Breast cancer is the most frequently diagnosed cancer in women. It is estimated that death from breast cancer will increase by 100% in the developing world by 2020 (Rastogi, Hildesheim et al. 2004).
Because of its frequent early age at diagnosis, its occurrence in otherwise healthy individuals, and its frequent fatal outcome, breast cancer is the most feared disease in women.
In the case of hormone-sensitive breast cancer, estrogens cause the cancer to grow. If tests show that the cancer cells possess estrogen receptors, antiestrogens are recommended to block the estrogen receptors and thus compete with the estrogens which stimulate growth of cancerous cells.
Among all risk factors, estrogens are well recognized to play the predominant role in breast cancer development and growth (McGuire, Carbone et al. 1975; Asselin and Labrie 1978; Davidson and Lippman 1989; Dowsett, Macaulay et al. 1993). In 75-80% of established breast cancers, estradiol is the main factor responsible for stimulation of the cell cycle machinery (Prall, Sarcevic et al. 1997). More than 75% of diagnosed breast cancers show the presence of estrogen and/or progesterone receptors (Chlebowski, Hendrix et al. 2003; Munster 2006).
In addition to efficacy with a long duration of response, the goal of treatment of breast cancer includes optimizing quality of life. Endocrine therapies are generally well-tolerated in patients with estrogen and/or progesterone receptor positive breast cancer, and they are usually as effective as cytotoxic chemotherapy (Buzdar 2001; Dodwell, Wardley et al. 2006).
Estrogen blockade is a most successful first-line, and best tolerated, strategy for the treatment of estrogen-sensitive breast cancer. One approach consists of blocking the formation of estrogens with inhibitors of aromatase (Brodie and Njar 2000), while another approach is to block activation of the estrogen receptors with anti-estrogens (Labrie, Labrie et al. 1999).
Since the first step in the action of estrogens in the mammary gland is binding to estrogen receptors (Green, Walter et al. 1986; Kumar and Chambon 1988), a logical approach for the treatment of estrogen-sensitive breast cancer is the use of anti-estrogens, or compounds which block the interaction of estrogens with their specific receptors. Until relatively recently, no agent with pure anti-estrogenic activity, under in-vivo conditions, had been available.
In addition to their use as first-line therapy, different endocrine therapies having no or only partial cross-resistance are successful in inducing a large proportion of positive responses in advanced breast cancers which progress after previous hormone therapy, thus delaying the use of more toxic chemotherapy. There is, thus, the need for new endocrine agents which will further delay the use of chemotherapy. In the metastatic setting, patients who respond initially to any hormone therapy, including non-steroidal aromatase inhibitors, eventually develop resistance and progressive disease, thus requiring second-line hormone therapy. There are several available agents: exemestane, a non-steroidal aromatase inhibitor; fulvestrant, a steroidal anti-estrogen; and, tamoxifen, a first generation SERM which can be non-cross resistant with the agents used as first-line therapy.
Of all available anti-estrogens, acolbifene, an anti-estrogen or selective estrogen receptor modulator (SERM) developed by Endoceutics, is the most potent and the only complete blocker of the action of estrogens in the human mammary gland and uterus. Consequently, it is completely free of any estrogenic stimulatory activity in these two tissues.
Previously, estrogen blockade was believed to be limited to a reduction of tumor growth but acolbifene has been shown to cause eradication of the majority of human breast tumors in in-vivo preclinical models. The tumoricidal action of estrogen blockade observed in xenografts of human breast cancer tumors apparently results from a more efficient blockade of the estrogen receptor.
Acolbifene acts by blocking access of estrogens to the estrogen receptors with a high level of efficacy due to its high affinity for the estrogen receptors. In addition, in the absence of estrogens, it prevents activation of the estrogen receptors by growth factor-stimulated kinases. Moreover, acolbifene causes the decrease or degradation of estrogen receptors in the mammary gland and uterus.
Highlights of the Action of Endoceutics Acolbifene in Breast Cancer:
Only one Phase III clinical trial is required before submission for commercialization.
Development status: Phase III
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