Steroid Sulfatase Inhibition in Hormone-Dependent Cancers

Steroid sulfatase (STS) catalyses the hydrolysis of oestrogen and androgen precursors, notably estrone-sulphate and dehydroepiandrosterone-sulphate, within tumour microenvironments. In hormone-dependent malignancies such as postmenopausal breast, endometrial and ovarian cancers, intracrine conversion of circulating steroid sulphates by STS constitutes a pivotal source of bioactive oestrogens that drive proliferation through oestrogen receptor signalling. Targeting STS thus represents a pre-receptor approach to diminish intratumoural hormone supply upstream of receptor antagonism. First-generation sulphamate inhibitors, including the irreversible agent Irosustat, have demonstrated biological activity and moderate clinical benefit, particularly when combined with aromatase inhibitors. However, limited efficacy in certain cohorts has spurred the design of second- and third-generation inhibitors with enhanced potency, selectivity and pharmacokinetics. Concurrently, elucidation of the interplay between STS, sulphotransferases, which catalyse the reverse sulphation reaction, and membrane transporters mediating steroid uptake has deepened understanding of local hormone homeostasis. These advances underscore the global significance of STS inhibition, highlighting potential for combination regimens and biomarker-driven patient stratification in oestrogen-driven cancers.

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Steroid Sulfatase Inhibition in Hormone-Dependent Cancers publication trend

The graph below shows the total number of articles in steroid sulfatase inhibition in hormone-dependent cancers across all publications each year (not limited to Nature Index journals).

Technical terms

Steroid sulfatase (STS): Enzyme converting inactive steroid sulphates (e.g. estrone-sulphate) into active hormones.
Sulphotransferase (SULT): Enzyme catalysing sulphation of free steroids, opposing STS action.
Intracrine: Hormone synthesis and action within the same cell, bypassing systemic endocrine pathways.
Aromatase: Enzyme that converts androgens into oestrogens, a parallel pathway in local oestrogen biosynthesis.
Irosustat: Irreversible sulphamate-based STS inhibitor evaluated in clinical trials for hormone-dependent cancers.

References

1. Steroid sulfatase and sulfotransferases in the estrogen and androgen action of gynecological cancers: current status and perspectives. Essays in Biochemistry (2024).
2. The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases. Frontiers in Pharmacology (2016).
3. The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers. Frontiers in Pharmacology (2017).
4. Steroid Sulphatase and Its Inhibitors: Past, Present, and Future. Molecules (2021).
5. The Significance of the Sulfatase Pathway for Local Estrogen Formation in Endometrial Cancer. Frontiers in Pharmacology (2017).
6. IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients. Breast Cancer Research and Treatment (2017).
7. Design, synthesis, and biological evaluation of new arylamide derivatives possessing sulfonate or sulfamate moieties as steroid sulfatase enzyme inhibitors. Bioorganic & Medicinal Chemistry (2016).
8. C‑3- and C‑4-Substituted Bicyclic Coumarin Sulfamates as Potent Steroid Sulfatase Inhibitors. ACS Omega (2018).