A recent study published in Oncotarget calls into question whether PDE5 inhibitors like sildenafil are a good idea for GBM after all. The study is called Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome. (click on title to redirect to the article).
The two main reason it has been included in GBM cocktails are for 1) proposed blood-brain barrier opening effects and 2) inhibition of immune suppressor cells as seen in mouse models and for other PDE5 inhibitors (tadalafil) in human studies.
This new study however, identifies high PDE5 expression in GBM as a positive prognostic factor. First, in a series of 69 GBM patients, high protein expression of PDE5 was independently associated with better survival in a multivariate analysis which included EGFRvIII expression, age, KI-67, KPS, MGMT status, and PDE5 protein expression.
This finding was validated in two additional GBM cohorts from "publicly available gene expression datasets". In these GBM datasets, high expression of PDE5 mRNA was likewise associated with improved survival. Recurrent tumors tended to have lower PDE5 expression than newly diagnosed tumors.
Cell line studies showed that PDE5 knockdown increased the invasiveness of cell lines and enhanced the survival of GBM cells following irradiation.
Although it's not clear how much sildenafil actually gets into a brain tumor to exert direct effects on PDE5 in gliomas (myself and others had been promoting sildenafil for potential indirect benefits on immune cell populations and BBB permeability), this study will certainly make us think twice about PDE5 inhibitors as a therapeutic strategy for GBM.
No comments:
Post a Comment