Development of TGF-beta antagonists for cancer therapy

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

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. We previously uncovered heterogeneous responses to TGF-beta antagonism in mouse models of metastatic breast cancer, with TGF-beta pathway blockade inhibiting metastasis in some models but stimulating it in others. These data suggested that contrary to dogma, some advanced tumors retain tumor suppressive responses to TGF-beta, and that TGF-beta antagonism is deleterious in these instances. Similar results were seen in a clinical trial treating small cell lung cancer patients with a dual TGF-beta/PDL1 inhibitor. We are collaborating with clinicians to analyze clinical material from this trial to test the hypothesis that the undesirable stimulatory effect of TGF-beta antagonism is due to interference with inhibitory effects of TGF-beta specifically on the cancer stem cell subpopulation. These findings highlighted the need for a more granular and detailed understanding of the role of TGF-beta at different stages of cancer progression. 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. We are finalizing the generation of a comprehensive visual atlas of TGF-beta pathway activation across normal adult mouse tissues to serve as a reference for studying the role of TGF-beta in pathological conditions. In intercrosses with mouse models of metastatic breast cancer, we observe very heterogeneous patterns of TGF-beta pathway activation within the developing tumors suggesting that TGF-beta pathway activation occurs only in specific subpopulations of tumor cells. We are now applying single cell 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.