Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

Abstract

The enthusiasm with which the clinical community has embraced the use of antiestrogenic therapy to treat breast cancer is based upon the proven record of success that first the nonsteroidal antiestrogen tamoxifen and then the aromatase inhibitor have demonstrated in clinical trial. The reasons for the enthusiasm are obvious. Antihormonal therapy, particularly aromatase inhibition to create a "no estrogen state" in the postmenopausal breast cancer patient is effective, saves women's lives, is contributing successfully to reducing the national mortality from breast cancer, is relatively cheap and has fewer side effects and easy administration (oral) than any other anticancer strategy. However, the successful application of a therapeutic strategy to block the known growth stimulation property of estrogen in breast cancer was not greeted with such enthusiasm 40 years ago.Estrogen is essential for life. Without the critical role of estrogenic steroids, reproduction would not be possible. Based on emerging knowledge from laboratory studies, the value of modulating the steroid environment during the menstrual cycle was advanced to clinical testing during the 1950's as a means of oral contraception. The results of these studies were to change society forever.The Worcester Foundation for Experimental Biology is the place where Gregory Pincus established the scientific principles necessary to propose clinical testing of the oral contraceptive and M.C. Chang subsequently established the first protocols to perform in vitro fertilization. Simply stated, the Worcester Foundation was, at that time, the world center for steroid endocrinology and reproductive biology. Over the years, hundreds of scientists have trained at the Foundation and subsequently spread their knowledge throughout the world [1]. However, fashions in research change and new opportunities emerge.In 1971, President Nixon made a national commitment to seek a cure for cancer by signing the National Cancer Act. Mahlon Hoagland, the President of the Worcester Foundation, responded to the initiative by appointing Professor Elwood V. Jensen, Director of the Ben May Cancer Research Laboratory at the University of Chicago, to be a member of the Foundation's Scientific Advisory Board. Jensen had discovered the estrogen receptor (ER) as the putative mechanism of estrogen action in its target tissues [2]. The known link between estrogen and breast cancer suggested that "antiestrogenic strategies" might have potential as therapeutic Correspondence to: V. Craig Jordan, v.craig.jordan@fccc.edu. Present Address: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be d...

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

“…Overall, the strategy of targeted long-term "antiestrogenic" [25] treatment for breast cancer has presaged the current fashion of targeting anticancer agents to other organ sites in the body.…”

“…The story is naturally dependent on the fashions in therapeutic research at the time. What seems obvious to us as a successful research strategy today, with millions of women taking tamoxifen, was not so 30 years ago at the beginning when the clinical community and pharmaceutical industry did not see "antihormones" as a priority at all for drug development [25]. In 1972, tamoxifen was declared an orphan drug with no prospects [2].…”

Expression characteristics of prostate-derived Ets factor support a role in breast and prostate cancer progression

“…Among the major solid tumors, breast and prostate cancers are perhaps unique in having a history of targeted therapies. Thus, patients with estrogen receptor (ER)-positive and Her2/neu-over expressing breast tumors or androgen receptor (AR)-positive prostate tumors are routinely treated with specific inhibitors that result in consistent remissions in the setting of early disease (7)(8)(9). Similarly, a less common neoplasm, gastrointestinal stromal tumor, also shows high susceptibility to targeted inhibition of the activity of mutated KIT oncogene (10).…”

Synthesis and biological evaluation of 3-(azolylmethyl)-1H-indoles and 3-(α-azolylbenzyl)-1H-indoles as selective aromatase inhibitors

“…A great number of steroidal compounds structurally related to the natural substrates (androstenedione or testosterone) have been developped. 4-Hydroxyandrostenedione (4-OHA) [5,6] was the first aromatase steroidal inhibitor to become available, and had high enzyme selectivity. But it had to be administered as a parental formulation due to its poor oral bioavailability.…”

“…One of these, exemestane [11], has proved to be orally effective in postmenopausal women and reached the market in 1999. Steroidal inhibitors bind either very tightly or irreversibly to aromatase and then cause its inactivation [6,12].…”