Medical Student Research Fellowship for Summer 2008
Mentor: John D. Minna & Alexander Pertsemlidis
Department: Internal Medicine
Room number: NB 8.206 (JM) & NB10.212 (AP)
Mail Code: 8593 (JM) & 8591 (AP)
Phone number: 84902 (JM) & 81921 (AP)
E-mail: John.Minna@utsouthwestern.edu & Alexander.Pertsemlidis@utsouthwestern.edu
Project title: MicroRNA (miRNA) Regulation of Sensitivity to Chemotherapy in Non-Small Cell Lung Cancer (NSCLC)
Human subjects IRB approved project number (where applicable):
Animal subjects IRB approved project number (where applicable):
Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)
Brief Description of Project:
The primary objective of this proposal is to determine if and how miRNAs contribute to differential sensitivity of non-small cell lung cancers(NSCLCs) to chemotherapeutic agents. We have profiled miRNA expression in a panel of NSCLC cell lines, and identified miRNAs that are differentially expressed, including several whose expression is inversely related to responsiveness to paclitaxel treatment. Transient expression of molecular mimics of these miRNAs in chemoresistant cell lines conferred a 200- to 300-fold increase in paclitaxel sensitivity. To identify potential targets of these miRNAs, we developed new computational method to predict interactions between miRNAs and mRNAs. We identified 20 candidate regulatory targets of miRNAs relevant to chemosensitivity. We have validated two of these regulatory targets by demonstrating differential protein expression between sensitive and resistant cell lines. These data suggest that miRNAs can modulate the response of lung cancers to chemotherapy.
We are currently using a combination of in silico, in vitro and in vivo approaches to address the following questions: Do miRNA expression profiles correlate with drug sensitivity patterns in lung cancer cell lines? Can miRNA expression levels be manipulated to increase drug sensitivity in cultured lung cancer cells and in mouse models of human lung cancer? What functional roles do miRNAs play in drug sensitivity/resistance of lung cancer cells?
Identifying aberrant miRNA expression consistent with the models of miRNA involvement in cancer can provide new insight into lung cancer disease mechanisms, and a new set of diagnostic markers and therapeutic targets which could play a significant role in the treatment of human disease.
Yao Ma has worked in both the Minna and Pertsemlidis labs as a summer student. This work has included measuring sensitivity to paclitaxel of a large number of NSCLC cell lines and validating the initial findings that transient and stable transfection of specific miRNAs sensitize cells to paclitaxel. His role this year is to continue investigating the functional effects of miRNAs on drug resistance in lung cancer cells.
Previous Research Activities or Publications with Medical Students:
(with student Yao Ma):
" Characterizing sensitivity of NSCLC cell lines to a spectrum of chemotherapy drugs:
" Characterizing sensitivity of NSCLC cells transfected with specific miRNAs in order to induce sensitivity or resistance to paclitaxel
" Measuring miRNA expression in a panel of NSCLC cell lines