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TGF Beta Inhibition for Cancer Therapy

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The importance of perturbation in transforming growth factor beta (TGFβ) signaling for the onset and progression of cancer is well established. Many tumors over express TGFβ, and high circulating levels of TGFβ1 in cancer patients are frequently associated with poor prognosis. TGFβ has context-dependent biphasic action during tumorigenesis. Because of this, it is essential to take due care about the selection of patients most likely to benefit from anti-TGFβ therapy. Anti-TGFβ therapy aims to target both the tumor cell and the tumor microenvironment and may well have systemic effects of relevance to tumorigenesis. Extra-tumoral targets include stromal fibroblasts, endothelial and pericyte cells during angiogenesis, and the local and systemic immune systems, all of which can contribute to the pro-oncogenic effects of TGFβ. Many different approaches have been considered, such as interference with ligand synthesis using oligonucleotides, sequestration of extracellular ligand using naturally-occurring TGFβ binding proteins, recombinant proteins or antibodies, targeting activation of latent TGFβ at the cell surface, or signal transduction within the cell. Consideration of which patients might benefit most from anti-TGFβ therapy should include not only tumor responses to TGFβ (which depend on activation of other oncogenic pathways in the cancer cell), but also germline genetic variation between individuals. Ultimately, a deep understanding of the interacting networks of signal pathways that regulate TGFβ outcome in tumor and host cells should allow judicial choice of drugs. This review discusses the progress made in the pre-clinical and clinical testing of TGFβ inhibitors, and discusses considerations of target populations and potential drug regimens.

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Keywords: TGFβ; TGFβ inhibition; anti-TGFβ therapy; cancer

Document Type: Research Article

Affiliations: Cancer Research Institute, University of California at San Francisco, 2340 Sutter Street, P.O. Box 0875, Room S231, San Francisco, California 94143-0875, USA.

Publication date: November 1, 2006

More about this publication?
  • Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes, genes.
    Each issue of the journal contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in cancer.
    As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.
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