Cancer is one of the leading causes of death in the world today, causing nearly 10 million deaths in 2018 alone. Despite extensive research into new treatments, when these eventually reach the market, they are often very expensive. The strategy of drug repurposing is being applied to identify already approved drug products as potential cancer therapies. This can bring new cancer treatments to patients faster and at a lower price. A review, published in Signal Transduction and Targeted Therapy [1], summarizes approaches used for drug repurposing and discusses the main barriers to uptake.
The study also presents various promising repurposed non-oncology drugs for clinical cancer management [2].
The study outlines that, before an old drug can be selected for evaluation as an anticarcinogen with effectiveness and therapeutic potential, a mechanistic assessment of the drug effect in preclinical models is required. There are a number of systematic approaches that must be applied to carry out this assessment. Broadly, these are computational and experimental, and they are most successful when carried out in a collaborative and flexible manner.
The most commonly used computational and experimental approaches and examples of drug repurposing cases are detailed below.
Computational and experimental approaches to drug repurposing
Computational approaches based on molecular theory (MOT)
Computational approaches based on MOT create an understanding of a drug at the molecular level and match it with clinical symptoms of neoplasms. These are different symptoms from those for which the drug was originally approved or developed. The study outlines that these approaches involve comprehensive analysis of experimental data, such as chemical or protein structure, gene or protein expression, and various omics data. This then assists researchers in putting forward a repurposing hypothesis.
In these computational approaches, molecular structure analysis can predict binding site complementarity between ligands and targets. The study notes that, high-quality structural data of known receptor targets involved in cancer, can accurately predict specific drug targets using drug libraries.
Another computational approach involves signature or pathway matching. Today, a variety of omics studies of cancer are caried out, these deepen our understanding of tumour hallmarks at the molecular level; and provide big data that can support drug repurposing through the application of advanced bioinformatics. Using this approach, there are a number of ways whereby novel drug–disease relationships can be identified to indicate potential drug repurposing possibilities for cancer treatment.
Computational approaches based on Real World Data (RWD)
Computational approaches based on Real World Data (RWD) can also aid in drug repurposing. RWD is mainly composed of real electronic health records (EHRs) of patients characterized by large and complex datasets. The study notes that patient data have considerable value as a source for drug repurposing by identifying consistent signals. In addition, with an abundance of EHR data, statistical significance is of importance.
Experimental approaches based on intermolecular interactions
The study outlines that, proteomic techniques using a combination of affinity chromatography and mass spectrometry, can show protein interactions based on intermolecular forces. Such methods have been widely used for target validation which has facilitated drug repurposing. Here, cells and/or animals are treated with selected drugs and then undergo proteome analysis to quantify any protein changes that occurred.
In addition, the study notes that approaches based on chemical genetics are also dependent on intermolecular forces and can help explain the relationship between binding and drug efficacy.
Experimental approaches based on phenotypic screening
The study highlights that phenotypic screening is a direct way of drug repurposing as it analyses the relative effects in a model even if preceding studies have not identified candidate drugs targets. Such phenotypic screening uses cell based in vitro assays.
Challenges for drug repurposing
A variety of non-oncology drugs have already been repurposed for cancer treatment. However, very few of these are included in published clinical cancer practice guidelines. These products have the advantage of exhibiting demonstrated anticancer pharmacokinetic properties, and acceptable safety and tolerability in humans. However, they may fail to become accepted treatment options with high uptake due to competition from successful new drug development. The products may also face legal and regulatory barriers, such as patent-related considerations and inequitable prescription charges, these are further outlined below.
Patent-related considerations
The study notes that, for drug product patent holders, a repurposed product for cancer therapy could bring considerable profit. However, the intellectual property status of these candidates is often ambiguous and unpatentable. As such, it is generally non-profit organizations (such as universities and hospitals) who are interested in developing such drugs as returns on investment could be low. The Repurposing Drugs in Oncology (ReDo) project, less than 5% of the 72 products being trialed are sponsored by pharmaceutical companies.
In addition, a new method-of-use patent can be obtained for off-patent drugs and the repurposing of generics. However, the patent application process is strict and required detailed data. Such patents can be challenged by generics companies which are costly in terms of time and money. As such, the study notes that patent consideration-induced market exclusivity is a key hurdle in drug repurposing.
Inequitable prescription charges
The pharmaceutical industry can influence the drugs prescribed by physicians and bought by patients through promotion and marketing. In some cases, this can lead to standardized therapies being those that are more costly, despite not being clinically advantageous over cheaper drug options.
Conclusions
The study notes that the use of non-oncology drugs that have the potential to target the multiple hallmarks of cancer and related cancer biology, rather than directly killing the cancer cells, can play a role in the road towards precision and personalized treatment. In addition, the ever-increasing availability of biomedical data from public databases and the continued advances in techniques and analytical methods, have great potential to be used for the accurate identification of repurposing candidates.
Conflict of interest
The work of the paper [1] was supported by grants from the Chinese NSFC (nos. 81821002, 81790251, and 81773143), and Guangdong Basic and Applied Basic Research Foundation (2019B030302012).
The authors declare no competing interests.
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References
1. Zhang Z, Zhou L, Xie N, Nice EC, Zhang T, Cui , et al. Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduct Target Ther. 2020;5(1):113.
2. Jensen AR. Repurposing non-oncology drugs for cancer treatment. Generics and Biosimilars Initiative Journal (GaBI Journal). 2021;10(2):51-2. doi:10.5639/gabij.2021.1002.011
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