{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T14:27:12Z","timestamp":1761920832033,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T00:00:00Z","timestamp":1608595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Malignant pleural mesothelioma (MPM) is an aggressive cancer defined by loss-of-function mutations with few therapeutic options. We examined the contribution of the transcription factor Signal transducer and activator of transcription 3 (STAT3) to cell growth and gene expression in preclinical models of MPM. STAT3 is activated in a variety of tumors and is thought to be required for the maintenance of cancer stem cells. Targeting STAT3 using specific small hairpin RNAs (shRNAs) or with the pharmacologic inhibitors atovaquone or pyrimethamine efficiently reduced cell growth in established cell lines and primary-derived lines while showing minimal effects in nontransformed LP9 mesothelial cells. Moreover, atovaquone significantly reduced viability and tumor growth in microfluidic cultures of primary MPM as well as in an in vivo xenotransplant model. Biological changes were linked to modulation of gene expression associated with STAT3 signaling, including cell cycle progression and altered p53 response. Reflecting the role of STAT3 in inducing localized immune suppression, using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response, including upregulation of ICOSLG (Inducible T-Cell Costimulator Ligand or B7H2). Thus, our data strongly support a role for STAT3 inhibitors as anti-MPM therapeutics.<\/jats:p>","DOI":"10.3390\/cancers13010007","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T12:42:28Z","timestamp":1608640948000},"page":"7","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM)"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6592-9636","authenticated-orcid":false,"given":"Moshe","family":"Lapidot","sequence":"first","affiliation":[{"name":"Department of Surgery, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abigail E.","family":"Case","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dalia","family":"Larios","sequence":"additional","affiliation":[{"name":"Department of Surgery, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen I.","family":"Gandler","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengcheng","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isidora","family":"To\u0161i\u0107","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"name":"Department of Medicine, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellen L.","family":"Weisberg","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"name":"Department of Medicine, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Poitras","sequence":"additional","affiliation":[{"name":"Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, MA 02210, USA"},{"name":"Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prafulla C.","family":"Gokhale","sequence":"additional","affiliation":[{"name":"Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, MA 02210, USA"},{"name":"Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cloud P.","family":"Paweletz","sequence":"additional","affiliation":[{"name":"Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7414-3632","authenticated-orcid":false,"given":"Klaus","family":"Podar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Karl Landsteiner University of Health Sciences, 3500 Krems an der Donau, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9643-7626","authenticated-orcid":false,"given":"Ravi","family":"Salgia","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA 91010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srinivas V.","family":"Saladi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA"},{"name":"Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1823-7930","authenticated-orcid":false,"given":"James D.","family":"Griffin","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"name":"Department of Medicine, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7698-8364","authenticated-orcid":false,"given":"David A.","family":"Frank","sequence":"additional","affiliation":[{"name":"Department of Medical 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USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.21037\/amj.2018.09.11","article-title":"Diagnosis and management of mesothelioma","volume":"3","author":"Liou","year":"2018","journal-title":"AME Med. 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