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Mechanistic Validation of Potential Anti-Breast Cancer Therapeutics

Chuang, Hsiao-Ching
http://rave.ohiolink.edu/etdc/view?acc_num=osu1338213365

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Pharmacy.
Breast caner is a heterogeneous disease and this makes breast cancer a difficult disease – different patients need different therapies. According to the histopathological classification, breast cancer could be divided into three distinct subtypes: ER-, PR-positive; HER2-positive; and those tumors without ER, PR or HER2 expression (triple negative breast cancers, TNBCs). The ER-, PR-positive patients could be treated with anti-estrogen therapy, including tamoxifen and aromatase inhibitors. The gold standard treatment for HER2-positive patients is trastuzumab. These therapies all show favorable effects. TNBC is totally different from previous two types: having unique gene profiling, aggressive behavior and poor prognosis. Unfortunately, the only available therapeutic option for TNBC, until recently, was chemotherapy. Further studies for developing the treatment of TNBCs are essential and urgent. In the first part of this dissertation work, α-tocopheryl succinate was chosen as a leading compound to develop potent antiadhesion agents. Adhesion is an essential step for tumor metastasis; therefore, agents with the ability to block adhesion may be able to suppress tumor metastasis of breast cancer patients. Our structural optimization led to compound 5 which exhibited an-order-of-magnitude higher potency than α-tocopheryl succinate in blocking the adhesion of 4T1 metastatic breast cancer cells to extracellular matrix proteins. Evidence indicates that the ability of compound 5 to block cell adhesion and migration was attributable to its effect on disrupting focal adhesion and actin cytoskeletal integrity by facilitating the degradation of focal adhesion kinase. Interactions between tumor cells and the ECM in the tumor microenvironment have been increasingly recognized as critical modulators of the metastatic potential of tumor cells. Consequently, the ability of compound 5 to block such interactions provides a unique pharmacological tool to shed light onto mechanisms that govern cell adhesion and tumor metastasis. In the second part of this dissertation work, we focused on the mechanistic validation of different poly (ADP-ribose) polymerase (PARP) inhibitors. Recent results of a randomized phase II clinical trial showed that BSI-201 when added to platinum-containing combination chemotherapy statistically significantly improved the outcome of metastatic TNBC patients relative to chemotherapy alone. Although PARP inhibitors may represent the first “targeted treatment” for TNBC, the mechanism(s) by which the different PARP inhibitors cause cell death remains unknown. In this study, we investigated the cellular mechanism of four PARP inhibitors in three different TNBC cell lines. Our examination of the antitumor activities of four clinically relevant PARP inhibitors in TNBC cells indicates the involvement of different mechanisms of action beyond PARP inhibition among these agents. The studies presented here provide two novel findings: identification of a novel compound with potent antiadhesion activity and using in vitro model to identify the mechanisms of action beyond PARP inhibitors. This provides the rationale for how to use these individual PARP inhibitors in clinical.
Ching-Shih Chen (Advisor)
Robert Brueggemeier (Committee Member)
Pui-Kai Li (Committee Member)
Dale Hoyt (Committee Member)
Charles Shapiro (Committee Member)
97 p.
Biomedical Research; Pharmacy Sciences
&945; -tocopheryl succinate; anti-adhesion; triple-negative breast cancer; PARP inhibitor

Recommended Citations

Citations

  • Chuang, H.-C. (2012). Mechanistic Validation of Potential Anti-Breast Cancer Therapeutics [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338213365

    APA Style (7th edition)

  • Chuang, Hsiao-Ching. Mechanistic Validation of Potential Anti-Breast Cancer Therapeutics. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1338213365.

    MLA Style (8th edition)

  • Chuang, Hsiao-Ching. "Mechanistic Validation of Potential Anti-Breast Cancer Therapeutics." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338213365

    Chicago Manual of Style (17th edition)

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© 2012, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.