者中已有51人入选。这项研究的主要目标是确定每个手臂的应答率。次要目标包括无进展存活率、总体存活率和安全性。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记物，包括雌二醇和研究生物标记物NGAL和MMP-9；3)我将评估作为临床试验的一部分收集的组织是否有相关的次级终点，包括ER、ER、孕激素受体、芳香化酶和EGFR的肿瘤水平以及EGFR突变和其他选定的生物标记物。在这个项目结束时，我将能够进行由研究人员发起的临床试验，并进行广泛的相关性分析。这将通过实施拟议的研究，在项目过程中接受指导，并通过加州大学洛杉矶分校临床研究(K30)理学硕士课程进行授课学习来实现。在这次研究培训结束时，我将作为一名独立的内科科学家在面向患者的肺癌研究中处于有利地位，我预计将竞争独立研究资金。

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.