Clinically Irrelevant Concentrations of Kinase Inhibitors Contribute to Failure of Drug Repurposing Efforts in Clinical Trials: a Meta-Analysis
Open Access
- Author:
- Shah, Anushka
- Area of Honors:
- Biology
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Justin R Pritchard, Thesis Supervisor
Richard W Ordway, Thesis Honors Advisor - Keywords:
- clinical trials
repurposing
cancer
kinase inhibitors
meta-analysis
biology
in vitro
drug concentrations - Abstract:
- Given drug development’s rising costs and the need to combat cancer’s devasting consequences, drug repurposing – positioning approved drugs to treat diseases beyond their original context – is an efficient approach to develop new cancer treatments. The repurposing of targeted kinase inhibitors has especially been encouraged. However, the overall high failure rates of cancer clinical trials indicate a negative outlook for repurposing and call for explanations. A major consideration is ineffective preclinical development, starting from in vitro studies where faulty claims of a drug’s activity can be based on clinically irrelevant concentrations. This misleading in vitro rationale can support clinical lines of research. To further explore these issues, we used the clinicaltrials.gov and MEDLINE databases to conduct a meta-analysis on clinical trials involving established kinase inhibitors, imatinib and erlotinib, and the concentrations used by supporting in vitro studies. Our objective was to understand if there is a relationship between clinical outcomes of the drugs in the tested diseases and the clinical relevance of the supporting in vitro concentrations. We found that the imatinib and erlotinib repurposing efforts were more likely to fail and were correlated with exceedingly high concentrations used in supporting in vitro studies. Our findings highlight and expand existing in vitro and clinical trial trends involving other cancer drugs and non-cancer drugs. Future meta-analyses can extend into other kinase inhibitors and other preclinical development considerations. The work reported here adds support to the concept that improving translational cancer research will lead to successful drug repurposing and positive clinical trials.