title: Anti-tumor activity of the TGF-β receptor kinase inhibitor galunisertib (LY2157299 monohydrate) in patient-derived tumor xenografts.
abstract: OBJECTIVE
  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.
authors.affiliation: In Vitro Screening, Oncotest GmbH, Am Flughafen 12-14, 79108, Freiburg, Germany, Armin.Maier@oncotest.de.
authors.forename: Armin
authors.initials: A
authors.lastname: Maier
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Peille
authors.forename: Vincent
authors.initials: V
authors.lastname: Vuaroqueaux
authors.forename: Michael
authors.initials: M
authors.lastname: Lahn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D011804:Quinolines; D016212:Transforming Growth Factor beta; C557799:LY-2157299