Researchers identified ten potential new and experimental combinations for treating breast cancer, using in-silico analysis. A team of researchers at the Institute for Research in Biomedicine (IRB Barcelona) studied the pairing of 64 drugs used for treating breast cancer, where half of them already existed and the remaining half were investigational drugs.
Among the 10 combinations, 7 were tested in breast cancer cells in-vitro analysis and the results demonstrated synergy among the drugs; the effect was higher when used with combinations. One of these combinations was confirmed to be effective in mice. The findings in mouse models denote that the combination of two drugs namely raloxifene and cabozantinib, which were prescribed by oncologists, “significantly” enhance the anti-tumour potential of the two drugs.
Breast Cancer Treatment With Combined Drugs
According to Patrick Aloy, who serves as ICREA researcher and also as the head of the Structural Bioinformatics And Network Biology Lab at IRB Barcelona, “We find many more synergistic combinations in-silico than combinatorial assays till date with high-performance lab techniques, and we can offer experimental information. This denotes that earlier computational analyses provide better results and are more consistent.” The researchers noted that in 70% of the combinations tested, the synergic effect of the two drugs is “much higher” than the effect of each drug alone and hence, the similar effect could be obtained even by a smaller dose.
For this study, when scientists tested the combination of raloxifene and cabozantinib as treatment in mice, they noticed that the tumor got reduced in size by 60%, whereas individually the effect of each drug only prohibited tumour growth. Additionally, with the combination, the dosage of raloxifene can be three times smaller and the dose of cabozantinib can be 25 times smaller when compared to the treatments now. “This smaller dosage itself is highly significant since drugs are toxic in nature and are meant to kill cells. When a smaller dose has the same or greater therapeutic effect, it is an important benefit for the patients, since side effects could be reduced. In addition resistance would be delayed or avoided¯ explains Aloy.
One of the challenges of cancer treatment that oncologists and patients have to deal with is treatment resistance. Cancer cells turn out to be “resistant” to drugs that should destroy them. Resistance occurs since the cancer cell, by means of random mutations, begins to escape from the effect of the drug. Among 15% of cases, different molecular signaling pathways are triggered to permit tumour cells to divide again or to avoid programmed cell death. Combination therapy by two or more drugs appears as a promising strategy to handle this type of treatment resistance.
“Our studies have facilitated us to identify the signalling pathways that are triggered by the combined action of two drugs,” says Samira Jaeger, who is the first author of this study. The scientists confirmed at the molecular level that the molecules predicted in the in-silico models were really suppressed. “By combination of drugs, we intend to attack the cancerous cell from various sides at the same time, therefore it will be hard for the cell to resist against the treatment, since the pathways that permit it to live and multiply will be affected simultaneously,” she clarifies.
Having confirmed the computational network model, the scientists have three lines of study currently. First, with the objective of focusing on clinical applications, they will test combination therapy raloxifene and cabozantinib in cancerous cells obtained from patients and transferred in mice. Second, with the same objective of discovering more efficient treatments for breast cancer, the lab will work on combining an anti-tumour agent with a drug used to treat other conditions like high blood pressure and diabetes. Lastly, Aloy’s lab is enhancing an experimental method which will facilitate them to confirm the combination therapies that have the highest enduring effectiveness in fighting against resistance.