Repurposing approved drugs for cancer therapy

Abstract

Background: Many drugs approved for other indications can control the growth of tumor cells and limit adverse events (AE).

Data sources: Literature searches with keywords 'repurposing and cancer' books, websites: https://clinicaltrials.gov/, for drug structures: https://pubchem.ncbi.nlm.nih.gov/.

Areas of agreement: Introducing approved drugs, such as those developed to treat diabetes (Metformin) or inflammation (Thalidomide), identified to have cytostatic activity, can enhance chemotherapy or even replace more cytotoxic drugs. Also, anti-inflammatory compounds, cytokines and inhibitors of proteolysis can be used to control the side effects of chemo- and immuno-therapies or as second-line treatments for tumors resistant to kinase inhibitors (KI). Drugs specifically developed for cancer therapy, such as interferons (IFN), the tyrosine KI abivertinib TKI (tyrosine kinase inhibitor) and interleukin-6 (IL-6) receptor inhibitors, may help control symptoms of Covid-19.

Areas of controversy: Better knowledge of mechanisms of drug activities is essential for repurposing. Chemotherapies induce ER stress and enhance mutation rates and chromosome alterations, leading to resistance that cannot always be related to mutations in the target gene. Metformin, thalidomide and cytokines (IFN, tumor necrosis factor (TNF), interleukin-2 (IL-2) and others) have pleiomorphic activities, some of which can enhance tumorigenesis. The small and fragile patient pools available for clinical trials can cloud the data on the usefulness of cotreatments.

Growing points: Better understanding of drug metabolism and mechanisms should aid in repurposing drugs for primary, adjuvant and adjunct treatments.

Areas timely for developing research: Optimizing drug combinations, reducing cytotoxicity of chemotherapeutics and controlling associated inflammation.

Keywords: Covid-19 adjuvant treatments; cytokine storm; interferons (IFN); interleukin-2 (IL-2); metformin; proteosome inhibitors; thalidomide; tumor necrosis factor (TNF); unfolded protein response (UPR).

Fig. 1

Alkylating agents used for treating leukemias, chlorambucil (left) and bufulfone (myleran, right) were patterned after toxic nitrogen mustard gas (center) during many design iterations. 3D chemical structures are from Pubchem; atom colors are: carbon, gray; hydrogens, small white; nitrogen, blue; sulfur, yellow; chloride, green; oxygen, red.

Fig. 2

Metformin (dimethylbiguanide) used for diabetes treatment.