Activity and Safety of the Antiestrogen EM-800, the Orally Active Precursor of Acolbifene, in Tamoxifen-Resistant Breast Cancer

Labrie, Fernand; Champagne, Pierre; Labrie, Claude; Roy, Jean; Laverdière, Jacques; Provencher, Louise; Potvin, M; Drolet, Y; Pollak, Michael; Panasci, Lawrence C.; Bernard, Loris; Dufresne, Jean; Latreille, Jean; Robert, Jean; Samson, Benoît; Jolivet, Jacques; Yelle, Louise; Cusan, Lionel; Diamond, P.; Candas, Bernard

doi:10.1200/jco.2004.05.122

Cited by 35 publications

(20 citation statements)

References 36 publications

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“…While hormone therapy was previously believed to be only cytostatic, it was observed, for the first time with an hormonal agent, that ACOL caused the disappearance of 61 % of human breast cancer tumors in nude mice, thus demonstrating cytotoxic activity [84]. In phase II and III clinical trials, the compound has shown positive responses in women who had failed tamoxifen treatment [49], thus supporting the superiority of ACOL over tamoxifen, an observation well demonstrated in a series of preclinical studies [48].…”

Section: Introductionmentioning

confidence: 95%

Specific transcriptional response of four blockers of estrogen receptors on estradiol-modulated genes in the mouse mammary gland

Calvo

Luu‐The

Belleau

et al. 2012

Breast Cancer Res Treat

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Novel agents for the endocrine therapy of breast cancer are needed, especially in order to take advantage of the multiple consecutive responses observed in metastatic progressing breast cancer following previous hormone therapy, thus delaying the use of cytotoxic chemotherapy with its frequent poor tolerance and serious side effects. Acolbifene (ACOL) is a novel and unique antiestrogen which represents a unique opportunity to achieve the most potent and specific blockade of estrogen action in the mammary gland and uterus while exerting estrogen-like beneficial effects in other tissues, especially the bones. To better understand the specificity of action of ACOL, we have used Affymetrix GeneChips containing 45,000 probe sets to analyze 34,000 genes to determine the specificity of this compound compared to the pure antiestrogen fulvestrant, as well as to the mixed antagonists/agonists tamoxifen and raloxifene to block the effect of estradiol (E(2)) and to induce effects of their own on the genomic profile in the mouse mammary gland. The genes modulated by E(2) were those identified in two separate experiments and validated by quantitative real-time PCR (qPCR). Three hours after the single subcutaneous injection of E(2) (0.05 μg), the simultaneous administration of ACOL, fulvestrant, tamoxifen, and raloxifene blocked by 98, 61, 43, and 92 % the number of E(2)-upregulated genes, respectively. On the other hand, 70, 10, 25, and 55 % of the genes down-regulated by E(2) were blocked by the same compounds. Of the 128 genes modulated by E(2), 49 are associated with tumorigenesis while 22 are known to be associated with breast cancer. When used alone, ACOL modulated the smallest number of genes also influenced by E(2), namely 4 %, thus possibly explaining potential utilities of this compound in breast cancer prevention and therapy.

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Section: Introductionmentioning

confidence: 95%

Specific transcriptional response of four blockers of estrogen receptors on estradiol-modulated genes in the mouse mammary gland

Calvo

Luu‐The

Belleau

et al. 2012

Breast Cancer Res Treat

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“…Development of EM-652 is ongoing. The development of EM-800 for advanced breast cancer has been halted, despite 35% of patients (nZ43) with tamoxifen-resistant breast cancer who had been treated with EM-800 experiencing CB in a phase II study (Labrie et al 2004). In comparison, O43.5% of tamoxifen-resistant patients treated with fulvestrant experience CB .…”

Section: Other Pure Oestrogen Antagonists In Developmentmentioning

confidence: 99%

Pure oestrogen antagonists for the treatment of advanced breast cancer

Howell¹

2006

Endocr Relat Cancer

108

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For more than 30 years, tamoxifen has been the drug of choice in treating patients with oestrogen receptor (ER)-positive breast tumours. However, research has endeavoured to develop agents that match and improve the clinical efficacy of tamoxifen, but lack its partial agonist effects. The first 'pure' oestrogen antagonist was developed in 1987; from this, an even more potent derivative was developed for clinical use, known as fulvestrant (ICI 182,780, 'Faslodex'). Mechanistic studies have shown that fulvestrant possesses high ER-binding affinity and has multiple effects on ER signalling: it blocks dimerisation and nuclear localisation of the ER, reduces cellular levels of ER and blocks ER-mediated gene transcription. Unlike anti-oestrogens chemically related to tamoxifen, fulvestrant also helps circumvent resistance to tamoxifen. There are extensive data to support the lack of partial agonist effects of fulvestrant and, importantly, its lack of cross-resistance with tamoxifen. In phase III studies in patients with locally advanced or metastatic breast cancer, fulvestrant was at least as effective as anastrozole in patients with tamoxifen-resistant tumours, was effective in the first-line setting and was also well tolerated. These data are supported by experience from the compassionate use of fulvestrant in more heavily pretreated patients. Further studies are now underway to determine the best strategy for sequencing oestrogen endocrine therapies and to optimise dosing regimens of fulvestrant. At present, and for the foreseeable future, fulvestrant is the only oestrogen antagonist with no agonistic effects licensed for the treatment of advanced breast cancer in postmenopausal women. Other similar oestrogen antagonists are undergoing research and development, with a few currently being evaluated in phase II trials.

