Gamma-Secretase and Notch Signaling: Novel Therapeutic Targets In Breast Cancer

摘要

We are on track and have made significant progress in our project. We have determined that, as predicted by our hypothesis, LY411,575 is a Notch inhibitor which synergizes with paclitaxel. We have discovered an additional synergism with tamoxifen. We have made several key mechanistic observations on how Notch inhibition causes growth arrest and death in breast cancer cells regardless of ER status. We have determined the optimal conditions for in vivo administration of LY411,575 and we have obtained preliminary xenograft data which confirm significant anti- tumor activity at safe doses of this compound. We expect to complete our study and publish its results within the expected 3- year time frame. We expect our results will not only demonstrate that a GSI/paclitaxel regimen is a promising treatment for ER negative breast cancer, but also that a GSI/tamoxifen combination could be just as promising in ER positive cancers. Based on these data, we will propose 2 phase 1 clinical trials of this compound or its close derivative(s) produced by Eli Lilly in the neo-adjuvant setting at first. In conclusion, we expect that the completion of this project will directly lead to the identification of a new broadly active class of agents for the treatment of breast cancer, the clarification of their primary mode of action and the suggestion of possible combination therapeutic regimens.