Abstract
Cancer is a leading cause of mortality worldwide and matters are only set to worsen as its incidence continues to rise. Traditional approaches to combat cancer include improved prevention, early diagnosis, optimized surgery, development of novel drugs, and honing regimens of existing anti-cancer drugs. Although discovery and development of novel and effective anti-cancer drugs is a major research area, it is well known that oncology drug development is a lengthy process, extremely costly and with high attrition rates. Furthermore, those drugs that do make it through the drug development mill are often quite expensive, laden with severe side-effects and unfortunately, to date, have only demonstrated minimal increases in overall survival. Therefore, a strong interest has emerged to identify approved non-cancer drugs that possess anti-cancer activity, thus shortcutting the development process. This research strategy is commonly known as drug repurposing or drug repositioning and provides a faster path to the clinics. We have developed and implemented a modification of the standard drug repurposing strategy that we review here; rather than investigating target-promiscuous non-cancer drugs for possible anti-cancer activity, we focus on the discovery of novel cancer indications for already approved chemotherapeutic anti-cancer drugs. Clinical implementation of this strategy is normally commenced at clinical phase II trials and includes pre-treated patients. As the response rates to any non-standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I (Top1) inhibitors and Top1 as a potential predictive biomarker as case in point.
Highlights
Despite the significant improvements in diagnosis and treatment experienced in the past few decades, cancer remains the leading cause of death worldwide, and deaths from cancer are forecasted to reach a staggering 13.2 million deaths by 2030 [1]
This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I (Top1) inhibitors and Top1 as a potential predictive biomarker as case in point
Currently, few people would argue against that the future of drug development in oncology lies with the identification of predictive biomarkers capable of identifying those subsets of patients who will benefit from a given therapy
Summary
Despite the significant improvements in diagnosis and treatment experienced in the past few decades, cancer remains the leading cause of death worldwide, and deaths from cancer are forecasted to reach a staggering 13.2 million deaths by 2030 [1]. Overall, targeted therapies have shown relatively modest clinical benefit, presumably due to intrinsic resistance of tumors to inhibition of signaling intermediates, due mainly to redundancy in signaling pathways in cancer cells [4,5,6,7,8] As a consequence, these novel treatment modalities are not single-agent treatments as they, most often, are combined with conventional cytotoxic drugs. Camptothecins are used for standard treatment of CRC but not breast cancer [21] These differences in standard clinical use of chemotherapeutic agents essentially reflect the magnitude of clinical benefit attained by the different drugs in clinical trials for each specific disease.
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