Patrizia Carpinelli, Paolo Cappella, Marco Losa,Valter Croci, Roberta Bosotti, Luisa Lanfrancone, Antonella Isacchi and Jürgen Moll
Biomarkers that indicate biological activity and/or efficacy are a potentially useful tool in the development of molecularly targeted therapeutics. Most pharmacodynamic assays measure the response to drugs in tissues, a procedure requiring tissue biopsies, which is often not available. In this study, we identify GDF15 as a potential plasma biomarker for Danusertib (formerly PHA-739358), an Aurora kinase inhibitor, currently in phase I/II clinical studies. Cell lysates and cell-free culture supernatants from human tumor isogenic cell lines were assessed for GDF15 levels following treatment with Danusertib, by using Western Blotting and Elisa. GDF15 levels were also measured in plasma from xenografted mice as well as in plasma from patients before and after Danusertib treatment. At the protein level an increased level of GDF15 was found in tissue culture cells after Danusertib treatment and GDF15 expression was also detected in plasma of xenografted mice treated with the compound. Hence, both cellular and xenograft models of human cancer showed a clear correlation with p53 pathway activation. Danusertib treatment also resulted in a significantly increased expression of GDF15 protein levels in the plasma of examined patients, underlining technical feasibility of translating this putative biomarker to clinical studies. Determination of GDF15 levels in plasma is feasible and enabled us to follow the kinetic of Danusertib activity in plasma from cancer xenografted mice and from patients. These findings should allow us to evaluate systematically the kinetics of p53 activation by Danusertib in future clinical studies.
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