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author:("Sadiq, aha")
1.  Resistance to EGFR-TKI can be mediated through multiple signaling pathways converging upon cap-dependent translation in EGFR-wild type NSCLC 
For the majority of patients with non-small cell lung cancer, response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) is suboptimal. In models of acquired resistance to EGFR-TKI, activation of Akt phosphorylation is frequently observed. Since Akt activation results in downstream initiation of cap-dependent protein translation, we hypothesized that a strategy of targeting cap-dependent translation in combination with erlotinib might enhance therapy.
NSCLC cells that are wild-type for Egfr were assayed for sensitivity to erlotinib. Serum-starved NSCLC cells were assayed for EGFR signaling and downstream pathway activation by immunoblot after stimulation with EGF. EGFR signaling and signaling mediators of cap-dependent translation were assayed by immunoblot under serum replete conditions 24 hours after treatment with erlotinib. Finally, combination treatment with erlotinib and 2 different cap-dependent translation inhibitors were done to assess the effect on cell viability.
EGFR signaling is coupled to activation of cap-dependent translation in EGFR wild-type cells. Erlotinib inhibits EGFR phosphorylation in EGFR-TKI resistant cells, however, results in activation of downstream signaling molecules including Akt and ERK1/2 resulting in maintenance of eIF4F activation. eIF4F cap-complex formation is maintained in erlotinib resistant cells, but not in erlotinib sensitive cells. Finally, using an antisense oligonucleotide against eIF4E and a small-molecule inhibitor to disrupt eIF4F formation, we show that cap-dependent translation inhibition can enhance sensitivity to erlotinib.
The results of these studies support further clinical development of translation inhibitors for treatment of NSCLC in combination with erlotinib.
PMCID: PMC3745544  PMID: 23883783
EGFR; erlotinib; non-small cell lung cancer; eIF4E; cap-dependent translation
2.  MET As a Possible Target for Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2013;31(8):1089-1096.
Lung cancer is a heterogeneous group of disorders that is now being subdivided into molecular subtypes with dedicated targeted therapies. The MET receptor tyrosine kinase has been identified as aberrantly overexpressed, potentially having activating mutations, and amplified in certain subsets of lung cancers. The ligand hepatocyte growth factor (HGF) can also be overexpressed in lung cancer or expressed in stroma, and both the MET receptor and the HGF ligand can be targets for therapeutics, especially in lung cancer. Activation of MET leads to a plethora of biochemical and biologic changes both in normal and cancerous cells. Preclinically, it has been shown that silencing or inactivating MET leads to decreased viability of cancer cells. There are a number of compounds against MET/HGF in clinical trials that have been shown to be active in lung cancers. This review will summarize the biology of MET as well as its therapeutic inhibition in lung cancer.
PMCID: PMC3589702  PMID: 23401458
3.  Utilisation of a thoracic oncology database to capture radiological and pathological images for evaluation of response to chemotherapy in patients with malignant pleural mesothelioma 
BMJ Open  2012;2(5):e001620.
An area of need in cancer informatics is the ability to store images in a comprehensive database as part of translational cancer research. To meet this need, we have implemented a novel tandem database infrastructure that facilitates image storage and utilisation.
We had previously implemented the Thoracic Oncology Program Database Project (TOPDP) database for our translational cancer research needs. While useful for many research endeavours, it is unable to store images, hence our need to implement an imaging database which could communicate easily with the TOPDP database.
The Thoracic Oncology Research Program (TORP) imaging database was designed using the Research Electronic Data Capture (REDCap) platform, which was developed by Vanderbilt University. To demonstrate proof of principle and evaluate utility, we performed a retrospective investigation into tumour response for malignant pleural mesothelioma (MPM) patients treated at the University of Chicago Medical Center with either of two analogous chemotherapy regimens and consented to at least one of two UCMC IRB protocols, 9571 and 13473A.
A cohort of 22 MPM patients was identified using clinical data in the TOPDP database. After measurements were acquired, two representative CT images and 0–35 histological images per patient were successfully stored in the TORP database, along with clinical and demographic data.
We implemented the TORP imaging database to be used in conjunction with our comprehensive TOPDP database. While it requires an additional effort to use two databases, our database infrastructure facilitates more comprehensive translational research.
The investigation described herein demonstrates the successful implementation of this novel tandem imaging database infrastructure, as well as the potential utility of investigations enabled by it. The data model presented here can be utilised as the basis for further development of other larger, more streamlined databases in the future.
PMCID: PMC3488720  PMID: 23103606
Basic Sciences

Results 1-3 (3)