Prognostic Significance of Actuvated Akt/PKB in Cancer

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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.