Irosustat: Difference between revisions

By inhibiting STS, irosustat prevents the conversion of hormonally inactive [[steroid]] [[sulfate]]s such as [[dehydroepiandrosterone sulfate|{{abbr|DHEA|dehydroepiandrosterone}} sulfate]] (DHEA-S) and [[estrone sulfate]] (E1S) into their respective active forms, {{abbrlink|DHEA|dehydroepiandrosterone}} and [[estrone]] (which, in turn, can be transformed into more potent [[androgen]]s and [[estrogen]]s, respectively).<ref name="pmid21342037" /> Administration of 5&nbsp;mg/day irosustat to women with breast cancer for 5&nbsp;days inhibited STS activity by 98 to 99% in [[breast]] [[tumor]] [[tissue (biology)|tissue]] and significantly decreased serum levels of estrone (by 76%), estradiol (by 39%), DHEA (by 41%), [[androstenediol]] (by 70%), [[androstenedione]] (by 62%), and [[testosterone]] (by 30%), whereas levels of DHEA-S and E1S increased slightly (by 1.1% and 7.4%, respectively).<ref name="pmid21342037" />▼

Despite Irosustat being quickly degraded in plasma ''ex vivo'', this is prevented ''in vivo'' by its sequestration almost completely inside red blood cells after oral administration, being bound to carbonic anhydrase II (CA II) like its parent steroidal sulfamate ester [[Estradiol sulfamate|E2MATE]] and thus avoiding first pass metabolism.<ref>{{Cite journal|last=Ireson|first=C R, Chander S K, Purohit A, Parish D C, Woo L W L, Potter B V L & Reed M J|date=2004|title=Pharmacokinetics of the nonsteroidal steroid sulphatase inhibitor 667 COUMATE and its sequestration into red blood cells in rats.|journal=Br. J. Cancer|volume=91|issue=7|pages=1399–1404 |doi=10.1038/sj.bjc.6602130|pmid=15328524|pmc=2409900}}</ref> The X-ray crystal structure of the drug bound to CAII has been determined.<ref>{{Cite journal|last=Lloyd|first=M D, R L Pederick, R Natesh, L W L Woo, A Purohit, M J Reed, K R Acharya & B V L Potter|date=2005|title=Crystal structure of human carbonic anhydrase II at 1.95 Å resolution in complex with 667-Coumate, a novel anti-cancer agent.|journal=Biochem. J.|volume=385|issue=Pt 3|pages=715–720|doi=10.1042/BJ20041037|pmid=15453828|pmc=1134746}}</ref>▼

