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Cell Cycle Inhibition Therapy:Stathmin As A Potential Therapeutic Target For Breast Cancer
Tumor Cell Biology IV
TECHNICAL ABSTRACT BACKGROUND: Recent advances in the molecular understanding of the role of microtubule regulatory proteins provide new opportunities for designing more effective therapeutic strategies for breast cancer. Stathmin is the founding member of a family of microtubule destabilizing proteins that plays a critical role in the regulation of the mitotic spindle. The innovative approach that we propose is based on the identification of a new molecular target, stathmin, whose level of expression correlates with the malignant behavior of breast cancer cells. High levels of stathmin in breast cancer correlates with poor prognosis. HYPOTHESES: We hypothesize that gene therapy strategies directed against stathmin, a molecule critical for mitotic progression, would have significant anti-tumor effects. Although taxol is effective against breast cancer, its utility is limited due to toxicity. Thus, a secondary hypothesis is that the combination of two treatment modalities that target the mitotic pathway (i.e. stathmin inhibition and taxol exposure) would have synergistic antitumor effects. STUDY DESIGN: Our research strategy is based on the ability of the ribozymes that we designed to target stathmin mRNA selectively for degradation. More recently, we developed an adenoviral vector that carries the gene encoding the same ribozyme. This recombinant adenovirus can efficiently inhibit stathmin expression in breast cancer cells. We are now ready to test the efficacy of anti-stathmin adenovirus in preclinical models of breast cancer. SPECIFIC AIMS: We aim to (1) fully investigate the effects of adenovirus-mediated gene transfer of anti-stathmin ribozyme on growth, clonogenicity and apoptosis, both as single agent and in combination with chemotherapeutic agents in different breast cancer cell lines; (2) investigate the effects of stathmin inhibition and overexpression in normal mammary epithelial cells; (3) investigate the therapeutic efficacy of the same recombinant adenovirus, both as a monotherapy and as a combination therapy in orthotopic mouse models of breast cancer. SIGNIFICANCE: These studies will validate stathmin as an attractive new molecule to target in breast cancer therapies that aim to disrupt the mitotic apparatus. It will also provide a rational basis for effective synergistic combination of different therapeutic modalities at low doses. The success of these studies will set the stage for testing of this new therapy in patients with breast cancer.
PUBLIC ABSTRACT BACKGROUND: Current treatments for breast cancer are largely unsatisfactory. Recent advances in the molecular understanding of the role of microtubule regulatory proteins provide new opportunities for designing more effective therapeutic strategies. Stathmin is a major cellular protein that plays a critical role in the regulation of the microtubule cytoskeleton and the mitotic spindle of dividing cells. Interestingly, stathmin is expressed at high levels in breast cancer that correlates with more aggressive disease with poor prognosis. HYPOTHESIS: The major hypothesis that we propose to test is that gene therapy strategies directed against stathmin, a molecule critical for cell division, would have significant antitumor effects. Taxol is an anti-mitotic agent that is effective against breast cancer. However, its utility is limited due to toxicity. Thus, a secondary hypothesis is that the combination of two interventions that interfere with normal cell cycle progression through its effects on microtubules (i.e. taxol exposure and stathmin inhibition) will have more potent antitumor activity than either treatment alone. STUDY DESIGN: We will use ribozymes which are RNA molecules that we designed to selectively target stathmin mRNA for degradation. More recently, we developed an adenoviral gene transfer vector that carries the anti-stathmin ribozyme to inhibit stathmin expression. We will utilize the recombinant adenoviral vector to target stathmin mRNA in cell culture and animal models of breast cancer. SPECIFIC AIMS: We aim to (1) fully investigate the efficacy of anti-stathmin adenovirus as single agent and in combination with chemotherapeutic agents like taxol in different breast cancer cell lines; (2) investigate the effects of stathmin inhibition and overexpression in normal mammary epithelial cells; (3) investigate whether the same recombinant adenovirus can result in tumor regression in animal models of breast cancer either as a single agent or in combination with chemotherapeutic agents. SIGNIFICANCE: These studies will provide the proof of principle that stathmin provides an attractive molecular target that could serve as the primary focus of novel approaches to breast cancer. It will also provide a potential advantage of using combination therapy with anti-mitotic agents like taxol to result in more potent therapeutic effects at low doses. These studies will set the stage for testing of this novel approach in the treatment of breast cancer patients.