Abstracts - Orals, Featured Poster Presentations, and Posters
FP07-New Players in Hormonal Control of Breast & Prostate Cancer
Presentation Start Time: 11:30 AM
Room 206 (Moscone Center)
Poster Board SAT-297
There is now compelling evidence to suggest that drugs that function as pure estrogen receptor (ERα) antagonists, or Selective Estrogen Receptor Degraders (SERDs) would have clinical utility in the treatment of advanced tamoxifen and aromatase resistant breast cancers. Notable is the favorable clinical activity in advanced breast cancer of ICI 182,780 (ICI, Fulvestrant) a first in class ER antagonist/SERD. Unfortunately, the utility of ICI is limited by its poor pharmaceutical properties, and thus the full potential of targeting ERα in late stage disease has not been realized. Whereas compounds with improved characteristics are currently in development, we reasoned, based on our understanding of ERα pharmacology, that there may already exist among the most recently developed Selective Estrogen Receptor Modulators (SERMs) compounds that could function as pure antagonists in breast tumors and which could see near-term use in the treatment of advanced disease. Thus, the objective of this study was to identify among available SERMs drugs with unique pharmacological activities, and to evaluate their potential clinical utility using predictive models of advanced breast cancer. Mechanistic differences between SERMs were determined using a molecular profiling approach that distinguished compounds based upon (a) their impact on ERα conformation and (b) their ability to induce different gene expression profiles in relevant cell model systems. In this manner, it was determined that the SERM bazedoxifene (BZA) most closely resembled ICI. It was further shown that this SERM effectively inhibited the growth of both tamoxifen sensitive and tamoxifen resistant breast tumor xenografts. While BZA induces a unique conformational change in ERα structure that results in its proteasome dependent degradation in cellular and xenograft models of breast cancer, it was determined that competitive antagonism by BZA was sufficient to block ERα transactivation and breast cancer cell proliferation. Based on the results of these studies we conclude that BZA, or other SERMs that exhibit the pharmacological properties of a pure antagonist, may be effective in the treatment and prevention of breast cancer. Bazedoxifene has recently been approved for use in the European Medicines Agency for the treatment of osteoporosis and thus may represent a near-term therapeutic option for patients with advanced breast cancer.
Disclosure: SEW: Consultant, Pfizer Global R&D. DPM: Principal Investigator, Novartis Pharmaceuticals, Principal Investigator, Pfizer, Inc., Principal Investigator, GlaxoSmithKline, Research Funding, Lilly USA, LLC. Nothing to Disclose: ERN, CAC
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Sources of Research Support:
This work was funded by a research grant from Pfizer pharmaceuticals.