Anticancer drug development The Way Forward
Anticancer drug development: the grand challenges
Author: William N. Hait
The past three decades have seen spectacular advances in our understanding of the molecular and cellular biology of cancer. However, with a few notable exceptions, such as the treatment of chronic myeloid leukaemia with imatinib, these advances have so far not been translated into major increases in long-term survival for many cancers. Furthermore, data suggest that the overall success rate for oncology products in clinical development is ~10%, and the cost of bringing a new drug to market is over US$1 billion. Understanding the reasons — and suggesting potential solutions — requires a careful analysis of the grand challenges of anticancer drug development.
Understanding the target in context
The anticancer drug discovery process often begins with a promising target; however, there are several reasons why the eventual outcome for a particular cancer target may be disappointing. For example, the role of the target in the pathogenesis of specific human malignancies may be incompletely understood, leading to disappointing results.
First, many targets lie within signal transduction pathways that are altered in cancer, but, owing to the complex nature of these pathways, upstream or downstream components may make modulating the target of little or no value. For example, RAS mutations activate signalling pathways that are downstream of the epidermal growth factor receptor (EGFR), rendering EGFR inhibitors such as cetuximab inactive.
Second, target overexpression is often overrated.There are some instances in which overexpression predicts response to treatment; for example, HER2 overexpression in breast cancer patients predicts a response rate to the HER2-targeted antibody trastuzumab of 16-23%. For other drugs, such as dihydrofolate reductase inhibitors, overexpression of their target predicts resistance. Other potential drug targets are overexpressed in many types of cancer, but this does not predict response, as is the case with several drugs that target EGFR.
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