Unlocking hidden potential: advancements, approaches, and obstacles in repurposing drugs for cancer therapy

Abstract

High rates of failure, exorbitant costs, and the sluggish pace of new drug discovery and development have led to a growing interest in repurposing "old" drugs to treat both common and rare diseases, particularly cancer. Cancer, a complex and heterogeneous disease, often necessitates a combination of different treatment modalities to achieve optimal outcomes. The intrinsic polygenicity of cancer, intricate biological signalling networks, and feedback loops make the inhibition of a single target frequently insufficient for achieving the desired therapeutic impact. As a result, addressing these complex or "smart" malignancies demands equally sophisticated treatment strategies. Combinatory treatments that target the multifaceted oncogenic signalling network hold immense promise. Repurposed drugs offer a potential solution to this challenge, harnessing known compounds for new indications. By avoiding the prohibitive costs and long development timelines associated with novel cancer drugs, this approach holds the potential to usher in more effective, efficient, and cost-effective cancer treatments. The pursuit of combinatory therapies through drug repurposing may hold the key to achieving superior outcomes for cancer patients. However, drug repurposing faces significant commercial, technological and regulatory challenges that need to be addressed. This review explores the diverse approaches employed in drug repurposing, delves into the challenges faced by the drug repurposing community, and presents innovative solutions to overcome these obstacles. By emphasising the significance of combinatory treatments within the context of drug repurposing, we aim to unlock the full potential of this approach for enhancing cancer therapy. The positive aspects of drug repurposing in oncology are underscored here; encompassing personalized treatment, accelerated development, market opportunities for shelved drugs, cancer prevention, expanded patient reach, improved patient access, multi-partner collaborations, increased likelihood of approval, reduced costs, and enhanced combination therapy.

The positive aspects of drug repurposing in oncology are underscored here; encompassing personalized treatment, accelerated development, market opportunities for shelved drugs, cancer prevention, expanded patient reach, improved patient access, multi-partner collaborations, increased likelihood of approval, reduced costs, and enhanced combination therapy.

Fig. 1. A common drug development timeline [161].

Repurposed drugs can often join this timeline in the third stage (clinical trials) skipping up to 7 years of study that a new drug would require. Created using Biorender, May 2023.

Fig. 2. Potential screening methods for identifying efficacious repurposed drugs.

These methods may either be in vitro or in vivo studies, and may include drug-based phenotypic screens, target-based high throughput assays. Alternatively, computational or virtual screening (in silico) may be done through signature matching (using –omics data), AI or machine and deep learning, genome-wide association studies and disease/target association studies, or chemical similarity and molecular docking simulations. Created using Biorender, February 2023.

Fig. 3. Rationale for combination therapy in oncology.

The use of multiple drugs can target the inter-tumoural heterogeneity between patients, intra-tumoural heterogeneity within the same tumour (including the cancer stem cell subpopulation). Multiple drugs also target multiple pathways which may be redundant or compensatory allowing full cessation of proliferation, invasion and metastasis. Created using Biorender, May 2023.