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Cellular Oncology
Published in: Cellular Oncology 2/2015

Open Access 01-04-2015 | Original Paper

Anti-tumor activity of the TGF-β receptor kinase inhibitor galunisertib (LY2157299 monohydrate) in patient-derived tumor xenografts

Authors: Armin Maier, Anne-Lise Peille, Vincent Vuaroqueaux, Michael Lahn

Published in: Cellular Oncology | Issue 2/2015

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Abstract

Purpose

The transforming growth factor-beta (TGF-β) signaling pathway is known to play a critical role in promoting tumor growth. Consequently, blocking this pathway has been found to inhibit tumor growth. In order to achieve an optimal anti-tumor effect, however, it remains to be established whether blocking the TGF-β signaling pathway alone is sufficient, or whether the tumor microenvironment plays an additional, possibly synergistic, role.

Methods

To investigate the relevance of blocking TGF-β signaling in tumor cells within the context of their respective tissue microenvironments, we treated a panel of patient-derived xenografts (PDX) with the selective TGF-β receptor kinase inhibitor LY2157299 monohydrate (galunisertib) and assessed both the in vitro and in vivo effects.

Results

Galunisertib was found to inhibit the growth in an in vitro clonogenic assay in 6.3 % (5/79) of the examined PDX. Evaluation of the expression profiles of a number of genes, representing both canonical and non-canonical TGF-β signaling pathways, revealed that most PDX exhibited expression changes affecting TGF-β downstream signaling. Next, we subjected 13 of the PDX to an in vivo assessment and, by doing so, observed distinct response patterns. These results suggest that, next to intrinsic, also extrinsic or microenvironmental factors can affect galunisertib response. pSMAD2 protein expression and TGF-βRI mRNA expression levels were found to correlate with the in vivo galunisertib effects.

Conclusions

From our data we conclude that intrinsic, tumor-dependent TGF-β signaling does not fully explain the anti-tumor effect of galunisertib. Hence, in vivo xenograft models may be more appropriate than in vitro clonogenic assays to assess the anti-tumor activity of TGF-β inhibitors such as galunisertib.
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Metadata
Title
Anti-tumor activity of the TGF-β receptor kinase inhibitor galunisertib (LY2157299 monohydrate) in patient-derived tumor xenografts
Authors
Armin Maier
Anne-Lise Peille
Vincent Vuaroqueaux
Michael Lahn
Publication date
01-04-2015
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 2/2015
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-014-0210-8

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