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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Antibody targeting of TGF-β in cancer patients

Scott Lonning1, Joan Mannick, John M McPherson

  • 1Genzyme Corporation, 1 Mountain Rd., Framingham, MA 01701, USA.

Current Pharmaceutical Biotechnology
|May 31, 2011
PubMed

Insights

Transforming growth factor-beta (TGF-β) paradoxically promotes cancer despite its tumor-suppressing roles. Inhibiting TGF-β shows promise in preclinical models, and early human trials suggest safety for cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Transforming growth factor-beta (TGF-β) has a complex role in cancer, with mutations disrupting its antiproliferative signals contributing to malignancy.
  • Loss of TGF-β sensitivity often leads to its overexpression, promoting tumor growth and metastasis within the tumor microenvironment.

Purpose of the Study:

  • To review the dual role of TGF-β in cancer development and progression.
  • To evaluate the therapeutic potential of TGF-β inhibition in cancer treatment.
  • To assess the safety and tolerability of TGF-β antagonists in preclinical and clinical settings.

Main Methods:

  • Review of published studies on TGF-β signaling in cancer.
  • Analysis of preclinical data from murine cancer models using TGF-β inhibitors (antibodies, soluble receptors, small molecules).
  • Evaluation of toxicology data from animal studies and human Phase 1 clinical trials of anti-TGF-β antibodies.

Main Results:

  • TGF-β mutations are key in malignant transformation, yet elevated TGF-β in the tumor microenvironment promotes cancer progression.
  • Inhibition of TGF-β signaling demonstrated beneficial effects in preclinical cancer models.
  • Toxicology studies in animals and Phase 1 human trials indicated that anti-TGF-β antibodies are well-tolerated with reversible or self-limiting adverse effects.

Conclusions:

  • Despite its complex role, targeting TGF-β represents a potential therapeutic strategy for cancer.
  • Neutralizing anti-TGF-β antibodies, like fresolimumab, show a favorable safety profile in early-phase human trials, warranting further investigation.

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