{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T12:40:12Z","timestamp":1769604012988,"version":"3.49.0"},"reference-count":21,"publisher":"Endocrinology Research Centre","issue":"6","license":[{"start":{"date-parts":[[2023,1,8]],"date-time":"2023-01-08T00:00:00Z","timestamp":1673136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.probl-endojournals.ru\/jour\/about\/editorialPolicies#openAccessPolicy"}],"content-domain":{"domain":["www.probl-endojournals.ru"],"crossmark-restriction":true},"short-container-title":["Probl Endokrinol (Mosk)"],"abstract":"<jats:p><jats:bold>BACKGROUND<\/jats:bold>: Adrenocortical cancer (ACC) is an orphan malignant tumor of the adrenal cortex with a predominantly poor prognosis and an aggressive clinical course. Nowadays, mitotane is a non-alternative drug in the treatment of ACC. The search for prognostic parameters that determine the sensitivity of ACC to ongoing treatment is currently an urgent task. Expression levels of the large subunit of ribonucleotide reductase M1 (RRM1), cytochrome P450 2W1 (CYP2W1), and sterol- O-acyltransferase-1 (SOAT1) are considered as potential predictors of response to mitotane therapy.<jats:bold>AIM<\/jats:bold>: To assess the immunohistochemical expression of RRM1, CYP2W1 and SOAT1 in ACC as markers of clinical outcomes and response to the therapy with mitotane.<jats:bold>MATERIALS AND METHODS<\/jats:bold>: The study included 62 patients older than 17 years of age with a diagnosis of ACC confirmed histologically and immunohistochemically. Mitotane therapy was initiated in 29 patients in the postoperative period, 33 patients were under dynamic observation without concomitant drug treatment. Antibodies to RRM1, CYP2W1, SOAT1 were used diluted in accordance with recommendations of firms-manufacturers for immunohistochemical detection. RESULTS: In the group of patients with low and moderate RRM1, CYP2W1 and SOAT1 immunoreactivity in the tumor and no antitumor therapy, a better DFS was noted (p=0.037, p=0.020 and p=0.001, respectively) compared to the group of patients receiving mitotane therapy at this level of marker expression. With high immunoreactivity of the markers, no statistically significant differences in DFS were found.<jats:bold>CONCLUSION<\/jats:bold>: Consistent with the findings in our study, low expression of RRM1, CYP2W1 and SOAT1 was associated with worse DFS with antitumor therapy. The results of the work indicate the need to assess the levels of immunoreactivity of these markers in patients with ACC before starting treatment with mitotane in order to predict the efficiency of therapy.<\/jats:p>","DOI":"10.14341\/probl13172","type":"journal-article","created":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T12:20:40Z","timestamp":1674735640000},"page":"76-88","update-policy":"https:\/\/doi.org\/10.14341\/crossmarkpolicy2018","source":"Crossref","is-referenced-by-count":3,"title":["Morphological predictors of the efficacy of mitotane therapy in adrenocortical cancer"],"prefix":"10.14341","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5917-6869","authenticated-orcid":true,"given":"A. V.","family":"Tkachuk","sequence":"first","affiliation":[{"name":"Endocrinology research center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7098-4584","authenticated-orcid":true,"given":"D. G.","family":"Beltsevich","sequence":"additional","affiliation":[{"name":"Endocrinology research center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2611-9320","authenticated-orcid":true,"given":"E. E.","family":"Porubayeva","sequence":"additional","affiliation":[{"name":"Endocrinology research center; FMSMU I.M. Sechenov First Moscow State Medical University (Sechenov University)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6891-0009","authenticated-orcid":true,"given":"L. S.","family":"Urusova","sequence":"additional","affiliation":[{"name":"Endocrinology research center"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"5458","published-online":{"date-parts":[[2023,1,8]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Fassnacht M, Dekkers OM, Else T, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the study of adrenal tumors. Eur J Endocrinol. 2018;179(4):G1-G46. doi: https:\/\/doi.org\/10.1530\/EJE-18-0608","DOI":"10.1530\/EJE-18-0608"},{"key":"ref2","unstructured":"Lloyd RV, Osamura R, Rosai J, et al. WHO Classification of Tumours Editorial Board. Endocrine and Neuroendocrine tumours. Fifth Edition. Lyon: IARC; 2022."},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"Fassnacht M, Assie G, Baudin E et al. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(11):1476-1490. doi: https:\/\/doi.org\/10.1016\/j.annonc.2020.08.2099","DOI":"10.1016\/j.annonc.2020.08.2099"},{"key":"ref4","unstructured":"Obshherossijskij nacional\u2019nyj sojuz \u00abAssociacija onkologov Rossii\u00bb, Obshhestvennaja organizacija \u00abRossijskaja Associacija Jendokrinologov\u00bb. Klinicheskie rekomendacii: Rak kory nadpochechnika (Adrenokortikal\u2019nyj rak). 2020 g. (In Russ.). \u0414\u043e\u0441\u0442\u0443\u043f\u043d\u043e \u043f\u043e: https:\/\/oncology-association.ru\/wp-content\/uploads\/2020\/09\/adrenokortikalnyj_rak.pdf \u0421\u0441\u044b\u043b\u043a\u0430 \u0430\u043a\u0442\u0438\u0432\u043d\u0430 \u043d\u0430 12.05.2022."},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"Hescot S, Amazit L, Lhomme M, et al. Identifying mitotane-induced mitochondria-associated membranes dysfunctions: metabolomic and lipidomic approaches. Oncotarget. 