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“…Newer SERMs such as acolbifene (Acol, EM-652) and its prodrug (EM-800) have been used to prevent the development of and to treat established mammary tumors in animal models (10 -12), and caused the disappearance of 60% of human breast cancer tumors in nude mice (13). Acol also showed positive responses in women who failed tamoxifen treatment (14), suggesting the superiority of Acol over tamoxifen in a series of preclinical studies (15). The SERM arzoxifene (Arz) also prevented mammary carcinogenesis in rats (16) and decreased ER expression in humans in a phase 1 chemoprevention trial (17).…”

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The Combination of the Rexinoid, LG100268, and a Selective Estrogen Receptor Modulator, Either Arzoxifene or Acolbifene, Synergizes in the Prevention and Treatment of Mammary Tumors in an Estrogen Receptor–Negative Model of Breast Cancer

Liby

Rendi

Suh

et al. 2006

Clinical Cancer Research

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Purpose: We tested whether a selective estrogen receptor modulator (SERM) and a rexinoid are active for prevention and treatment in the mouse mammary tumor virus-neu mouse model of estrogen receptor^negative breast cancer. Experimental Design: For prevention, mice were fed a powdered control diet, the SERM arzoxifene (Arz, 20 mg/kg diet), the rexinoid LG100268 (268, 30 mg/kg diet), or the combination for 60 weeks. In a second prevention study, mice were fed Arz (6 mg/kg diet), 268 (30 mg/kg diet), the combination of Arz and 268, the SERM acolbifene (Acol, 3 mg/kg diet), or the combination of Acol and 268 for 52 weeks. For the treatment studies, mice with tumors were fed combinations of a SERM and 268 for 4 weeks. Results: The rexinoid 268 and the SERMs Arz and Acol, as individual drugs, delayed the development of estrogen receptor^negative tumors. Moreover, the combination of a SERM and 268 was strikingly synergistic, as no tumors developed in any mouse fed the combination of 268 and a SERM. Moreover, this drug combination also induced significant tumor regression when used therapeutically. These drugs did not inhibit transgene expression in vitro or in vivo, and the combination of Arz and 268 inhibited proliferation and induced apoptosis in the tumors. Conclusion: The combination of a rexinoid and SERM should be considered for future clinical trials.Despite the development of selective estrogen receptor (ER) modulators (SERMs), aromatase inhibitors, and the monoclonal antibody trastuzumab (Herceptin), breast cancer still claims >40,000 lives in the U.S. each year (1). Because of the genetic and epigenetic complexities of an invasive cancer, arresting or reversing carcinogenesis at its earliest stages offers an attractive alternative to treating advanced disease (2, 3). However, the realities of the clinic mean that new drugs and new drug combinations are desperately needed for both the prevention and treatment of breast cancer.A number of drugs have been shown to prevent or treat ER+ breast cancer. SERMs such as tamoxifen and raloxifene are effective in women for both prevention (4 -8) and treatment (9). Newer SERMs such as acolbifene (Acol, EM-652) and its prodrug (EM-800) have been used to prevent the development of and to treat established mammary tumors in animal models (10 -12), and caused the disappearance of 60% of human breast cancer tumors in nude mice (13). Acol also showed positive responses in women who failed tamoxifen treatment (14), suggesting the superiority of Acol over tamoxifen in a series of preclinical studies (15). The SERM arzoxifene (Arz) also prevented mammary carcinogenesis in rats (16) and decreased ER expression in humans in a phase 1 chemoprevention trial (17).In addition to the SERMs, retinoids, such as 9-cis-retinoic acid (18,19), or rexinoids [selective ligands for the retinoid X receptors (RXRs)], such as LGD1069 (bexarotene, Targretin; refs. 20, 21) and LG100268 (268; refs. 22, 23), have been reported to prevent and treat mammary tumors in animal models of ER+ breast ...

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Activity and Safety of the Antiestrogen EM-800, the Orally Active Precursor of Acolbifene, in Tamoxifen-Resistant Breast Cancer

Cited by 35 publications

References 36 publications

Specific transcriptional response of four blockers of estrogen receptors on estradiol-modulated genes in the mouse mammary gland

Specific transcriptional response of four blockers of estrogen receptors on estradiol-modulated genes in the mouse mammary gland

Pure oestrogen antagonists for the treatment of advanced breast cancer

The Combination of the Rexinoid, LG100268, and a Selective Estrogen Receptor Modulator, Either Arzoxifene or Acolbifene, Synergizes in the Prevention and Treatment of Mammary Tumors in an Estrogen Receptor–Negative Model of Breast Cancer

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