The significance of drug repurposing in the future of AML treatment

A Layman’s Literature Review for the project “Characterisation of repurposed drugs as novel therapies in Acute Myeloid Leukaemia (AML)”

Abstract

Acute myeloid leukaemia (AML) is a cancer of the blood and the bone marrow which can affect any person at any stage of their life. Currently in use is a dual phase treatment course of chemotherapy that is intensive, often destructive and even fatal. Therefore, there is a large necessity for better treatment strategies to be discovered and employed. Drug repurposing can offer as a beneficial route of study into novel therapies for the treatment of AML and other diseases alike. Targeted compounds such as Bromocriptine and Tivantinib, which are specific to the indications of disease, can be studied at lower cost and with a shorter timescale. Alongside this is a lower risk of failure and the ability to use combination therapies where compounds are working in synergy. This means a greater chance of benefitting patients. Drug repurposing is not without its downfalls however. Chance findings related to reports of clinical trial members are often how a drug is found for repurposing and applying drugs with primary indications in one disease type to a completely new area often has low success. Such challenges of drug repurposing imply that greater care and study is needed before selecting it as a strategy. (199)

Introduction

Drug repurposing is the use of already known drugs, some of which successful and some failed in previous testing, as treatment for a new disease. Thalidomide, for example, seems a villainous drug to most due to causing serious birth defects in babies through use in morning sickness by pregnant women during the 1950s. Through repurposing however, it has now been shown to have a vast array of therapeutical uses such as in multiple myeloma, leprosy and Crohn’s disease (1).  The ReDO Project further put into practice this repurposing strategy and, in doing so, identified that out of 268 non-cancer drugs, 73% showed an anti-cancer effect (2). This conveys that there is a promising benefit and future in studying already known compounds for a variety of uses. Cancer is a wide term used to describe abnormal growth of cells over time. A blood cancer is a cancer which affects the blood, bone marrow and the lymphatics. Leukaemia occurs when a cell within the bone marrow, the production site of myeloid (red blood cells and white blood cells) and of lymphoid cells (B and T cells), goes rogue and multiplies greatly. Leukaemia can be further split up into acute or chronic, myeloid or lymphoid leukaemia. Acute myeloid leukaemia (AML) refers to a cancer caused by mutation (change within genes) in an immature cell of myeloid lineage whereas, chronic myeloid leukaemia would refer to one of mature myeloid lineage.

Current treatment strategies are harsh on the recipient’s body due to the nature of the chemotherapy used. In a study of 71 patients with AML, only 16 patients survived a course of chemotherapy without any adverse side reactions (3). Drug repurposing is therefore important in the world of cancer due to its identification of less toxic therapeutical compounds compared to some of those used in common therapies. Furthermore, it provides a greater chance of survival for vulnerable groups in AML, such as geriatric patients, to whom the current chemotherapy may prove more harmful than beneficial. (331)

Discussion

Drug Repurposing- Positives, Limitations and Challenges

Drug repurposing, also known as drug repositioning, is an efficient approach which cuts down on the time and money needed for development of a new drug. It has two routes, old drug against new target or old target with new drug (4). Current processes of drug identification and eventual development mean that the time scale can be up to 17 years in order to carry out the full 5 stage FDA process (see Figure 1a) (5). Drug repurposing can reduce this time to around 10-12 years through bypassing stages such as toxicity testing, manufacture and some clinical testing (see Figure 1b) (6).

Figure 1: A simplified schematic to show the process for (a) newly proposed drugs and (b) repurposed drugs.

Figures adapted from information in (5,6)

Mifepristone, an emergency contraceptive, was able to be clinically tested as a repurposed drug for Cushing’s syndrome with 28 people in comparison to a newly developed compound, levoketoconazole, which needed approximately 90 for the same use (7,8). This shows that the magnitude of further testing can be reduced and, in turn, the cost of running the testing will still be lower as well as also having a reduced time scale. On average, 40% of the cost of running a repurposed drug is reduced against that of investigating a newly developed compound (9). This is achieved through such bypasses given the repurposed drug has been approved for safe use, has a known mode of action and side effects and has its toxicity outlined through previous clinical testing. Such cut downs on time and cost through previously obtained knowledge are especially appealing when it comes to looking for treatments of rare diseases.

