Prognostic Significance of Actuvated Akt/PKB in Cancer

描述（由申请人提供）： 该K23应用程序提出了一个精心策划的指导以患者为导向的研究计划，并在临床和实验室调查方法中进行并行多学科教学培训。候选人计划作为一名独立的临床研究者的职业生涯，专注于与化疗耐药性和预后结果的分子决定因素相关的以患者为导向的研究。杜兰/路易斯安那州立大学综合临床研究中心（包括GCRC核心实验室）将作为主要研究中心，并提供研究支持。病理学系和杜兰/路易斯安那州立大学GCRC将提供结构化的指导。大卫博士的研究计划题为“活化Akt/PKB在非小细胞肺癌中的预后意义：病例对照前瞻性研究”将结合流行病学、生物统计学、社区卫生、人类遗传学和分子医学已经形成了临床研究公共卫生硕士学位的基础，她同时从公共卫生和热带医学的TU学校攻读在TU NIH赞助的临床研究课程奖励计划（K30奖）的赞助下。该提议是基于这样的假设，即活化的，即磷酸化的Akt/PKB（磷酸化Akt）的过表达是人非小细胞肺癌（NSCLC）中的促存活信号转导机制，其可以拮抗治疗诱导的细胞凋亡。基于初步研究的结果，进一步假设肿瘤抑制蛋白PTEN的丢失或失活允许NSCLC肿瘤细胞中不受调节的Akt磷酸化、减少的凋亡和增加的存活。具体目标是：1）证明诊断时磷酸化Akt和PTEN状态对新诊断的NSCLC患者的治疗反应和生存期的预测价值，以及2）通过在显示对易瑞沙具有化学抗性或化学反应的人NSCLC细胞系中用siRNA差异性地操纵磷酸化Akt和PTEN的表达来直接测试磷酸化Akt和PTEN在化学反应性中的机制作用该研究的目的是推动NSCLC的靶向肿瘤特异性疗法的开发。大卫博士将从因疑似原发性肺癌接受诊断性支气管镜检查的患者人群中招募病例和对照受试者，并对其进行随访。她将对所有研究患者进行长达36个月的随访。她将在所有接受化疗的病例患者中评估两个化疗周期后的肿瘤反应。本研究的开展将加强和扩大GCRC核心实验室和肺部生物学组的活动。该研究项目是大卫博士的职业目标的核心，即进行独立和原创性的研究，以确定可能拮抗非小细胞肺癌治疗诱导的细胞凋亡的信号转导蛋白。为此，将向她提供实现这些目标所需的受保护的时间和机构资源。

DESCRIPTION (provided by applicant): This K23 application proposes a carefully planned program of mentored patient-oriented research and concurrent multidisciplinary didactic training in the methods of clinical and laboratory investigation. The candidate plans a career as an independent clinical investigator focusing on patient-oriented research related to molecular determinants of chemoresistance and prognostic outcome. The Tulane/LSU General Clinical Research Center, including the GCRC Core Laboratory, will serve as the primary performance site and will provide research support. The Department of Pathology and the Tulane/LSU GCRC will provide structured mentoring. Dr. David's research plan entitled "Prognostic Significance of Activated Akt/PKB in Non-Small Cell Lung Cancer: A Case-Control Prospective Study" will incorporate the basic principles of Epidemiology, Biostatistics, Community Health, Human Genetics and Molecular Medicine which have formed the basis of the Master of Public Health in Clinical Research degree that she is concurrently pursuing from the TU School of Public Health and Tropical Medicine under the auspices of the TU NIH-sponsored Clinical Research Curriculum Award Program (K30 Award). The proposal is predicated on the hypothesis that overexpression of activated, i.e. phosphorylated, Akt/PKB (phosphoAkt) is a pro-survival signal transduction mechanism in human non-small cell lung cancer (NSCLC) which may antagonize therapy-induced apoptosis. It is further postulated based on results of preliminary studies that loss or inactivation of the tumor suppressor protein PTEN permits unregulated Akt phosphorylation, reduced apoptosis and increased survival in NSCLC tumor cells. The specific aims are: 1)To demonstrate the predictive value of phosphoAkt and PTEN status at diagnosis with respect to therapeutic response and survival in newly diagnosed NSCLC patients and 2)To directly test the mechanistic roles of phosphoAkt and PTEN in chemoresponsiveness by differentially manipulating their expression with siRNAs in human NSCLC cell lines shown to be chemoresistant or chemoresponsive to Iressa (gefitinib).The objective of the study is to drive the development of targeted tumor-specific therapies for NSCLC. Dr. David will recruit and follow case and control subjects from a population of patients undergoing diagnostic bronchoscopy for suspected primary lung cancer. She will follow all study patients for up to 36 months. She will assess tumor response after two cycles of chemotherapy in all case patients who receive chemotherapy. The performance of this study will enhance and expand the activities of the GCRC Core Laboratory and the Lung Biology Group. This research program is central to Dr. David's career goals, which are to perform independent and original research that is relevant to identifying signal transduction proteins which may antagonize therapy-induced apoptosis in non-small cell lung cancer. To this end she will be provided the protected time and institutional resources necessary to achieve these goals.