Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM)

Our plain-English summary of Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM), by M. Lapidot, A.E. Case, D. Larios, et al (Cancers, 2020).

The study

• Authors: M. Lapidot, A.E. Case, D. Larios, H.I. Gandler, C. Meng, I. Tošić, E.L. Weisberg, M.J. Poitras, P.C. Gokhale, C.P. Paweletz, K. Podar, R. Salgia, S.V. Saladi, J.D. Griffin, D.A. Frank, R. Bueno, M. Sattler
• Journal: Cancers
• Published: 2020;13(1)
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This laboratory study tested whether a protein called STAT3, which switches genes on, helps malignant pleural mesothelioma cells grow, and whether drugs that block STAT3 activity slow them. It did not study asbestos exposure or patients' outcomes. The authors used established mesothelioma cell lines, cell lines grown from patients' tumors, three fresh patient tumor samples, non-cancerous LP9 mesothelial cells, and mice carrying tumor tissue derived from a patient's mesothelioma. Lowering STAT3 levels reduced growth of two mesothelioma cell lines. The drugs atovaquone, pyrimethamine and nifuroxazide reduced growth of four mesothelioma cell lines, with larger doses giving larger reductions. LP9 cells resisted atovaquone and pyrimethamine up to 30 micromolar. In fresh patient samples, atovaquone and nifuroxazide significantly reduced growth but pyrimethamine did not. In mice, atovaquone reduced tumor growth by 38% (p less than 0.0005) without changing body weight. Pyrimethamine also significantly reduced tumor growth, but by less. Both drugs increased expression of several immune-related genes, including ICOSLG. The authors concluded that their data support STAT3 inhibitors as possible mesothelioma treatments. They described the mouse model as proof-of-concept.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (preclinical) study using cell lines, primary patient-derived cells, 3D cultures of fresh patient specimens, and a mouse xenograft model
• Who was studied: Four established malignant pleural mesothelioma cell lines (H28, H2804, H2052, MSTO-211H), non-cancerous LP9 mesothelial cells, four cell lines newly derived from surgical tumor specimens (MS1-MS4), three freshly isolated patient specimens (Boston, Brigham and Women's Hospital / Dana-Farber Cancer Institute), and female NSG mice implanted with MS4 tumor fragments, 8 to 12 mice per treatment group
• Exposure: No asbestos exposure was studied. The study reduced STAT3 using small hairpin RNAs and tested the drugs atovaquone, pyrimethamine and nifuroxazide. In mice, atovaquone was given at 200 mg/kg and pyrimethamine at 75 mg/kg by once-daily oral gavage for 22 days.
• Main results:
  • In non-cancerous LP9 mesothelial cells, expressing an activated form of STAT3 increased growth by 52% compared with control cells, in the absence of epidermal growth factor (p less than 0.05)
  • Reducing STAT3 with small hairpin RNAs showed STAT3 was critical for growth of the MSTO-211H and H28 mesothelioma cell lines
  • Each drug reduced growth of the H28, H2052, H2804 and MSTO-211H cell lines, with larger effects at higher doses. LP9 cells were resistant to atovaquone or pyrimethamine up to 30 micromolar. LP9 cells' IC50 for nifuroxazide was about 10 times greater than for the mesothelioma cell lines.
  • In three freshly isolated patient specimens, atovaquone and nifuroxazide significantly reduced growth, whereas pyrimethamine did not
  • In mice carrying MS4 tumors, atovaquone was followed with a 38% reduction in tumor mass growth over 25 days (p less than 0.0005), and the mice's body weight did not change
  • In mice, pyrimethamine significantly reduced tumor growth (p less than 0.05), but the changes were smaller than with atovaquone
  • In H28, MSTO-211H and H2804 cells, both atovaquone and pyrimethamine significantly increased expression of the immune genes CD276, CD70, TNFSF9, TNFSF4 and ICOSLG. Their effects on CD40 and TNSF18 were inconsistent.
• The authors' conclusion: The authors concluded that their data strongly support a role for STAT3 inhibitors as anti-mesothelioma treatments. They also said combination studies with other therapies, including immune checkpoint inhibitors, are warranted.
• Limitations the authors state:
  • The mouse model was a proof-of-concept, and the authors did not try to optimize the dose
  • Higher drug concentrations were needed in 3D patient specimen cultures than in standard flat (monolayer) cell cultures
  • Differences in gene expression between models may reflect the different drugs used or the different genetic and cell-type backgrounds of the models

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, STEM, Mesothelial Cells.

Related studies

• Signal Transducer and Activator of Transcription 1 (STAT1) Knock-down Induces Apoptosis in Malignant Pleural Mesothelioma — L. Arzt, I. Halbwedl, et al. (2017)
• Prognostic Bone Metastasis-Associated Immune-Related Genes Regulated by Transcription Factors in Mesothelioma — Z. Hao, S. Wang, et al. (2022)
• Essential role of the histone lysine demethylase KDM4A in the biology of malignant pleural mesothelioma (MPM) — M. Lapidot, A.E. Case, et al. (2021)
• Asbestos induces inflammatory cytokines in the lung through redox sensitive transcription factors — M.I. Luster, P.P. Simeonova (1998)
• Signal transducer and activator of transcription 1 (STAT1) acts like an oncogene in malignant pleural mesothelioma — L. Arzt, H. Kothmaier, et al. (2014)
• Asbestos induction of nuclear transcription factors and interleukin 8 gene regulation — P.P. Simeonova, M.I. Luster (1996)

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