A rare disease is a disease such as AML, which affects a small portion of people in comparison to other diseases like coronary heart disease. For pharmaceutical companies, the negatives would outweigh the positives to begin research and development into most compounds directed at these rare diseases due to the costs of clinical testing, development and mass production whilst coupled with further losses in commercial value. This was especially true in the USA prior to the introduction of the Orphan Drug Act 1983 where only 10 products for rare diseases were approved, now rising to over 600 “orphan drug” approvals due to the incentivisation given to the companies through the initative (10).

Given the reduced cost of repurposed drugs, there is also the ability for research groups to study compounds that are directed towards these rare diseases without involving the pharmaceutical industry.

Drug repurposing is not without limitations however. Although these omitted processes and steps help reduce the risk associated with failure of drug development (see Figure 2), repurposing is not a guaranteed strategy to ensure a successful drug will be found. Failures in repurposed drugs often occur during the second phase of clinical testing (4). This however is usually not due to its pharmacokinetic profile (how the drug acts within a living organism) as there is copious information to outline such and so, reduced attrition rates.

There is also a degree of serendipity when it comes to drug repurposing, for instance, a patient has two indications and by chance, they can both be treated with exactly the same drug. A good example of such drug would be Viagra (sildenafil). Originally used to try and treat angina, a condition where reduced blood flow to the heart muscle causes chest pain, it became apparent that it was useful in the treatment of erectile dysfunction also (11). This does however rely on an individual reporting such effects.

A further challenge of drug repurposing is due to limited data relating to success rates, especially high ones. A drug which is successful for initial use which is applied in the same area i.e. one type of cancer drug being used to treat another, can give high success rates. It changes however when you apply a drug to a completely different area, with a large decrease in success. This is even more substantial with drugs that have failed initial indication (12). This opposes the main idea for use of drug repurposing as, in most cases, the desired outcome is to treat in a completely new area. (679)

Figure 2- A graph showing the risk against reward of various drug strategies.

Note the position of drug repositioning as low risk and high reward in comparison to other common strategies. *Small markets refers to development of drugs for rare diseases and has been backed by acts such as the Orphan Drug Act.

Figure taken from (6)

Acute Myeloid Leukaemia and Drug Repurposing

Acute Myeloid Leukaemia is a cancer of the blood and bone marrow. Specifically, it is the overproduction and overpopulation of immature myeloid cells due to a failure in differentiation (becoming more specialised) which, in turn, impede the bone marrow from its function of creating healthy blood cells. As a result, the decreased number of mature white cells leads to frequent infection and decreased red cells leads to anaemia. Furthermore, pain in joints and bones is common due to the vast number of leukemic cells.

AML is the most common leukaemia found in adults. Although it can occur at any stage of life, the average age of diagnosis is 68 (13). Age plays an important role in the overall survival (OS) of AML patients as, for a diagnosis made before the age of 45, there is a 60.4% relative 5-year survival which decreases to 7.9% when the age is above 65 for all races and both sexes (14). Typically, there are two phases for treatment of AML, induction therapy and post-remission/maintenance therapy in respective order. The aim of induction therapy is to kill as many of the leukaemia cells as possible through use of agents such as cytarabine and daunorubicin resulting in less cancer through the body or no cancer at all, called partial/complete remission respectively. Around 60-80% of patients below and 40-60% of patients above 60 years old enter complete remission (15).

