Development of TGF-beta antagonists for cancer therapy

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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 previously 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, and we are continuing to test this hypothesis. We are collaborating with clinicians to analyze clinical material from cancer patients treated with TGF-beta antagonists, to extend these mechanistic analyses to the more relevant clinical setting. Currently, one 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 normal homeostasis and tumorigenesis. To address this issue, we have generated and rigorously validated a transgenic TGF-beta pathway reporter mouse, in which cells with active TGF-beta signaling light up green through expression of a fluorescent protein. These cells can be identified in situ by immunofluorescence and recovered by FACS sorting for molecular analyses. In intercrosses with mouse models of metastatic breast cancer, we observe heterogeneous patterns of TGF-beta pathway activation within the developing tumors. We are now applying spatial transcriptomic and high dimensional imaging technologies to identify the nature and activities of TGF-beta responder cells in the evolving tumor ecosystem. We anticipate that this information will lead to safer and more effective deployment of TGF-beta antagonists to treat cancer.