2017;8(66):109924-109940. doi: https:\/\/doi.org\/10.18632\/oncotarget.18968","DOI":"10.18632\/oncotarget.18968"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"Sbiera S, Leich E, Liebisch G, et al. Mitotane inhibits Sterol-O-Acyl transferase 1 triggering lipid-mediated endoplasmic reticulum stress and apoptosis in adrenocortical carcinoma cells. Endocrinology. 2015;156(11):3895-3908. doi: https:\/\/doi.org\/10.1210\/en.2015-1367","DOI":"10.1210\/en.2015-1367"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"Paragliola RM, Torino F, Papi G, et al. Role of Mitotane in Adrenocortical Carcinoma \u2013 Review and State of the art. Eur Endocrinol. 2018;14(2):62. doi: https:\/\/doi.org\/10.17925\/EE.2018.14.2.62","DOI":"10.17925\/EE.2018.14.2.62"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"Corso CR, Acco A, Bach C, et al. Pharmacological profile and effects of mitotane in adrenocortical carcinoma. Br J Clin Pharmacol. 2021;87(7):2698-2710. doi: https:\/\/doi.org\/10.1111\/bcp.14721","DOI":"10.1111\/bcp.14721"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"Lehmann TP, Wrzesi\u0144ski T, Jagodzi\u0144ski PP. The effect of mitotane on viability, steroidogenesis and gene expression in NCI-H295R adrenocortical cells. Mol Med Rep. 2013;7(3):893-900. doi: https:\/\/doi.org\/10.3892\/mmr.2012.1244","DOI":"10.3892\/mmr.2012.1244"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"Volante M, Terzolo M, Fassnacht M, et al. Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer. Clin Cancer Res. 2012;18(12):3452-3461. doi: https:\/\/doi.org\/10.1158\/1078-0432.CCR-11-2692","DOI":"10.1158\/1078-0432.CCR-11-2692"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"Lacombe AMF, Soares IC, Mariani BMP, et al. Sterol O-Acyl transferase 1 as a prognostic marker of adrenocortical carcinoma. Cancers (Basel). 2020;12(1):247. doi: https:\/\/doi.org\/0.3390\/cancers12010247","DOI":"10.3390\/cancers12010247"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"Guo J, Johansson I, Mkrtchian S, et al. The CYP2W1 enzyme: regulation, properties and activation of prodrugs. Drug Metab Rev. 2016;48(3):369-378. doi: https:\/\/doi.org\/10.1080\/03602532.2016.1188939","DOI":"10.1080\/03602532.2016.1188939"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"Ronchi CL, Sbiera S, Volante M, et al. CYP2W1 is highly expressed in adrenal glands and is positively associated with the response to mitotane in adrenocortical carcinoma. PLoS One. 2014;9(8):e105855. doi: https:\/\/doi.org\/10.1371\/journal.pone.0105855","DOI":"10.1371\/journal.pone.0105855"},{"key":"ref14","unstructured":"Lloyd RV, Osamura RY, Kl\u00f6ppel G, Rosai J. WHO Classification of Tumours of Endocrine Organs. Fourth Edition. Lyon: IARC; 2017."},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"Germano A, Rapa I, Volante M, et al. RRM1 modulates mitotane activity in adrenal cancer cells interfering with its metabolization. Mol Cell Endocrinol. 2015;401(3):105-110. doi: https:\/\/doi.org\/10.1016\/j.mce.2014.11.027","DOI":"10.1016\/j.mce.2014.11.027"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"Terzolo M, Fassnacht M, Perotti P, et al. Results of the ADIUVO study, the first randomized trial on adjuvant mitotane in adrenocortical carcinoma patients. J Endocr Soc. 2021;5(S1):A166-\u0410167. doi: https:\/\/doi.org\/10.1210\/jendso\/bvab048.336","DOI":"10.1210\/jendso\/bvab048.336"},{"key":"ref17","unstructured":"Stenstedt K, Hallstrom M, Johansson I, et al. The expression of CYP2W1: A prognostic marker in colon cancer. Anticancer Res. 2012;(32):3869-3874"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"Zhang K, Jiang L, He R, et al. Prognostic value of CYP2W1 expression in patients with human hepatocellular carcinoma. Tumor Biol. 2014;35(8):7669-7673. doi: https:\/\/doi.org\/10.1007\/s13277-014-2023-9","DOI":"10.1007\/s13277-014-2023-9"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"van Koetsveld PM, Creemers SG, Dogan F, et al. The efficacy of mitotane in human primary adrenocortical carcinoma cultures. J Clin Endocrinol Metab. 2020;105(2):407-417. doi: https:\/\/doi.org\/10.1210\/clinem\/dgz001","DOI":"10.1210\/clinem\/dgz001"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"Weigand I, Altieri B, Lacombe AMF, et al. Expression of SOAT1 in adrenocortical carcinoma and response to mitotane monotherapy: An ENSAT multicenter study. J Clin Endocrinol Metab. 2020;105(8):2642-2653. doi: https:\/\/doi.org\/10.1210\/clinem\/dgaa293","DOI":"10.1210\/clinem\/dgaa293"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"Smith DC, Kroiss M, Kebebew E, et al. A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma. Invest New Drugs. 2020;38(5):1421-1429. doi: https:\/\/doi.org\/10.1007\/s10637-020-00899-1","DOI":"10.1007\/s10637-020-00899-1"}],"container-title":["Problems of Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.probl-endojournals.ru\/jour\/article\/viewFile\/13172\/10382","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T12:21:36Z","timestamp":1674735696000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.probl-endojournals.ru\/jour\/article\/view\/13172"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,8]]},"references-count":21,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,1,20]]}},"URL":"https:\/\/doi.org\/10.14341\/probl13172","relation":{},"ISSN":["2308-1430","0375-9660"],"issn-type":[{"value":"2308-1430","type":"electronic"},{"value":"0375-9660","type":"print"}],"subject":[],"published":{"date-parts":[[2023,1,8]]}}}