Abstract
Abstract Women whose risk of breast cancer is elevated (based on Gail or Tyrer-Cuzik models) have only limited options to intervene in attempt to alter disease progression, and most options are of limited efficacy or have unwanted side effects. Options include increased surveillance, lifestyle changes, drugs such as tamoxifen or aromatase inhibitors, or removal of target tissue. Options that are more efficacious, better tolerated, and more empowering are needed for women in high-risk cohorts. For this purpose, we have developed AFPep, a homobiotic, selective anti-estrogenic/anti-breast cancer active site-analog of alpha-fetoprotein (AFP). AFPep stops growth of human breast cancers growing in xenograft models and prevents development of either estrogen-induced or MNU-induced mammary cancers in rats. In all models, AFPep is effective against tamoxifen-resistant breast cancer, is additive with tamoxifen (allowing dose reduction of tamoxifen), and reduces the uterine hyperplasia induced by tamoxifen. AFPep does not disrupt the estrous cycle of rats, nor does it alter fertility or fecundity and does not induce teratogenicity. The mechanism of action of AFPep differs from that of tamoxifen in that AFPep inhibits phosphorylation of the estrogen receptor leading to a downstream biomarker profile consistent with inhibition of tumor growth. AFPep is orally bioavailable and well tolerated in mice, rats, dogs and primates. The therapeutic index of AFPep in rats shows a substantially broader safety margin than that of currently used agents. AFPep may offer an effective, well tolerated option for women in high risk cohorts who wish to mitigate their risk of breast cancer. Citation Format: Samuel B. Fordyce, Thomas T. Andersen, James A. Bennett. AFPep mitigates the risk of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1154.
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