A Phase II Multicenter Randomized Open-Label Study of Oral Steroid Sulphatase (STS) Inhibitor Irosustat (BN83495) Versus Megestrol Acetate (MA) in Women with Advanced/Recurrent Endometrial Cancer (EC)

Pautier, Patricia; Lobbedez, F. Joly; Melichar, Bohuslav; Kutarska, E.; Hall, Geoff; Reed, Nicole

doi:10.1016/s0923-7534(20)33559-6

Cited by 6 publications

(3 citation statements)

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“…Progression free survival, clinical benefits, overall survival and safety were evaluated as secondary endpoints. Although the primary endpoint was not reached, the study found clinical benefit from 27 , with 47.2% of patients having stable disease, 36.1% alive without progression at six months, and 11.1% having a complete or partial response 86. Again, the treatment was well tolerated and STS inhibition was associated with a significant reduction in the levels of some circulating steroid hormones and, in some patients, prolonged clinical partial responses.…”

Section: Coumatesmentioning

confidence: 92%

Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women’s Health

Thomas

Potter

2015

J. Med. Chem.

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In 1994, following work from this laboratory, it was reported that estrone-3-O-sulfamate irreversibly inhibits a new potential hormone-dependent cancer target steroid sulfatase (STS). Subsequent drug discovery projects were initiated to develop the core aryl O-sulfamate pharmacophore that, over some 20 years, have led to steroidal and nonsteroidal drugs in numerous preclinical and clinical trials, with promising results in oncology and women's health, including endometriosis. Drugs have been designed to inhibit STS, e.g., Irosustat, as innovative dual-targeting aromatase-steroid sulfatase inhibitors (DASIs) and as multitargeting agents for hormone-independent tumors, such as the steroidal STX140 and nonsteroidal counterparts, acting inter alia through microtubule disruption. The aryl sulfamate pharmacophore is highly versatile, operating via three distinct mechanisms of action, and imbues attractive pharmaceutical properties. This Perspective gives a personal view of the work leading both to the therapeutic concepts and these drugs, their current status, and how they might develop in the future.

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Section: Coumatesmentioning

confidence: 92%

Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women’s Health

Thomas

Potter

2015

J. Med. Chem.

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“…Irosustat (STX64) is a potent tricylic coumarin-based sulfamate that irreversibly blocks STS activity, and it has been examined in phase II clinical trials for the treatment of patients with advanced hormone-dependent breast and endometrial cancers (Stanway et al, 2007 ). Although the breast cancer data have not yet been published (ClinicalTrials.gov Identifier: NCT01662726) https://clinicaltrials.gov/ct2/show/NCT01662726 ), the effects in endometrial cancer were not as good as the effects of medroxyprogesterone acetate, which is in clinical use for cases of advanced/ recurrent cancer (Pautier et al, 2012 ).…”

