Heterogeneity of response to anti-TGF-β antibody therapy in preclinical models.

Wednesday, November 06, 2013 — Poster Session I
4:00 p.m. – 6:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NCI	CANCER-20

Authors

Y. Yang
J. Weng
M. Welsh
D. Weinberg
D. Luger
N. Guan
M. Shan
J. Webster
K.C. Flanders
S.M. Lonning
J. McPherson
L.M. Wakefield

Abstract

TGF-βs are pleiotropic growth factors with complex roles in tumorigenesis. Overexpression of TGF-β1 in many advanced human tumors correlates with metastasis and poor prognosis, and TGF-β antagonists are being developed for cancer therapy. Using a panel of syngeneic mouse transplant models of metastatic breast cancer, we found that an anti-TGF-β neutralizing antibody suppresses metastasis in several models, including the widely-used 4T1 model. However, as expected from the complexity of TGF-β action, responses were heterogeneous and anti-TGF-β antibody treatment had no effect or even stimulated metastasis in other models. This panel of models provides a powerful platform to identify candidate biomarkers for their ability predict therapeutic response to TGF-β antibodies. Previously we have shown that therapeutic outcome does not correlate with the expression of TGF-β ligands, the growth inhibitory response of the tumor model to TGF-β in vitro, the level of Six-1 expression, or the activation of non-canonical TGF-β signaling through formation of mixed Smad complexes. We next performed extensive histopathologic and immunohistochemical characterization of the tumor models to look for features that might correlate with therapeutic response.