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 resutls 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. By using a computer-based differential display analysis tool, we have recently identified the T-box transcription factor Brachyury 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. EMT is a phenotypic switch that allows epithelial tumor cells to detach from the primary tumor, metastasize at distal sites, and to acquire mechanisms of resistance to multiple conventional therapies and targeted therapies. 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. We now 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. 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. These Brachyury-specific T cells were efficient at lysing Brachyury-positive tumor cell lines in vitro. We previously demonstrated that infection of CLL cells with modified vaccinia Ankara (MVA) expressing the costimulatory molecules B7-1, ICAM-1, and LFA-3 (designated TRICOM) increased expression of these costimulatory molecules on the surface of CLL cells and thus augmented their antigen-presenting capability. We further evaluated an alternative MVA vector platform encoding for human CD40L in comparison with MVA-TRICOM for their ability to enhance the immunogenicity of CLL cells, in vitro. Our results indicated that MVA-TRICOM-infected and MVA-CD40L-infected CLL cells are equally potent at inducing autologous T-cell proliferation. Therefore, the results from this study further support the rationale for the use of CLL cells modified ex vivo with recombinant MVA as a whole tumor-cell vaccine for the immunotherapy of CLL, either by modification with the MVA-CD40L or MVA-TRICOM vector.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Scientific Cores Intramural Research (ZIC)
Project #
1ZICBC010937-04
Application #
8350114
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2011
Total Cost
$923,127
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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