Section: Pharmacological Interventions That Target Intracrine Actionsmentioning

confidence: 99%

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

2017

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Endometrial and ovarian cancers predominately affect women after menopause, and are more frequently observed in developed countries. These are considered to be hormone-dependent cancers, as steroid hormones, and estrogens in particular, have roles in their onset and progression. After the production of estrogens in the ovary has ceased, estrogen synthesis occurs in peripheral tissues. This depends on the cellular uptake of estrone-sulfate and dehydroepiandrosterone-sulfate, as the most important steroid precursors in the plasma of postmenopausal women. The uptake through transporter proteins, such as those of the organic anion-transporting polypeptide (OATP) and organic anion-transporter (OAT) families, is followed by the synthesis and action of estradiol E2. Here, we provide an overview of the current understanding of this intracrine action of steroid hormones, which depends on the availability of the steroid precursors and transmembrane transporters for precursor uptake, along with the enzymes for the synthesis of E2. The data is also provided relating to the selected transmembrane transporters from the OATP, OAT, SLC51, and ABC-transporter families, and the enzymes involved in the E2-generating pathways in cancers of the endometrium and ovary. Finally, we discuss these transporters and enzymes as potential drug targets.Keywords: sulfatase, aromatase, 17beta-hydroxysteroid dehydrogenase, transporters, OATP, ABC-transporter HORMONE-DEPENDENT CANCERSSteroid hormones have important roles in human physiology, and the disruption of androgen, estrogen, and progesterone actions are implicated in the development of hormone-dependent cancers and benign hormone-dependent diseases. Hormone-dependent cancers include prostate, breast, endometrial, and ovarian cancers, which comprise more than 20% of all cancers in humans, and more than 35% of cancers in women (Ferlay et al., 2013). Indeed, in women, breast cancer is the most frequent cancer in the developed world. In 2012, 1,671,149 new cases of breast cancer were estimated worldwide, with 521,907 associated deaths. In the developed world, endometrial cancer is the most common among gynecological cancers. Worldwide, there were 319,605 new cases and 76,160 deaths from endometrial cancer in 2012 alone (Ferlay et al., 2013). The most deadly of the hormone-dependent cancers is ovarian cancer. Worldwide, there were 238,719 new cases and 151,905 deaths from ovarian cancer in 2012 (Ferlay et al., 2013).

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“…In this study, irosustat was evaluated vs. progestin megestrol acetate in 73 patients, with median age 68 years (range, 37–85 years). Here, 36 patients were randomized to irosustat (40 mg/day), and 37 to megestrol acetate (160 mg/day) (Pautier et al, 2012 ). After 6 months of treatment, 36.1 and 56.8% of the patients treated with irosustat and megestrol acetate, respectively, were alive and without disease progression.…”

Section: Sulfatase Inhibitors and Clinical Trialsmentioning

confidence: 99%

The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases

Rižner

2016

Front. Pharmacol.

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Gynecological diseases such as endometriosis, adenomyosis and uterine fibroids, and gynecological cancers including endometrial cancer and ovarian cancer, affect a large proportion of women. These diseases are estrogen dependent, and their progression often depends on local estrogen formation. In peripheral tissues, estrogens can be formed from the inactive precursors dehydroepiandrosterone sulfate and estrone sulfate. Sulfatase and sulfotransferases have pivotal roles in these processes, where sulfatase hydrolyzes estrone sulfate to estrone, and dehydroepiandrosterone sulfate to dehydroepiandrosterone, and sulfotransferases catalyze the reverse reactions. Further activation of estrone to the most potent estrogen, estradiol, is catalyzed by 17-ketosteroid reductases, while estradiol can also be formed from dehydroepiandrosterone by the sequential actions of 3β-hydroxysteroid dehydrogenase-Δ4-isomerase, aromatase, and 17-ketosteroid reductase. This review introduces the sulfatase and sulfotransferase enzymes, in terms of their structures and reaction mechanisms, and the regulation and different transcripts of their genes, together with the importance of their currently known single nucleotide polymorphisms. Data on expression of sulfatase and sulfotransferases in gynecological diseases are also reviewed. There are often unchanged mRNA and protein levels in diseased tissue, with higher sulfatase activities in cancerous endometrium, ovarian cancer cell lines, and adenomyosis. This can be indicative of a disturbed balance between the sulfatase and sulfotransferases enzymes, defining the potential for sulfatase as a drug target for treatment of gynecological diseases. Finally, clinical trials with sulfatase inhibitors are discussed, where two inhibitors have already concluded phase II trials, although so far with no convincing clinical outcomes for patients with endometrial cancer and endometriosis.

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A Phase II Multicenter Randomized Open-Label Study of Oral Steroid Sulphatase (STS) Inhibitor Irosustat (BN83495) Versus Megestrol Acetate (MA) in Women with Advanced/Recurrent Endometrial Cancer (EC)

Cited by 6 publications

References 0 publications

Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women’s Health

Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women’s Health

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases

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