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Oncogenes, tumor suppressor genes, signal transduction, gene therapy
The main goal of my research is to understand the molecular mechanisms of gene regulation and the functionality of oncogenes and tumor suppressor genes in the development of human cancers. By targeting the dysfunction or deregulation of oncogenes and tumor suppressor genes, we aim to develop novel molecular/gene therapy strategies for human cancers. We have used the HER-2/neu oncogene, which encodes a receptor tyrosine kinase, as a model system to reach our goals. Overexpression of the HER-2/neu gene correlates with the relapse and survival rates for many human cancers, including breast and ovarian cancers. We have previously shown that increased expression of HER-2/neu enhances the malignancy and metastatic potential of cancer cells and induces resistance of cancer cells to chemotherapeutic agents, which provide scientific basis for poor clinical outcome of HER-2/neu-overexpressing cancer.
We have used several approaches in our research efforts. These include the development of gene therapy using transcriptional regulators possessing anti-cancer activities such as the adenovirus 5 E1A. The E1A has been shown to inhibit oncogenic signaling pathways including downregulation / inactivation of HER-2/neu overexpression, Akt, IKK and NF-kB, as well as to activate tumor suppression pathways such as enhanced expression of p53, p21cip1/WAF1, PP2A phosphatase and E-Cadherin. Using the E1A/liposome complex, we have previously shown the therapeutic efficacy together with safety toxicity studies in a few orthotopic animal models. These data allow us to conclude several Phase I/II clinical trials in targeting cancers of breast, ovary and head and neck and have further validated the feasibility of E1A/liposome gene therapy for cancer treatment. Currently, under the support of an Ovarian SPORE grant, a Phase I/II entitled “A Phase I/II randomized study of intraperitoneal tgDCC-E1A and intravenous paclitaxel in women with platinum-resistant ovarian cancer" is ongoing at M. D. Anderson Cancer Center. In addition, we intend to identify more therapeutic genes. To this regard, we recently found that BikDD, a mutant form of pro-apoptotic molecule, Bik, has more potent capability in killing cancer cells. Moreover, we have developed tumor-specific targeting systems and expression vectors, which have been subjected to several animal models, to allow therapeutic genes to be selectively delivered and expressed in tumor cells.
In the aspect of molecular and cellular functions, we have several exciting findings on novel signaling pathways including: IKK promotes tumor progression through inhibition of a Forkhead transcriptional factor, FOXO3a; nuclear localized receptor tyrosine kinases, EGFR and HER2 potentially harbor transcriptional activities; GSK-3b-regulated Snail could set a pace in epithelial-mesenchymal transition; and CXCR4 is a critical element in HER2-mediated metastasis.  

Aromatase Inhibitors, Steroid Biochemistry, Breast Cancer, Enzyme Inhibitors
The major research activities of Dr. Brueggemeier focus in the areas of steroid chemistry and biochemistry, hormones and cancer, medicinal chemistry, and radiochemistry. Research approaches involve the application of expertise in steroid chemistry/biochemistry to the examination of steroid biosynthesis, metabolism, and action at the molecular level. Results from these interdisciplinary investigations will aid in understanding the molecular and biochemical role(s) of estrogens in hormone-dependent cancers and in the development of new approaches to treatment of hormone-dependent cancers.
One research program focuses on the development of aromatase inhibitors for the treatment of estrogen-dependent breast cancer. Estrogens are biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase. Several inhibitors of aromatase have been studied, and several mechanism-based inhibitors are being utilized to probe the enzyme active site.

A second research project focuses on estrogens and estrogen metabolites and their roles in the development of certain estrogen-dependent cancers. One emphasis focuses on the biochemistry of the enzyme estrogen 2- and 4-hydroxylases and inhibition of the enzymes. A third project is the examination of the effects of these molecules on estrogen-induced responses in vitro and in vivo, with an emphasis on estrogen-induced growth factors in the TGFa and the FGF families and on growth inhibitory TGFb. A fourth research project focuses on examination of the breast cancer tissue microenvironment. The tissue microenvironment can influence the extent of estrogen biosynthesis and metabolism, result in altered levels of hormonally active estrogens and their metabolites, and therefore influence breast tumor development and growth. Biochemical and molecular examination of this hypothesis in vitro are being studied in human patient breast tissue specimens and in several human breast cancer cell systems currently in use in the laboratories. The studies include examining the extent of aromatase (CYP19) expression and cyclooxygenase (COX-1 and COX-2) expression in human breast cancer specimens and determining the biological consequences of estrogen biosynthesis and metabolism in the human breast cell systems. Finally, a new research thrust in Dr. Brueggemeier's laboratory is the development of directed combinatorial libraries and bioassay evaluation of nonsteroidal agents as potential agonists or antagonists of steroid biochemistry in breast cancer. The molecular scaffold used in this research project is the benzopyranone ring system, present in a number of natural products such as flavonoids and isoflavonoids. The synthesis uses readily available starting materials, employs mild and high yielding reactions, and is amendable to rapid synthesis of diverse libraries.

Publications