Matrix combination screening is a system that allows for the quick narrowing down of extensive lists of drug combinations with the potential to be beneficial to patients.
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How do scientists identify which drug combinations work the best?
For the treatment of diseases, such as cancer, HIV and malaria, multiple drugs are used in combination. It was through trial and error that effective combinations were found, and can include up to five drugs in certain cases, such as those affected with cancers of the blood.
As medicine has progressed, more and more drugs have become available for use, as well as trials. Due to this increase, there is need for a more effective method than trial-and-error to test which combinations are the most effective in treatment.
Problems with the trial-and-error approach
While treating patients with a combination of drugs, it is possible that undesired effects may occur. These occur in the absence of extensive studies on the interactions of drug combinations or their mode of actions.
In the case of malaria treatment, drugs used alongside artemisinin-based drugs could potentially be targeting the same pathway. This means that resistance to one of the drugs would indicate potential resistance to the others, and thus therapy failure.
Matrix combination screening is a method of rapidly screening the effect of drug combination on cells, or biochemical or molecular pathways, which play a role in disease. This way, the combinations, which are most effective without being toxic can be selected for further study in animals and humans. This in turn may lead to treatments that may be deliverable at lower, less toxic doses, and ones where treatment resistance does not develop rapidly.
How does this work in practice?
Antimalarial drugs
Malaria is a parasitic infection transmitted by mosquitos, which can be potentially life threatening. Due to the increased resistance of the Plasmodium parasites to antimalarial drugs, a combination therapy is used.
The study by Mott and co. used high-throughput matrix combination screening to find new, effective drug combinations against the Plasmodium parasite. An ideal combination would have pharmacokinetics and pharmacodynamics, which are compatible, as well as different mechanisms of action so that resistance to one drug does not lead to resistance in the others. Moreover, drug combinations should have no significant toxicity, and be effective against drug resistant parasites.
To start with, the team looked at 2317 compounds. These compounds included antimalarial drugs, investigational drugs, as well as small molecules, which could potentially have antimalarial functions. Initially, these compounds were tested alone, and those that were potent, “mechanistically interesting” and had clinical relevance were selected for the next step.
The researchers then carried out 11 rounds of combination screening, where the results of the previous screen informed the combinations used in the next round of screening. The compounds were plated in either a 6x6 (1:3 dilutions) or 10x10 (1:2 dilutions) matrices. By using this method, the team were able to screen 13,910 combinations on three different strains of P. falciparum, which resulted in 728,216 data points.
In these combination screens, the researchers included drug combinations, which were already approved. They found that two of the approved combinations showed favorable interactions. They also found 13 more combinations, which showed better synergy than the two combinations, and also found novel combinations that illustrated promise.
Ewing sarcoma
Ewing sarcoma is a cancer of the bone and soft-tissue, which is aggressive and mostly affects children and adolescents. Despite a better understanding of this disease process, those who have relapsing/recurrent or metastatic Ewing sarcoma have a poor prognosis. This is also not helped by the use of toxic drugs to treat the disease.
To find better treatment combinations, Heske and co. used matrix combination screening. They took a library of 1,912 compounds and exposed cell lines derived from Ewing sarcoma to these compounds. Of these, 679 were shown to be effective against the Ewing sarcoma cell lines.
After taking into account factors such as mechanism of action, potency, whether the compound is an approved drug, and activity across different screens, 66 compounds were selected for further combination screening.
From these matrix combination screens, the researchers found that PARP inhibitors and nicotinamide phosphoribosyl transferase inhibitors showed synergy, and thus compounds that target these could be used as a potential therapy for Ewing sarcoma.
Sometimes there is a need to analyze treatment combinations, in order to see if they are in fact the most effective treatment option. The two research examples, using the malaria parasite (Plasmodium) and Ewing sarcoma cells, show how a big number of combinations can be screened, so that only the most effective and the safest are selected for further in vivo testing.
Further Reading