Development of TGF-beta antagonists for cancer therapy

Division Of Basic Sciences - Nci

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Abstract

Based on promising preclinical results, a variety of TGF-beta pathway antagonists are in early phase clinical trials for the treatment of advanced cancer. However, given the complex biology of TGF-beta, the successful development of TGF-beta antagonists for cancer therapy will depend on a clear understanding of how these agents work, and the related question of how to select patients who will benefit from this type of treatment. Using a panel of 12 mouse syngeneic allograft models of metastatic breast cancer, with metastatic burden as the primary endpoint, we uncovered heterogeneous responses to TGF-beta antagonism. TGF-beta pathway blockade inhibited metastasis in some models, while having no effect on others. Importantly, in this expanded model panel, we found that TGF-beta antagonism actually stimulated metastasis in 25% of the models, suggesting that improved mechanistic understanding and good predictive biomarkers will be crucial for safe and effective deployment of TGF-beta antagonists clinically. We hypothesized that the undesirable stimulatory effect of TGF-beta antagonism is due to interference with inhibitory effects of TGF-beta on the cancer stem cell subpopulation. We are testing this hypothesis, using the cancer stem cell reporter developed in our companion project ZIA BC 005785, as well as other orthogonal techniques. Currently, a major barrier in the TGF-beta field is the relative lack of information about when and where TGF-beta signals in the adult organism in homeostasis, and how the spectrum of responding cells in the tumor ecosystem changes during tumor progression. To address this issue, we have generated and rigorously validated a transgenic TGF-beta pathway reporter mouse, in which tissues with active TGF-beta signaling light up green through expression of a fluorescent protein. Strikingly the TGF-beta pathway is highly active in tissues that show off-tumor toxicities when mice are treated with small molecule inhibitors of TGF-beta signaling. Through fluorescence imaging (epifluorescent and confocal microscopy) coupled with immunohistochemistry for GFP, this valuable new tool allows an organism to cellular level assessment of TGF-beta signaling. This mouse is giving important insights into patterns of TGF-beta pathway activation in the adult animal and how these are altered during tumor progression.