The ability of chemotherapy to extend the life of cancer patients is compromised by severe side effects such as marrow toxicity and generalized immunosuppression. These drawbacks have fueled tireless efforts to identify and develop novel anti-neoplastic agents and treatment modalities that will not only destroy the existing cancer, have minimal toxicity to the host, but also prevent disease recurrence. One drug that may have these properties is alpha-Tocopheryloxyacetic acid (a-TEA). Alpha-TEA is a lipophilic, esterase resistant, semi-synthetic analog of naturally-occurring vitamin E (RRR-alpha-tocopherol) that selectively induces apoptosis of cancer cells in vitro and suppresses tumor growth in pre-clinical animal models. Translation of the pre-clinical findings of a-TEA chemotherapy to the clinic has been hampered by its lipid solubility that requires dissolving it in organic solvents that are impractical for use in humans. We have developed a novel form of a-TEA, vesiculated a-TEA (Va-TEA) that is more water-soluble and is more relevant for clinical use. The goal of this study is to employ Va-TEA in combination with dendritic cell (DC) vaccination to prevent breast cancer metastases in the established and residual disease settings. In preliminary studies we have shown that Va-TEA efficiently kills tumor cells in vitro, causes DC maturation and inhibits tumor growth in vivo. The hypothesis to be tested is that the combination of oral Va-TEA plus DC vaccination will be highly effective in preventing cancer dissemination with minimal host toxicity. The rationale for this hypothesis is based on evidence that a-TEA induces apoptosis and secondary necrosis of tumor cells and that DCs are capable of ingesting killed tumor cells and cross-presenting tumor-associated antigens to T lymphocytes to induce tumor-specific immunity.
The Specific Aims of this study are to: 1) Determine the effectiveness of Va-TEA plus DC vaccination in preventing metastatic spread of cancer and 2) Elucidate the immunologic mechanisms of Va-TEA-mediated anti-tumor activity. Upon completion of this study we would have developed a novel approach to control the spread of primary cancer and improved our understanding of Va-TEA-mediated tumor immunity. The fulfillment of these objectives should have high translational potential for treating metastatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120552-05
Application #
7800437
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Muszynski, Karen
Project Start
2007-04-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$248,463
Indirect Cost
Name
Providence Portland Medical Center
Department
Other Clinical Sciences
Type
Organized Research Units
DUNS #
099142093
City
Portland
State
OR
Country
United States
Zip Code
97213
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Li, Yuhuan; Hahn, Tobias; Garrison, Kendra et al. (2012) The vitamin E analogue ?-TEA stimulates tumor autophagy and enhances antigen cross-presentation. Cancer Res 72:3535-45
Rodríguez-Enríquez, Sara; Hernández-Esquivel, Luz; Marín-Hernández, Alvaro et al. (2012) Molecular mechanism for the selective impairment of cancer mitochondrial function by a mitochondrially targeted vitamin E analogue. Biochim Biophys Acta 1817:1597-607
Hahn, Tobias; Bradley-Dunlop, Deborah J; Hurley, Laurence H et al. (2011) The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer. BMC Cancer 11:471
Hahn, Tobias; Jagadish, Bhumasamudram; Mash, Eugene A et al. (2011) ?-Tocopheryloxyacetic acid: a novel chemotherapeutic that stimulates the antitumor immune response. Breast Cancer Res 13:R4
Hahn, Tobias; Fried, Karen; Hurley, Laurence H et al. (2009) Orally active alpha-tocopheryloxyacetic acid suppresses tumor growth and multiplicity of spontaneous murine breast cancer. Mol Cancer Ther 8:1570-8