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Research Grants Awarded
Targeting the Hedgehog Pathway in the Treatment of Breast Cancer
Background: The hedgehog signaling pathway is important in the genesis and growth of several tumor types, including basal cell carcinomas, and carcinomas of the prostate, pancreas and lung. Hedgehog pathway inhibitor therapy, specifically compounds that inhibit the activity of the transmembrane receptor Smoothened, have proven efficacious in eliminating prostatic cancers in xenograft models. Data from our laboratory and that of others demonstrate that breast cancer cell lines grown in vitro are sensitive to the Smoothened antagonist cyclopamine, and that hedgehog signaling is activated in a subset of human breast cancers. These findings provide support for the clinical use of Smoothened antagonist in the treatment of breast cancer. Objective/Hypothesis: The overall objectives of this proposal are 1) to demonstrate the efficacy of Smoothened antagonists in reducing breast cancer growth and 2) to identify molecular predictors of responsiveness to Smoothened antagonists. Specific Aims: 1) Determine the efficacy of Smo antagonists and identify molecular indicators of responsiveness to hedgehog pathway inhibition by Smo antagonists in breast cancer cell lines in vitro and in vivo. 2) Determine the responsiveness of human breast cancer tissues grown as xenografts to cyclopamine and identify molecular indicators of response. Study Design: Initially, in vitro testing will be performed to identify sensitive and resistant breast cancer cell lines to Smoothened antagonists, then xenografts of sensitive and resistant cell lines will be prepared and treated with cyclopamine to determine in vivo response and molecular predictors of responsiveness. Finally, a xenograft model comprised of human breast cancer tissues will be used to test the efficacy of and identify predictors of response to cyclopamine. Potential Outcomes and Benefits: This project will provide ?proof-of- principle? for the clinical use of Smoothened antagonists in the treatment of breast cancer. If proven effective in these highly translational xenograft models, the potential for its clinical use will be high.
The hedgehog signaling pathway is important in the genesis and growth of several tumor types, including basal cell carcinomas of the skin, and carcinomas of the prostate, pancreas and lung. Recent evidence from our laboratory and others indicates a role for hedgehog signaling in the growth of breast cancers and that hedgehog signaling is important for breast cancer cell survival. There are several inhibitors of the hedgehog pathway that block the activity of a key pathway member, Smoothened. One of these Smoothened antagonists, cyclopamine, has proven effective in eliminating prostate cancers grown in mouse models. We have data indicating that cyclopamine induces cell death in breast cancer cell lines grown in culture. The goal of this project is to establish the efficacy of Smoothened antagonists in the treatment of breast cancer by utilizing highly translational xenograft models that include breast cancer cell lines and human breast cancer tissues. In addition, we will utilize these models to identify molecular predictors of response to Smoothened antagonists so that breast cancers can be tested for likelihood of response prior to treatment. This project will provide ?proof-of- principle? for the clinical use of Smoothened antagonists in breast cancer treatment. If proven effective in these models, the potential for its clinical use in the treatment of breast cancer will be high.