The chemotherapy drugs used as part of cancer treatments can have serious side effects, especially on heart tissue, resulting in arrhythmia and even heart failure. To limit these adverse effects, clinicians may reduce the dosages and increase the time periods between rounds of chemotherapy, but this reduces the efficacy of the anticancer treatment, and offers a worse quality of life for the patient. The damage to heart tissue is precipitated by p38 mitogen-activated protein kinases. These proteins perform many functions in the body, one of which is to respond to oxidative stress generation, ultimately triggering cell death. “Because of their particular mechanism of action, chemotherapy drugs such as anthracyclines cause oxidative stress accumulation, and cardiomyocytes are particularly sensitive to these changes,” explains p38_InTh project coordinator Angel Nebreda.
Over the past few years, researchers have looked for ways to inhibit the p38 signalling pathway to limit damage to healthy heart tissue during chemotherapy. These inhibitors typically work by preventing ATP from binding to the protein, blocking its function. However, clinical trials for these ATP competitors have produced disappointing results. The EU-funded p38_InTh project set out to advance the understanding of a novel group of compounds that are able to inhibit p38 proteins in a different way. “We have identified compounds that are not ATP competitors but interfere with p38 autophosphorylation,” adds Nebreda. “These compounds bind to the protein and induce a conformational change, which results in altered activity, but don’t directly interfere with ATP.” Experiments carried out by the Nebreda team at the Institute for Research in Biomedicine in Barcelona showed the compounds are very specific for p38 and are tolerated by rats in high concentrations. Additional tests demonstrate that the compounds do not interfere with the effect of chemotherapeutic drugs on cancer cells. “Academically we have nice compounds that are new, the big question now is if they are going to work in vivo,” says Nebreda.
Path to commercialisation
The project was supported by the European Research Council. “This funding was critical, it has really made an important contribution, and has allowed us to move forward from biochemistry and cell research to preclinical studies,” observes Nebreda. The team has filed an international patent application on their compounds, opening the door to commercialisation. “We are looking to see if we can license our best compounds, or make a spin-off company to continue developing the project. We need to engage pharmaceutical companies eventually, as the resources available in academia to follow this type of project are very limited,” explains Nebreda. Next, Nebreda plans to advance to animal experiments, testing the compounds in conditions involving heart damage such as chemotherapy treatment or infarction: “If the experiments with rats are successful, our next goal is to start thinking about clinical trials. It’s all very exciting.”
p38_InTh, chemotherapy, cancer, p38, heart, kinases, ATP, inhibitor