Complexities of TGF-β Targeted Cancer Therapy

Many advanced tumors produce excessive amounts of Transforming Growth Factor-beta (TGF-beta) which, in normal epithelial cells, is a potent growth inhibitor. However, in onco-genically activated cells, the homeostatic action of TGF-beta is often diverted along alternative pathways. Hence, TGF-beta 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-beta-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-beta overload. The tumor microenvironment is a target of TGF-beta action that stimulates tumor progression via pro-tumorigenic effects on vascular, immune, and fibroblastic cells. Bone is one of the richest sources of TGF-beta 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-beta. This leads to a vicious positive feedback of tumor progression, driven by ever increasing levels of TGF-beta released from both the tumor and bone matrix. It is for this reason, that pharmaceutical companies have developed therapeutic agents that block TGF-beta signaling. Nonetheless, the choice of drug design and dosing strategy can affect the efficacy of TGF-beta therapeutics. This review will describe pre-clinical and clinical data of four major classes of TGF-beta inhibitor, namely i) ligand traps, ii) antisense oligonucleotides, iii) receptor kinase inhibitors and iv) peptide aptamers. Long term dosing strategies with TGF-beta 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-beta inhibitors in oncology have therefore moved towards the use of combinatorial therapies and short term dosing, with considerable promise for the clinic.