As metastases are the major cause of cancer deaths, there is an urgent need for the development of cancer therapies aimed at interfering with tumor progression, which results into metastatic disease and acquisition of tumor resistance to many of the currently available therapeutics. The identification of crucial molecules that control tumor progression and that can be used as targets for anti-tumor strategies is an essential step in advancing novel therapeutic interventions aimed at preventing and/or treating metastatic disease. The epithelial-mesenchymal transition (EMT) is thought to be a critical step along the metastasis of carcinomas;in addition to gaining motility and invasiveness, tumor cells that undergo EMT also acquire increased resistance to many traditional cancer treatment modalities, including chemotherapy and radiation. As such, EMT has become an attractive, potentially targetable process for therapeutic interventions against tumor metastasis. The T-box transcription factor Brachyury has been identified as a molecule with a higly-tumor associated pattern of expression;Brachyury has been shown to be expressed in a variety of human tumor tissues and tumor cells lines, while its expression is absent in the majority of normal adult human tissues evaluated. We have now characterized the role of this molecule in the context of tumor progression by demonstrating that Brachyury is a driver of the epithelial-mesenchymal transition (EMT) of human carcinomas. Our results indicated that elevated Brachyury levels in human carcinoma cells results in the acquisition of a mesenchymal-like phenotype, tumor cell motility and invasiveness in vitro, as well as metastatic propensity in animal models. Because of its relevant role in metastasis and therapeutic resistance, Brachyury is an appealing target for interventions directed at the EMT process and serves as a model for more generally exploring cancer vaccine strategies against tumor progression. To this end, we have further demonstrated the suitability of Brachyury as a target for T-cell mediated immunotherapy of cancer by identifying a CD8 T-cell epitope of Brachyury capable of expanding Brachyury-specific T cells from the peripheral blood of cancer patients. In additional studies, we have also demonstrated a strong positive correlation between Brachyury expression levels in human carcinoma cells and their ability to withstand treatments with multiple chemotherapies and radiation. Our recent accomplishments also include the characterization of the role of the chemokine IL-8/IL-8 receptor axis in inducing Brachyury expression in epithelial tumor cells and the potential of IL-8 signaling blockade strategies for targeting of mesenchymal-like, invasive tumor cells. Analysis of Brachyury expression by PCR and by immunohistochemistry in human lung tumors and adult normal tissues have demonstrated Brachyury protein expression in 41% of primary lung carcinomas, including 48% of adenocarcinomas and 25% of squamous cell carcinomas. With the exception of normal testis and some thyroid tissues, the majority of normal tissues evaluated by immunohistochemistry were negative for the expression of Brachyury protein. We have also shown that the level of Brachyury expression in human lung cancer cell lines positively correlates with resistance to EGFR kinase inhibition, a small moleucule targeted therapy commonly utilized for the management of lung cancer. While being resistant to EGFR kinase inhibition, however, tumor cells expressing the Brachyury protein can be lysed by Brachyury-specific T cells, a result that supports the development of Brachyury-based immunotherapeutic approaches for the treatment of lung cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Scientific Cores Intramural Research (ZIC)
Project #
1ZICBC010937-05
Application #
8554084
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$848,816
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Hamilton, Duane H; McCampbell, Kristen K; Palena, Claudia (2018) Loss of the Cyclin-Dependent Kinase Inhibitor 1 in the Context of Brachyury-Mediated Phenotypic Plasticity Drives Tumor Resistance to Immune Attack. Front Oncol 8:143
Hamilton, Duane H; David, Justin M; Dominguez, Charli et al. (2017) Development of Cancer Vaccines Targeting Brachyury, a Transcription Factor Associated with Tumor Epithelial-Mesenchymal Transition. Cells Tissues Organs 203:128-138
David, Justin M; Dominguez, Charli; McCampbell, Kristen K et al. (2017) A novel bifunctional anti-PD-L1/TGF-? Trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells. Oncoimmunology 6:e1349589
Dominguez, Charli; McCampbell, Kristen K; David, Justin M et al. (2017) Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer. JCI Insight 2:
Dominguez, Charli; David, Justin M; Palena, Claudia (2017) Epithelial-mesenchymal transition and inflammation at the site of the primary tumor. Semin Cancer Biol 47:177-184
Shah, Sagar R; David, Justin M; Tippens, Nathaniel D et al. (2017) Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer. Cell Rep 21:495-507
Heery, Christopher R; Palena, Claudia; McMahon, Sheri et al. (2017) Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury. Clin Cancer Res 23:6833-6845
David, Justin M; Dominguez, Charli; Palena, Claudia (2017) Pharmacological and immunological targeting of tumor mesenchymalization. Pharmacol Ther 170:212-225
Tsang, Kwong Y; Fantini, Massimo; Fernando, Romaine I et al. (2017) Identification and characterization of enhancer agonist human cytotoxic T-cell epitopes of the human papillomavirus type 16 (HPV16) E6/E7. Vaccine 35:2605-2611
Fernando, Romaine I; Hamilton, Duane H; Dominguez, Charli et al. (2016) IL-8 signaling is involved in resistance of lung carcinoma cells to erlotinib. Oncotarget :

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