Drug repurposing for leukemia patient treatment: let’s take the stock.

Drug repurposing (also referred to as drug repositioning) is a drug discovery strategy in which drugs approved to treat certain diseases are tested in order to be re-proposed for the treatment of a different disease.

               The conventional process leading to the identification of new drugs includes a number of pre-clinical tests in in vitro and in vivo models (to test drug efficacy and toxicity), followed by three “clinical” phases: phase I, which is aimed to test in patients safety of the compounds;  phase II, to test in patients efficacy of the new drug; and phase III, to compare efficiency of the new treatments compared to the standard one.

In drug repurposing, instead, working with compounds that have been already approved to be used for the treatment of other human diseases –for which safety has been previously assessed– enables to skip phase I (and some of the pre-clinical studies). Therefore, compared to the conventional process for the identification of new drugs, drug repurposing is faster, less expensive, and does not require toxicity tests.

How does drug repurposing work? Two different approaches can be exploited for drug repurposing: 1) “experimental repurposing”, namely, by testing the ability of known drugs (by exploiting collections of chemical compounds –which are active against known targets, safe for patient administration and approved for the use in humans) to bind target proteins different from those they were initially approved for. Alternatively, by assessing, in vitro or in vivo, cell behaviour (for instance, cell growth or cell death) upon drug treatment; 2) by “computational  repurposing”, which relies on the integration of data on gene expression, chemical structure, proteomic and genomic data, based on the principle that similar drugs may have also the same biological effect, and act on the same targets and cell pathways.

Drug repurposing has been largely used in cancer research. In this context, we refer to either “soft” or “hard” repurposing. Soft repurposing means that a drug previously used for cancer treatment is used in a different cancer type, whereas hard repurposing means that a drug used in a different disease is used to treat cancer patients. In acute myeloid leukemia (cancer characterized by the hyperproliferation of blood cells that do not reach their final maturation), for instance, by a soft repurposing approach scientists demonstrated that arsenic trioxide, which is currently used for the treatment of acute promyelocytic leukemia (APL, a subtype of leukemia characterized by a chromosomal translocation) patients, is effective in non-APL leukemia patients when combined with other drugs, offering an option for patients who cannot undergo chemotherapy. An example of hard drug repurposing is thalidomide, which was initially used to ameliorate symptoms of morning sickness of pregnant women, then retracted from the market due to the effects on embryo development, and finally approved for the treatment of multiple myeloma.

The most promising drugs identified by drug repurposing are called “hits”. Hits need to be validated in pre-clinical studies. Of 32 compounds that so far have been identified by drug repurposing in acute myeloid leukemia, 27 were confirmed after pre-clinical validation, suggesting their potential efficacy for patient treatment. Among these, we can mention tigecycline, an antimicrobial which has been found to selectively kill leukemia cells and decrease tumor growth in mouse models by blocking mitochondrial protein synthesis; Metformin, a drug targeting cell metabolism, potentially effective in the treatment of acute myeloid leukemia. Similarly, Valproic acid, commonly used in epilepsy, has been evaluated as anti-cancer agent because of its ability to inhibit Histone deacetylases (proteins that, through chemical modifications of histone proteins associated with the DNA, are involved in DNA wrapping) which are often overexpressed in cancer cells, inhibiting key processes of leukemia cell growth; and inhibitors of lysine demethylase 1A (LSD1, another class of proteins that through chemical modifications of histone proteins associated with the DNA, are involved in DNA wrapping) usually used as antidepressants, are currently being tested as drugs for the treatment of acute myeloid leukemia.

Among the 32 compounds initially identified by drug repurposing, 13 are currently in clinical trial –either as single agent or in combination with other treatments. However, so far, none of them have been approved for the treatment of leukemia patients, mainly due to clinical inefficacy and toxicity; indeed, the combination with other treatments, aiming at a higher efficacy, actually frequently leads to unacceptable side effects.

In light of these data, the authors wonder about the actual success of drug repurposing in leukemia, highlighting that, in spite of the generally accepted opinion, so far, in acute myeloid leukemia, drug repurposing was not really faster compared to the conventional approaches for the identification of new drugs, and phase I trials (normally aimed at identifying the appropriate dose) cannot always be skipped as repurposing drugs are often administered at different doses compared to the original prescription or in combination with other drugs, thus requiring additional tests to assess toxicity and safety. Finally, the authors highlight some aspects to be considered in order to optimize this approach for acute myeloid leukemia, such as the improvement of pre-clinical screening, with more specific and appropriate tools, in order to get more robust candidates for clinical validation; the use of better disease models; sharing of all the screening data with other scientists; the parallel (epi)genetic profile of the patients, to allow for a more personalized, “patient-tailored” approach with the repurposed drugs, which can ultimately make them more effective.

Reference: Has Drug Repurposing Fulfilled its Promise in Acute Myeloid Leukaemia? Valli, Gruszka, Alcalay. J Clin Med 2020