Complexities of TGF-β Targeted Cancer Therapy

• Main Author: Erin C. Connolly, Julia Freimuth, Rosemary J. Akhurst
• Format: Article
• Language: English
• Published: Ivyspring International Publisher 2012-01-01
• Series: International Journal of Biological Sciences
• Online Access: http://www.biolsci.org/v08p0964.htm

<p>Many advanced tumors produce excessive amounts of Transforming Growth Factor-&#946; (TGF-&#946;) which, in normal epithelial cells, is a potent growth inhibitor. However, in oncogenically activated cells, the homeostatic action of TGF-&#946; is often diverted along alternative pathways. Hence, TGF-&#946; signaling elicits protective or tumor suppressive effects during the early growth-sensitive stages of tumorigenesis. However, later in tumor development when carcinoma cells become refractory to TGF-&#946;-mediated growth inhibition, the tumor cell responds by stimulating pathways with tumor progressing effects. At late stages of malignancy, tumor progression is driven by TGF-&#946; overload. The tumor microenvironment is a target of TGF-&#946; action that stimulates tumor progression <i>via</i> pro-tumorigenic effects on vascular, immune, and fibroblastic cells. Bone is one of the richest sources of TGF-&#946; in the body and a common site for dissemination of breast cancer metastases. Osteoclastic degradation of bone matrix, which accompanies establishment and growth of metastases, triggers further release of bone-derived TGF-&#946;. This leads to a vicious positive feedback of tumor progression, driven by ever increasing levels of TGF-&#946; released from both the tumor and bone matrix. It is for this reason, that pharmaceutical companies have developed therapeutic agents that block TGF-&#946; signaling. Nonetheless, the choice of drug design and dosing strategy can affect the efficacy of TGF-&#946; therapeutics. This review will describe pre-clinical and clinical data of four major classes of TGF-&#946; inhibitor, namely i) ligand traps, ii) antisense oligonucleotides, iii) receptor kinase inhibitors and iv) peptide aptamers. Long term dosing strategies with TGF-&#946; inhibitors may be ill-advised, since this class of drug has potentially highly pleiotropic activity, and development of drug resistance might potentiate tumor progression. Current paradigms for the use of TGF-&#946; inhibitors in oncology have therefore moved towards the use of combinatorial therapies and short term dosing, with considerable promise for the clinic.</p>