Tumor-Specific Efficacy of Transforming Growth Factor-BRI Inhibition in Eker Rats Nicholas J. Laping, 1 Jeffrey I. Everitt, 2 Kendall S. Frazier, 1 Mark Burgert, 1 Melisa J. Portis, 3 Caprice Cadacio, 4 Leslie I. Gold, 4 and Cheryl L. Walker 3 Abstract Purpose: Transforming growth factor h (TGF-h), 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-h signaling could be efficacious for lesions in whichTGF-h 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-h 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-h signaling with the ALK5/type I TGF-hR 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-h signaling with SB-525334 may be efficacious for mesenchymal tumors, inhibition of this signaling pathway seems to promote the development of epithelial tumors. The cytokine transforming growth factor h1 (TGF-h1) is the prototypic member of the TGF-h superfamily, which is composed of related growth factors such as activins and bone morphogenic proteins (1 – 3). TGF-hs are secreted as latent molecules (large latent complex) requiring local activation for receptor binding, which releases a 25 kDa active dimer composed of identical polypeptide chains (4, 5). TGF-hs exert a diverse range of biological functions regulating cell prolifer- ation (6, 7), apoptosis (8, 9), angiogenesis (10), immune function (11, 12), and synthesis of extracellular matrix components (13 – 15). The functional significance of TGF-h is underscored by the existence of three mammalian isoforms (TGF-h1, TGF-h2, and TGF-h3) that have both overlapping and isoform-specific functions. Whereas TGF-h isoforms are highly conserved at the amino acid level (70-80% homology) and bind identical receptors, their expression and function are highly regulated, as their promoters and mechanisms for activation of their respective latent forms are different (5, 16). TGF-hs signal through a heterotetrameric receptor complex that consists of dimers of type I and type II receptors, both of which are required for signal transduction (17 – 20). The TGF-h type II receptor binds ligand and the TGF-h type I receptor, also named activin-like kinase 5 (ALK5), is a serine/threonine kinase that phosphorylates intracellular secondary messengers Smad2 and Smad3. The phosphorylated Smad proteins bind Smad4, and the complex translocates to the nucleus to act as transcriptional regulators for responsive genes mediating a wide range of TGF-h functions. TGF-h signaling participates in opposing ways to tumorigen- esis, serving both inhibitory and promoting functions (21 – 23). It is now well recognized that whereas TGF-hs act as tumor suppressors early in the pathogenesis of epithelial lesions, in later stages of this disease, they may promote progression, epithelial to mesenchymal transition, and mediate metastasis. In addition, TGF-hs affect the tumor microenvironment by being immunosuppressive and angiogenic. Escape from TGF- h – mediated growth repression occurs in a significant propor- tion of epithelial tumors (4, 23, 24) and has been shown to be due to both down-regulation of TGF-h receptors and/or mutations in components of the signaling pathway (4, 25, 26). For example, in renal cell carcinoma (RCC), which arises from the epithelial cells of the renal nephron, loss of both type I and type II TGF-hRs occurs with a high frequency and is associated with tumor progression (27, 28). Cancer Therapy: Preclinical Authors’ Affiliations: 1 GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania; 2 GlaxoSmithKline, Research Triangle Park, North Carolina; 3 University of Texas M. D. Anderson Cancer Center, Science Park, Research Division, Smithville,Texas; and 4 NewYork University School of Medicine, NewYork, NewYork Received 7/24/06; revised 12/9/06; accepted 2/27/07. Grant support: NIH grants HD046282 and ES08263 (C.L. Walker); grants CA098258, ES07784, and a sponsored research agreement between GlaxoSmithKline and M. D. Anderson Cancer Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Cheryl L. Walker, University of Texas M. D. Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957. Phone: 512-237-9550; Fax: 512-237-2475; E-mail: cwalker@wotan.mdacc.tmc.edu. F 2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-06-1811 www.aacrjournals.org Clin Cancer Res 2007;13(10) May 15, 2007 3087 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/13/10/3087/1969350/3087.pdf by guest on 16 June 2022