The University of British Columbia
B.Sc., University of British Columbia, 2003
Friday, Nov 18, 2011 at 11 AM
LOCATION: Lecture Theatre, BCCRC
Bioinformatic Approaches to Drug Repositioning
Repositioning existing drugs for new therapeutic uses is an efficient approach to drug discovery, since approved drugs have known clinical histories. However, most successfully repositioned drugs to date have been serendipitously discovered. The goal of my thesis was to use computational methods to rationally predict drug repositioning candidates.
We first performed a virtual screen (VS) of 4621 drugs against 252 drug targets using molecular docking. Our method emphasized removing false positive predictions using stringent criteria from known-interaction docking, consensus scores, and rank information. Published literature indicated experimental evidence for 31 of the top predicted interactions, supporting our approach. We also validated the cancer drug nilotinib as a potent MAPK14 inhibitor in vitro, suggesting a potential use for this drug in treating inflammatory diseases.
The computational method was applied to the triple-negative breast cancer (TNBC) targets EGFR and p90RSK. For RSK, we also complemented the VS with a high-throughput experimental screen to predict top repositioning candidates. Secondary screens for top EGFR drugs were inconclusive but we found three novel RSK inhibitors from an off-patent drug database that inhibited RSK activity, blocked RSK signaling, and inhibited proliferation of TNBC cell lines. These drugs thus have potential to be repositioned to TNBCs.
Finally, we were able to rationally reposition renal cell carcinoma drugs for a patient with a rare adenocarcinoma of the tongue, using massively parallel sequencing to characterize the tumor. Whole genome and transcriptome sequencing of the patient’s tumor and normal cells detected sequence, copy number, and expression aberrations, and our analysis suggested that the tumor was driven by the RET oncogene. Treatment with RET-inhibiting drugs provided eight months of disease stabilization, after which the disease progressed. We also sequenced the post-treatment tumor and found changes consistent with acquired therapeutic resistance.
Overall, my thesis investigated two high-throughput approaches for drug repositioning research: virtual screening of drugs and targets and personalized medicine via sequencing.
Supervisor: Dr. Steven Jones, Department of Medical Genetics, University of British Columbia