Breast Cancer

What is a Hormone-Dependent Cancer? 

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 fearful disease in women.

In the case of hormone-dependent 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 its growth.

Mechanism of Action of Antiestrogens

 

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). Estrogen is the main modulator of the cell cycle in breast cancer. 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 optimal quality of life. Endocrine therapies are generally well tolerated in patients with estrogen and/or progesterone receptor positive breast cancer, as they usually are as effective as cytotoxic chemotherapy (Buzdar 2001; Dodwell, Wardley et al. 2006).
Estrogen blockade is the most successful first-line and best tolerated strategy for the treatment of estrogen-sensitive breast cancer. One approach consists in blocking the formation of estrogens with inhibitors of aromatase (Brodie and Njar 2000) while the other approach is to block activation of the estrogen receptors with antiestrogens (Labrie, Labrie et al. 1999).
Since the first step in the action of estrogens in the mammary gland is binding to the estrogen receptor (Green, Walter et al. 1986; Kumar and Chambon 1988), a logical approach for the treatment of estrogen-sensitive breast cancer is the use of antiestrogens, or compounds which block the interaction of estrogens with their specific receptors. Until relatively recently, no agent with pure antiestrogenic activity under in vivo conditions had been available.
In addition to 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. Non-cross resistant with the agents used as first line, the available agents are exemestane, a non steroidal aromatase inhibitor, fulvestrant, a steroidal antiestrogen and tamoxifen, a first generation SERM. 

Breast Cancer Prevention and Treatment

Of all available antiestrogens, the antiestrogen or selective estrogen receptor modulator (SERM) of Endoceuticsä (acolbifene) 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 while acolbifene has been shown to cause disappearance 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.

Mechanism of Action

Acolbifene acts by blocking access of estrogens to the estrogen receptors at a high level of efficacy. In addition, in the absence of estrogens, it prevents activation of the estrogen receptors by growth factor-stimulated kinases.

Moreover, acolbifene causes disappearance of the estrogen receptor in the mammary gland and uterus. 

Highlights of the Action of Endoceuticä acolbifene in Breast Cancer

  • No development of resistance to treatment or no loss of response has been observed with human breast cancer cells in vitro and in vivo
  • A positive response has been observed in women with advanced breast cancer, thus showing its clinical efficacy, even after failure of breast cancer to Tamoxifen
  • A potent inhibition (77%) of mammary gland cell proliferation has been observed in women at high risk of breast cancer in a phase II prevention study.
  • No significant drug-related side effects have been observed in phase I, II and III clinical trials
  • Other beneficial effects shown at the preclinical level:
    • Protection against bone loss:
      • It is about 10 times more potent than raloxifene in preventing bone loss in the rat
    • Decreases fat accumulation
    • Decreases insulin resistance
    • Decreases serum cholesterol and triglycerides

Only one Phase III clinical trial is required before commercialization.