Geldanamycin treatment does not result in anti-cancer activity in a preclinical model of orthotopic mesothelioma

Our plain-English summary of Geldanamycin treatment does not result in anti-cancer activity in a preclinical model of orthotopic mesothelioma, by M.L. Orozco Morales, C.A. Rinaldi, E. de Jong, et al (PloS One, 2023).

The study

• Authors: M.L. Orozco Morales, C.A. Rinaldi, E. de Jong, S.M. Lansley, Y.C.G. Lee, R.M. Zemek, A. Bosco, R.A. Lake, W.J. Lesterhuis
• Journal: PloS One
• Published: 2023;18(5):e0274364
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is characterised by its aggressive invasive behaviour, affecting the surrounding tissues of the pleura or peritoneum. We compared an invasive pleural model with a non-invasive subcutaneous model of mesothelioma and performed transcriptomic analyses on the tumour samples. Invasive pleural tumours were characterised by a transcriptomic signature enriched for genes associated with MEF2C and MYOCD signaling, muscle differentiation and myogenesis. Further analysis using the CMap and LINCS databases identified geldanamycin as a potential antagonist of this signature, so we evaluated its potential in vitro and in vivo. Nanomolar concentrations of geldanamycin significantly reduced cell growth, invasion, and migration in vitro. However, administration of geldanamycin in vivo did not result in significant anti-cancer activity. Our findings show that myogenesis and muscle differentiation pathways are upregulated in pleural mesothelioma which may be related to the invasive behaviour. However, geldanamycin as a single agent does not appear to be a viable treatment for mesothelioma.

Copyright: © 2023 Orozco Morales et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

In plain English

This was a laboratory study in mice and cell lines. It did not study asbestos exposure. The authors compared mesothelioma tumours grown in the chest cavity (pleural space) of mice, which invade nearby tissue, with tumours grown under the skin, which do not. They used two mouse mesothelioma cell lines, AB1 and AE17. In both, 419 genes were expressed differently, and the strongest pathways related to muscle contraction, cardiomyopathy and myogenesis (muscle formation). Database searches found geldanamycin to be the only drug significantly linked to this gene pattern in both databases. In lab dishes, low-nanomolar concentrations of geldanamycin reduced the growth of mouse and human mesothelioma cells, and of a non-cancerous mouse cell line, and reduced migration and invasion. In mice with tumours placed in the abdominal cavity, geldanamycin at 0.1 mg/kg had no significant effect on tumour growth compared with controls. Tumours in both groups invaded the liver, intestine and pancreas. Higher doses caused weight loss. The authors concluded that geldanamycin alone does not appear to be a viable treatment for mesothelioma.

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 study: gene-expression (RNA sequencing) comparison of tumour models in mice, a computer-based drug-repurposing search, cell-culture experiments, and a drug-treatment experiment in mice
• Who was studied: Female BALB/c and C57BL/6 mice (8 mice per group in the gene-expression comparison) given tumours from the mouse mesothelioma cell lines AB1 and AE17. Cell experiments used AB1 and AE17, the human mesothelioma cell lines VGE62, JU77 and MSTO-211H, and the non-cancerous mouse fibroblast line NIH3T3. Work was done in Western Australia.
• Exposure: No asbestos exposure was studied. The exposure was the drug geldanamycin. In mice it was given by intraperitoneal injection at 1, 0.5 or 0.1 mg/kg, twice a day for up to five days. In cell experiments it was tested at nanomolar concentrations.
• Main results:
  • 419 genes differed between invasive pleural tumours and non-invasive subcutaneous tumours in both the AE17 and AB1 mouse models
  • The most significant pathways in the pleural tumours related to muscle contraction, cardiomyopathy and myogenesis
  • Geldanamycin was the only drug significantly associated with the invasive gene signature in both drug databases (LINCS L1000 and CMap)
  • In cell experiments, geldanamycin reduced growth at low-nanomolar concentrations in all cell lines tested, including the non-cancerous NIH3T3 line
  • Geldanamycin significantly reduced growth of the human JU77 mesothelioma cells in a soft agar colony test at 6.25 nM and higher
  • In cell experiments, geldanamycin reduced cell migration and invasion, more so at higher concentrations
  • In mice with AB1-Luc tumours in the abdominal cavity, geldanamycin at 0.1 mg/kg had no significant effect on tumour growth compared with vehicle controls (figure reports n = 5)
  • Tumours in both treated and control mice invaded surrounding organs
  • Geldanamycin at 1 or 0.5 mg/kg caused weight loss in mice
• The authors' conclusion: The authors concluded that geldanamycin as a single agent does not appear to be a viable treatment for mesothelioma, and that other approaches will be needed to target mesothelioma invasion
• Limitations the authors state:
  • The difference between the cell and mouse results could reflect too narrow a therapeutic window: doses mice could tolerate may have been too low to work
  • Compensatory mechanisms in the living animal may let cancer cells escape the drug's effects
  • The muscle-related gene pattern may be a side effect of the tumour's surroundings rather than a driver of invasion
  • Drug-repurposing searches based on gene-signature overlap can produce false-positive hits
  • Geldanamycin also inhibited non-cancerous cells, which the authors suggest may relate to the toxicity seen at higher doses in mice

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleura, Peritoneum, Pleural Mesothelioma.

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