Treatment for AML has remained relatively standard since the “7+3” treatment began in 1973. 7 days of cytarabine followed by 3 days of daunorubicin. This treatment carries side effects of bleeding, vomiting and hair loss. Furthermore, the intensive treatment of AML is renowned for carrying a complication of treatment related mortality (TRM), death due to treatment. TRM is also related to age (16). Cytarabine has however been found to be effective at low doses in elderly unfit for aggressive treatments (17). Although this is generally regarded as the “gold-standard” drug for chemotherapy, resistance caused relapse is frequent and overall survival of patients remains low (18). Induction therapy is usually followed by allogenic haematopoietic stem cell transplant, a treatment involving a transplant of an acceptable donor’s stem cells into the patient, which has potential curative outcomes. This again is wearily used due to the comorbidities, weakness, resistance to treatment and incidence of secondary AML associated with increased age (19). This therefore highlights the necessity for a treatment which is less detrimental to the health of the recipient, especially given the correlations with age and complications are so strong, noting again that median age is 68.

AML is not one disease, but a disease consisting of many subtypes. In addition, there exists a vast amount of molecularly distinct subtypes which are also age-specific (20). This enforces the need for novel therapies related to the age of the patient as a one for all based therapy will not produce an effective outcome for all patients.

Bromocriptine is a drug used to treat hyperprolactinaemia, Parkinson’s and peripartum cardiomyopathy (21). The associated side effects are minimal, most reporting only nausea. A recent repurposing study into bromocriptine has shown it to have an anti-cancer (cytotoxic) specificity for leukemic cells, causing arrest of proliferation and triggering death of the cells via apoptosis. This drug also shows a marked cooperative effect (synergy) with the previously used cytarabine, meaning a greater positive acceptance (17).  This is a promising discovery into therapy for AML as it resets the trend of the toxic and widely acting chemotherapeutical treatments used which cause various adverse side effects. A directed treatment, specific to leukemic cells is of much greater value as it acts in a targeted manner to address the problem. A removal of associated TRM further means a potential therapy for paediatric and geriatric patient groups.

GSK3 is an important kinase involved in many normal cell pathways such as transcription, apoptosis and stem cell regulation. In cancer it is found to be self-contradictory however, causing pathways which are usually down-regulated to be upregulated. As a result, it plays a supporting role in the maintenance of cancer and specifically in AML (22, 23). A further repurposed drug for use against AML has been found in the form of Tivantinib. This drug was previously used as a MET inhibitor and has now been used to target and inhibit GSK3 and GSK3. It causes a potent inhibitory effect on the reproductive ability of cells in the bone marrow of AML patients as well as inducing apoptosis and differentiation (increased specialisation). Another desirable trait of Tivantinib is that it can act in synergy with another anti-cancer drug, ABT-199. This acts on BCL-2, an anti-apoptotic protein upregulated by cancer cells. This is important in AML as the current approved FDA compounds for GSK inhibition consists of only one, LiCl, with disputable strength as a therapy due to its non-specificity for GSK3 (24). Given the specificity of Tivantinib and its ability to be used in combination therapy with ABT-199, it poses as an exciting and promising novel repurposed drug for AML. This is something which is greatly needed due to the lack of success and toxicity associated with the traditional AML treatments. (862)

Conclusion

Drug repurposing is a promising route of drug “discovery” for introduction of novel disease therapies. Although often serendipitous, supplication of compounds for use in a shorter time gives a promising future for disease. Lower costs associated also mean a more appealing environment for the pharmaceutical industry and even for research groups outside the industry. As a result, rare diseases like AML are more likely to have novel therapies studied. AML is in need of a less intensive, less toxic regime for treatment. High relapse rates as well as poor overall success associated with current chemotherapy do not give much promise to patients or physicians alike. Repurposed drugs with high specificity for leukemic cells or targets within leukaemia, such as Bromocriptine or Tivantinib, give a much-needed boost to successful treatment with added benefits of lower toxicity and TRM. Greater research is however needed into repurposing drugs in order to ensure the low risk of failure and to keep an exciting field of study worthwhile over

de novo

practices. (167)

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