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Weinberg
CHAPTER 7
Tumor Suppressor Genes
www.rndsystems.com
Discovery of TGF-b
www.rndsystems.com
Structure of TGF-b
www.bio-techne.com
Dual role of TGF-bs in tumorigenesis
Vertebrate C. elegans
Extracellular
TGFb
Type II DAF-4
Receptor
Intracellular
Nucleus Nucleus
Receptor-regulated Smads
(R-Smads)
Inhibitory Smads
(I-Smads)
Common Mediator Smads
(Co-Smads)
Ten Dijke and Arthur, Nature Reviews Mol Cell Biol 2007
Smad Structure
In normal epithelial, neuronal and hematopoietic cells, TGF-b limits cell proliferation by
repressing Myc and inducing expression of CDK inhibitors p15 and p21.
TGF-b controls tumor progression at early stages of tumor development by inhibiting the
production of growth factors in surrounding tumor stroma.
• Antisense oligonucleotides
– Trabedersen (anti-TGF-b2) in phase III clinical trials for high-grade glioma,
pancreatic cancer and malignant melanoma
• Ligand traps (soluble TGF-b receptors or neutralizing antibodies)
– Fresolimumab (TGF-b monoclonal antibody) in phase II clinical trials for
glioma, metastatic breast cancer and pleural malignant mesothelioma
• Small molecular inhibitors
– Galunisertib/LY2157299 (Type I receptor kinase inhibitor) in phase II clinical
trials for glioblastoma, hepatocellular carcinoma, non-small cell lung cancer,
and pancreatic cancer
BANGs (BMP/Activin/Nodal/GDF) as
Therapeutic Targets