In 2004 Sterix Ltd was acquired by Ipsen and Irosustat continued in development through formal academic-industry partnerships by Ipsen with the University of Bath and Imperial College. The drug reached [[Phases of clinical research#Phase II|phase II]] [[clinical trial]]s in women with hormone-dependent breast cancer and endometrial cancer prior to the discontinuation of its initial development by Ipsen as a monotherapy for endometrial cancer in women with advanced/metastatic or recurrent estrogen-receptor positive endometrial cancer after a futility analysis of trial data.<ref name="AdisInsight" /><ref name="AvendanoMenendez2015">{{cite book|author1=Carmen Avendano|author2=J. Carlos Menendez|title=Medicinal Chemistry of Anticancer Drugs|url=https://books.google.com/books?id=VEibBwAAQBAJ&pg=PA105|date=11 June 2015|publisher=Elsevier Science|isbn=978-0-444-62667-7|pages=105–}}</ref> Results published in 2017 showed clinical activity and a good safety profile for Irosustat, with 36% of patients on Irosustat alive without progression at 6 months; 11% showed responses and there was more stable disease noted (47%) compared to the current therapy (32%), the progestin [[megestrol acetate]] (MA).<ref>{{Cite journal|vauthors=Pautier P, Vergote I, Joly F, Melichar B, Kutarska E, Hall G, Lisyanskaya A, Reed N, Oaknin A, Ostapenko V, etal |date=2017|title=A phase 2, randomized, open-label study of Irosustat versus megestrol acetate in advanced endometrial cancer.|journal=International Journal of Gynecological Cancer|volume=27|issue=2|pages=258–266 |doi=10.1097/IGC.0000000000000862|pmid=27870712|s2cid=3430946|url=https://lirias.kuleuven.be/handle/123456789/558056}}</ref> However, overall there were no statistically significant differences between Irosustat and the current standard of care MA in response and survival rates. It also reached a phase I trial in the US for prostate cancer, being safe and well tolerated in male patients with castration-resistant prostate cancer and ongoing androgen deprivation therapy. Pharmacodynamic proof of concept was demonstrated with Irosustat effecting nearly complete STS inhibition at three doses, and in all patients there was notable suppression of endocrine parameters.<ref>{{Cite journal|last=Denmeade|first=S, George D, Liu G, Peraire C, Geniaux A, Baton F, Ali T & Chetaille|date=2011|title=2011 A phase I pharmacodynamics dose escalation study of steroid sulphatase inhibitor Irosustat in patients with prostate cancer.|journal=European Journal of Cancer|volume=47|pages=S499 |doi=10.1016/S0959-8049(11)71998-0}}</ref> The development of Irosustat has continued with clinical trials overseen by CRUK designed to explore its activity in early breast cancer (IPET trial) <ref>{{Cite journal |vauthors=Palmieri C, Szydlo R, Miller M, Barker L, Patel NH, Sasano H, Barwick T, Tam H, Hadjiminas D, Lee J, etal|date=2017|title=IPET study: an FLT-PET window study to assess the activity of the steroid sulfatase inhibitor irosustat in early breast cancer.|journal=Breast Cancer Res. Treat.|volume=166|issue=2|pages=527–539 |doi=10.1007/s10549-017-4427-x|pmid=28795252|pmc=5668341}}</ref> and also in combination with an aromatase inhibitor (AI) (IRIS trial).<ref>{{Cite journal |vauthors=Palmieri C, Stein RC, Liu X, Hudson E, Nicholas H, Sasano H, Guestini F, Holcombe C, Barrett S, Kenny L, etal|date=2017|title=IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients.|journal=Breast Cancer Res. Treat.|volume=165|issue=2|pages=343–353 |doi=10.1007/s10549-017-4328-z|pmid=28612226|pmc=5543190}}</ref> The multicentre IRIS trial, an open-label phase II clinical study, explored the clinical value of adding an STS inhibitor in addition to a first-line AI in patients with advanced breast cancer and enrolled postmenopausal women with [[Hormone receptor positive breast tumor|ER+]] locally advanced or metastatic breast cancer who had benefited from a first-line AI but were subsequently progressing. The IPET trial was a pre-surgical window-of-opportunity study, assessing Irosustat for the first time in ER+ early breast cancer and recruiting postmenopausal women with untreated early disease. Importantly, these data are the first to demonstrate clinical activity of Irosustat in early breast cancer, albeit in a small patient population. The results of both trials were published in 2017, showing evidence of clinical benefit and underpinning the scientific concept of STS inhibition. Larger studies are now required. Irosustat was also evaluated as a combination therapy with an oral [[epidermal growth factor receptor]] [[tyrosine kinase inhibitor]] for the treatment of [[Non-Small Cell Lung Cancer]] Patients<ref>{{Cite web|title=A Pilot Study of a Steroid Sulphatase Inhibitor (BN83495) in Patients Receiving an Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) for the Treatment of Non-Small Cell Lung Cancer (NSCLC)|url=https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336296|url-status=live|website=Australian New Zealand Clinical Trials Registry}}</ref>. Clinical development continues and the current status was reviewed in 2018.<ref>{{Cite journal|last=Potter|first=BVL|date=2018|title=SULFATION PATHWAYS: Steroid Sulfatase Inhibition by Aryl Sulfamates: Clinical Progress, Mechanism, and Future Prospects.|journal=J Mol Endocrinol|volume=61|issue=2|pages=T233–T252 |doi=10.1530/JME-18-0045|pmid=29618488|doi-access=free}}</ref>▼

Importantly, it was demonstrated <ref>{{Cite journal|last=Pérez-Jiménez|first=Mercedes M.|last2=Monje-Moreno|first2=José M.|last3=Brokate-Llanos|first3=Ana María|last4=Venegas-Calerón|first4=Mónica|last5=Sánchez-García|first5=Alicia|last6=Sansigre|first6=Paula|last7=Valladares|first7=Amador|last8=Esteban-García|first8=Sara|last9=Suárez-Pereira|first9=Irene|last10=Vitorica|first10=Javier|last11=Ríos|first11=José Julián|date=2021-01-04|title=Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases|url=https://www.nature.com/articles/s41467-020-20269-y|journal=Nature Communications|language=en|volume=12|issue=1|pages=49|doi=10.1038/s41467-020-20269-y|issn=2041-1723|pmc=PMC7782729|pmid=33397961}}</ref> that oral treatment with Irosustat alleviates the symptoms of [[Alzheimer's disease|Alzheimer’s Disease]] in a murine model, indicating that the drug passes the [[blood–brain barrier]]. STS inhibitors could therefore potentially be employed to treat aging and aging-associated diseases.▼

==See also==▼