Tumor-specific efficacy of transforming growth factor-beta RI inhibition in Eker rats

  • Clin Cancer Res. 2007 May 15;13(10):3087-99. doi: 10.1158/1078-0432.CCR-06-1811.
Nicholas J Laping  1 ,  Jeffrey I Everitt ,  Kendall S Frazier ,  Mark Burgert ,  Melisa J Portis ,  Caprice Cadacio ,  Leslie I Gold ,  Cheryl L Walker
Affiliations
  • 1. GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, USA.
PMID: 17505012 DOI: 10.1158/1078-0432.CCR-06-1811
Abstract

Purpose: Transforming growth factor beta (TGF-beta), which generally stimulates the growth of mesenchymally derived cells but inhibits the growth of epithelial cells, has been proposed as a possible target for Cancer therapy. However, concerns have been raised that whereas inhibition of TGF-beta signaling could be efficacious for lesions in which TGF-beta promotes tumor development and/or progression, systemic pharmacologic blockade of this signaling pathway could also promote the growth of epithelial lesions.

Experimental design: We examined the effect of a TGF-beta inhibitor on mesenchymal (leiomyoma) and epithelial (renal cell carcinoma) tumors in Eker rats, which are genetically predisposed to develop these tumors with a high frequency.

Results: Blockade of TGF-beta signaling with the ALK5/type I TGF-beta R kinase inhibitor, SB-525334, was efficacious for uterine leiomyoma; significantly decreasing tumor incidence and multiplicity, and reducing the size of these mesenchymal tumors. However, SB-525334 was also mitogenic and antiapoptotic for epithelial cells in the kidney and exacerbated the growth of epithelial lesions present in the kidneys of these Animals.

Conclusion: Although pharmacologic inhibition of TGF-beta signaling with SB-525334 may be efficacious for mesenchymal tumors, inhibition of this signaling pathway seems to promote the development of epithelial tumors.

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