The collaborative research center "Pulmonary Hypertension and Cor pulmonale" is investigating pulmonary hypertension in detail and striving to develop new therapies. Prof. Dr. Friedrich Grimminger and Prof. Dr. Ralph Schermuly from the Department of Medicine at the Justus-Liebig-Universität Gießen (JLU) report on the identification of a molecular mechanism that controls the disease from the vessel wall.
Cyclin-dependent kinases (CDKs) 2, 4 and 6 are present in the lung tissue and in isolated cells of pulmonary arterial hypertension (PAH) patients in concentrations as conspicuous as those found only in breast cancer patients. Modern cancer therapy therefore also includes a drug blockade of these key proteins.
The authors of the study now used these CDK inhibitors, established in cancer therapy, in preclinical studies. They followed the hypothesis that these CDK inhibitors also inhibit the overactivated signaling pathway in lung patients so effectively that the disease comes to a standstill. Their hope of stopping the abnormal remodeling of the blood vessels was confirmed. Surprisingly, it was even possible to regenerate the already pathologically narrowed blood vessels.
The observation that pathological wall thickenings of the blood vessels that had already developed could be "repaired" is an unexpected success. The use of cancer drugs in heart failure is a completely new perspective. Two CDK inhibitors, Dinaciclib and Palbociclib, were used. "Palbociclib is approved for the treatment of advanced breast cancer due to its inhibitory properties on tumor cells," explains Prof. Grimminger, who himself works as an oncologist.
In the isolated cells, the targeted inhibition of CDKs by switching off a downstream signaling pathway (CDK retinoblastoma protein E2F signaling pathway) led to an interruption of cell growth and thus to a significant decrease in excessive cell proliferation. In two experimental models of PAH, Palbociclib showed a reduction in pathological vascular remodeling. This was accompanied by a significant improvement in overall cardiac output.
"The data show that the inhibition of CDK by drugs such as palbociclib represents a new therapeutic option for the treatment of PAH patients that targets the pathological vascular remodeling of the lung and right heart," explains Prof. Schermuly. Although the overall genesis and development of PAH are complex, the results suggest that the progression of the disease can be controlled by inhibiting vascular remodeling, thereby reducing patient distress.
Weiss A, Neubauer MC, Yerabolu D, Kojonazarov B, Schlueter BC, Neubert L, Jonigk D, Baal N, Ruppert C, Dorfmuller P, Pullamsetti SS, Weissmann N, Ghofrani HA, Grimminger F, Seeger W, Schermuly RT. Targeting cyclin-dependent kinases for the treatment of pulmonary arterial hypertension.
Nature Communication, 2019 May 17;10(1):2204. doi: 10,1038/s41467-019-10135-x.