Plk1 inhibitors have recently received the recognition of "Innovative Therapy in Leukemias" by the US Drug Regulatory Agency (FDA). However, a study published this week in the journal Nature Medicine by researchers at the National Cancer Research Center (CNIO) suggests that prolonged use of these inhibitors can produce not only problems of arterial hypertension but also blood vessel rupture and severe cardiovascular problems.
The promise of personalized medicine is based on knowing the function of each of our genes and proteins and selecting the appropriate drugs against those proteins according to the alterations of each patient. In recent years, inhibitors of cell cycle regulators - the process that controls the proliferation of tumor cells - have shown their utility in various tumors such as breast cancer. Among the new drugs that use this strategy is volasertib, a Plk1 protein inhibitor that has shown very promising results in the treatment of acute myeloid leukemia and has recently received the recognition of "Innovative Therapy" by the FDA for its effectiveness against This tumor in clinical trials.
"One of the problems we encounter when trying new drugs on patients is that we know very little about the actual function of the proteins they are targeting, " explains Marcos Malumbres , study coordinator and head of the Division Group Cell and Cancer of the CNIO. His team wanted to study the actual function of Plk1 protein in mammals using laboratory mice as a model. "Many of the proteins that are tested in clinical trials have been studied primarily in organisms such as yeast or flies or in human cells in culture. However, these studies are insufficient to know the relevance that a protein can have in one organ or another, "says Malumbres.
To study the role of Plk1, the researchers generated a mouse variant with decreased levels of that protein. "It was surprising, half the mice died of chest bleeding due to ruptured arteries," says Guillermo de Cárcer, a CNIO researcher and the first author of the article. "One of the most striking results was that the males died the first night spent with females in the same box. One of the situations that causes the greatest rise in blood pressure in young males. "
Plk1 had initially been characterized as a protein that controls how cells multiply, catching the attention of pharmaceutical companies who saw in it a new therapeutic target to slow tumor growth. Several inhibitors of this protein are found in clinical trials for various types of tumors . One of these inhibitors, volasertib, has recently been recognized as one of the best therapies against acute myeloid leukemias. Like most chemo drugs, volasertib causes some side effects still under study.
This team of researchers has also participated in the team of Juan Miguel Redondo of the National Center for Cardiovascular Research (CNIC), as well as scientists from the Cancer Research Center (CIC) in Salamanca, the University of Salamanca and London Research Institute, in London, treated mice with low doses of volasertib for two months. Mice with low levels of Plk1 or treated with volasertib had no growth problems but showed ruptured arteries and secondary cardiac problems. These results indicated that arteries are even more sensitive to inhibition of Plk1 than other tissues in adult organisms. In fact, the work shows that Plk1 is an essential protein for the contraction of cells that decorate the wall of arteries,
Cardiovascular problems and cancer are major causes of morbidity and mortality in advanced societies. The involvement of Plk1 in the control of both processes will have important repercussions on future biomedical developments. "Our data do not go against the use of Plk1 inhibitors in the clinic," warns Malumbres. "Unfortunately, all drugs have a side effect or another. The problem is not knowing it. We have to study very well and in suitable models the biological function of proteins before using them as therapeutic targets in patients. Only in this way will we be able to design adequate protocols for patients and with fewer side effects, "concludes the CNIO researcher.
Cárcer, G. D., Wachowicz, P., Martínez-Martínez, S., Oller, J., Méndez-Barbero, N., Escobar, B., . . . Malumbres, M. (2017). Plk1 regulates contraction of postmitotic smooth muscle cells and is required for vascular homeostasis. Nature Medicine. doi:10.1038/nm.4364