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

Sep 24, 2026

Uploaded by Oliver

Mesothelioma is an aggressive cancer with invasive growth affecting pleural or peritoneal tissues. This study compared an invasive pleural mesothelioma model with a noninvasive subcutaneous model and performed transcriptomic analyses on tumor samples to define disease-associated gene programs. The invasive pleural tumors showed enrichment for MEF2C and MYOCD signaling, muscle differentiation, and myogenesis. Connectivity map and LINCS analyses suggested geldanamycin antagonized this signature, but in vitro it reduced growth, invasion, and migration while in vivo administration produced no significant anti-cancer activity, indicating limited therapeutic viability.

LanguageEnglish

CategoryHealthcare

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Pages17

Reading Time43 min

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Abstract

Introduction

Mesothelioma background and invasion

Current treatment landscape

Systems biology and drug-disease associations

PLOS ONE OPEN ACCESS Citation: Orozco Morales ML, Rinaldi CA, de Jong E, Lansley SM, Lee YCG, Zemek RM, et al. (2023) Geldanamycin treatment does not result in anticancer activity in a preclinical model of orthotopic mesothelioma. PLoS ONE 18(5): e0274364 . [https://doi.org/10.1371/journal.pone.0274364](https://doi.org/10.1371/journal.pone.0274364) [Editor:](Editor: Luka Brcic)[ Luka Brcic](Editor: Luka Brcic), [Medical University of Graz](Medical University of Graz), AUSTRIA Received: September 11, 2022 Accepted: March 26, 2023 Published: May 5, 2023 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: [https://doi.org/10.1371/journal.pone.0274364](https://doi.org/10.1371/journal.pone.0274364) [Copyright:](Copyright:) © [2023](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. Data Availability Statement: The generated datasets used in this manuscript have been deposited at Gene Expression Omnibus (GEO) and are publicly available. Accession number is RESEARCH ARTICLE Geldanamycin treatment does not result in anti-cancer activity in a preclinical model of orthotopic mesothelioma M. Lizeth Orozco Morales1,2,3, Catherine A. Rinaldi1,2,4, Emma de Jong5, Sally M. Lansley3, Y. C. Gary Lee3, Rachael M. Zemek5, Anthony Bosco5, Richard A. Lake1,2,3, W. Joost Lesterhuis1,2,3,5 * 1 School of Biomedical Sciences, University of Western Australia, Crawley, Western Australia, Australia, 2 National Centre for Asbestos Related Diseases, Nedlands, Western Australia, Australia, 3 Institute for Respiratory Health, Nedlands, Western Australia, Australia, 4 Centre for Microscopy Characterisation and Analysis, Nedlands, Western Australia, Australia, 5 Telethon Kids Institute, The University of Western Australia, Nedlands, Western Australia, Australia * [willem.lesterhuis@uwa.edu.au](willem.lesterhuis@uwa.edu.au) 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 noninvasive 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. Introduction Mesothelioma is a cancer that usually arises in the pleura, occasionally developing from other serous membranes [ 1] . Its development is associated with asbestos exposure, with a latency period of approximately 40 years between exposure and diagnosis [2] . Mesothelioma’s morbidity is predominantly caused by local invasion into neighbouring tissues such as lungs, heart, diaphragm, and chest wall [3] . On a cellular level, local invasion is a coordinated process that requires the cancerous cells to interact with the tumour microenvironment, the cell matrix, or other

FAQs

What models and analyses were used to study mesothelioma in this paper?

The study compared an invasive pleural model with a noninvasive subcutaneous model and used transcriptomic analyses on tumor samples to characterize disease-associated gene programs.

What molecular features were linked to the invasive pleural tumors?

Invasive pleural tumors were enriched for genes associated with MEF2C and MYOCD signaling, muscle differentiation, and myogenesis.

Did geldanamycin show anti-cancer effects in vivo?

No. While geldanamycin at nanomolar concentrations significantly reduced cell growth, invasion, and migration in vitro, administration in vivo did not produce significant anti-cancer activity.

Sep 24, 2026

Uploaded by Oliver