Combined treatment with inhibitors of ErbB Receptors and Hh signaling pathways is more effective than single treatment in reducing the growth of malignant mesothelioma both in vitro and in vivo

Our plain-English summary of Combined treatment with inhibitors of ErbB Receptors and Hh signaling pathways is more effective than single treatment in reducing the growth of malignant mesothelioma both in vitro and in vivo, by R. Bei, M. Benvenuto, C. Focaccetti, et al (Journal of Translational Medicine, 2022).

The study

• Authors: R. Bei, M. Benvenuto, C. Focaccetti, S. Fazi, M. Moretti, D. Nardozi, V. Angiolini, S. Ciuffa, L. Cifaldi, R. Carrano, C. Palumbo, M.T. Miele, R. Bei, G. Barillari, V. Manzari, E. De Smaele, A. Modesti, L. Masuelli
• Journal: Journal of Translational Medicine
• Published: 2022;20(1):286
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a rare orphan aggressive neoplasia with low survival rates. Among the other signaling pathways, ErbB receptors and Hh signaling are deregulated in MM. Thus, molecules involved in these signaling pathways could be used for targeted therapy approaches. The aim of this study was to evaluate the effects of inhibitors of Hh- (GANT-61) and ErbB receptors (Afatinib)-mediated signaling pathways, when used alone or in combination, on growth, cell cycle, cell death and autophagy, modulation of molecules involved in transduction pathways, in three human MM cell lines of different histotypes. The efficacy of the combined treatment was also evaluated in a murine epithelioid MM cell line both in vitro and in vivo. This study demonstrated that combined treatment with two inhibitors counteracting the activation of two different signaling pathways involved in neoplastic transformation and progression, such as those activated by ErbB and Hh signaling, is more effective than the single treatments in reducing MM growth in vitro and in vivo. This study may have clinical implications for the development of targeted therapy approaches for MM.

© 2022. The Author(s).

In plain English

This laboratory study tested drug treatment; it did not study asbestos exposure or patients. The authors tested afatinib (which blocks ErbB receptors) and GANT-61 (which blocks Hedgehog signaling), alone and together. They used three human malignant mesothelioma cell lines (H-Meso-1, MM-F1, MM-B1) and one mouse line (#40a). In the dishes, afatinib 10 µM plus GANT-61 20 µM reduced cell survival more than either drug alone in all cell lines. Whether the two drugs worked together more than additively depended on the cell line and the dose. Mice were injected in the abdomen with mouse mesothelioma cells, 8 per group. At 35 days, the combination group's mean abdominal circumference (7.4 cm) was smaller than that of vehicle-treated control mice (10.3 cm) and of the single-drug groups. Combination-treated mice survived 49 days versus 30 days for controls (mean survival in the text, median in Table 1). The hazard ratio for control mice compared with combination-treated mice was 21.00 (95% confidence interval 4.548 to 96.91). The authors concluded that the combination was more effective than single treatments in reducing mesothelioma growth in vitro and in vivo.

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: experiments on human and mouse malignant mesothelioma cell lines, plus an animal experiment in mice
• Who was studied: Three human malignant mesothelioma cell lines: H-Meso-1 (epithelial morphology), MM-F1 (sarcomatous features) and MM-B1 (biphasic features). Also the mouse mesothelioma cell line #40a, and female C57BL/6 mice injected with #40a cells: 4 groups of 8 mice each, at the University of Rome Tor Vergata.
• Exposure: No asbestos exposure was studied. The exposures were two drugs: afatinib (AFA, an ErbB receptor inhibitor) at 2.5 to 10 µM and GANT-61 (GANT, a Hedgehog/GLI inhibitor) at 2.5 to 20 µM, alone or combined, in cell culture. In mice, AFA was given at 25 mg/kg and GANT at 50 mg/kg, alone or combined, injected into the abdomen twice a week. Control mice received the vehicle only (PBS + DMSO).
• Main results:
  • In all four cell lines, GANT 20 µM plus AFA 10 µM reduced cell survival significantly more than either drug alone at 24, 48 and 72 hours.
  • In MM-F1 and MM-B1 cells, the combination was synergistic (more than additive) at high concentrations for 48 and 72 hours.
  • In H-Meso-1 cells, the combination was less than additive at high concentrations but synergistic at 5 + 5 µM.
  • In the mouse #40a cells, the combination was less than additive at all doses except 2.5 + 2.5 µM at 24 and 48 hours.
  • In all cell lines, the combination increased the share of cells in the subG1 phase (a marker the authors used for apoptosis, a form of cell death) more than either drug alone.
  • In mice at 21 days, all three treated groups had a smaller abdominal circumference than controls, but there was no difference between single and combined treatments.
  • In mice at 35 days, the combination group had a mean abdominal circumference of 7.4 cm versus 10.3 cm in control mice (p = 0.00003). At 28 and 35 days it was also significantly lower than in the GANT-only group (p = 0.009 and p = 0.0001) and the AFA-only group (p = 0.03 and p = 0.02).
  • Survival was 49 days in combination-treated mice versus 30 days in control mice. The text calls this mean survival with p = 0.05; Table 1 lists it as median survival with p = 0.0003.
  • The hazard ratio for control mice compared with combination-treated mice was 21.00 (95% confidence interval 4.548 to 96.91). The authors describe this as control mice having a 21.00 times greater risk of tumor growth.
  • Combination-treated mice survived longer than GANT-only mice (49 vs 34.5 days, p = 0.002) and AFA-only mice (49 vs 38 days, p = 0.05). The hazard ratio was 9.369 (95% CI 2.335 to 37.58) for GANT-only mice compared with combination-treated mice, and 3.746 (95% CI 1.106 to 12.69) for AFA-only mice compared with combination-treated mice.
• The authors' conclusion: The authors concluded that combining inhibitors of the ErbB and Hedgehog signaling pathways was more effective than either treatment alone in reducing malignant mesothelioma growth in cell culture and in mice. They said the study may have clinical implications for developing targeted therapies.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Targeted Therapy, Epithelioid.

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