Ecteinascidin synthetic analogues: a new class of selective inhibitors of transcription, exerting immunogenic cell death in refractory malignant pleural mesothelioma

Our plain-English summary of Ecteinascidin synthetic analogues: a new class of selective inhibitors of transcription, exerting immunogenic cell death in refractory malignant pleural mesothelioma, by I.C. Salaroglio, P. Aviles, J. Kopecka, et al (Journal of Experimental & Clinical Cancer Research, 2024).

The study

• Authors: I.C. Salaroglio, P. Aviles, J. Kopecka, A. Merlini, F. Napoli, L. Righi, S. Novello, H. Sullivan, C. Cuevas, G.V. Scagliotti, C. Riganti
• Journal: Journal of Experimental & Clinical Cancer Research
• Published: 2024;43(1):327
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a highly chemo-refractory and immune-evasive tumor that presents a median overall survival of 12-14 months when treated with chemotherapy and immunotherapy. New anti-tumor therapies as well as the concomitant reactivation of immune destruction are urgently needed to treat patients with this tumor. The aim of this work is to investigate the potential effect of ecteinascidin derivatives as lurbinectedin as new first-line treatment option in MPM, alone and in combination with immunotherapy.

Methods: The antitumor activity of ecteinascidin synthetic analogues: lurbinectedin, ecubectedin and PM54 was evaluated in an array of patient-derived MPM cells in terms of cell proliferation, cell cycle, apoptosis, DNA damage and repair. Immunoblot was used to assess the cGAS/STING pathway. ELISA and flow cytometry-based assays were used to evaluate immunogenic cell death parameters and the effect on the immunophenotype in autologous peripheral blood monocyte-MPM cells co-cultures. Patient-derived xenografts (PDX) in humanized mice were used to evaluate the efficacy of ecteinascidins in vivo.

Results: Lurbinectedin, ecubectedin, and PM54 were effective in reducing cell proliferation and migration, as well as inducing S-phase cell cycle arrest and DNA damage in malignant pleural mesothelioma cells. These effects were more pronounced compared to the standard first-line treatment (platinum-based plus pemetrexed). Mechanistically, the drugs downregulated DNA repair genes, activated the cGAS/STING pathway, and promoted the release of pro-inflammatory cytokines. They also induced immunogenic cell death of mesothelioma cells, enhancing the activation of anti-tumor CD8+T-cells and natural killer cells while reducing tumor-tolerant T-regulatory cells and myeloid-derived suppressor cells in ex vivo co-cultures. These promising results were also observed in humanized patient-derived xenograft models, where the drugs were effective in reducing tumor growth and increasing the ratio anti-tumor/pro-tumor infiltrating immune populations, either alone or combined with the anti-PD-1L atezolizumab.

Conclusions: Collectively, these findings reveal a previously unknown mechanism of action of ecteinascidins that merits further investigation for potential clinical applications in the treatment of MPM, as new first line treatment in monotherapy or in association with immunotherapy.

© 2024. The Author(s).

In plain English

This was a laboratory and animal study. It did not study asbestos exposure or test the drugs in patients. The authors tested three related experimental drugs, lurbinectedin, ecubectedin and PM54, on malignant pleural mesothelioma cells grown from 12 patients' tumors in Italy. They compared them with cisplatin plus pemetrexed, the standard first treatment. In the cultures, the three drugs cut cell viability by half at much lower concentrations than cisplatin plus pemetrexed (median 0.1, 0.15 and 0.17 nM versus 6.0 nM). They also reduced cell movement and invasion, damaged DNA, and raised markers of a kind of cell death that alerts the immune system. In long-term tests, most cultures rebounded after cisplatin plus pemetrexed but stayed low with the three drugs. In mice carrying tumors from two patients (4 mice per group), the drugs gave smaller final tumors than an inactive control. In mice with human immune cells, atezolizumab alone also reduced tumors, and adding any of the drugs worked significantly better than atezolizumab alone. The authors noted the small number of cell lines and mouse models. They concluded the drugs merit clinical evaluation in mesothelioma patients.

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: Preclinical laboratory study: experiments on patient-derived mesothelioma cells grown in culture, plus animal experiments in mice implanted with patient-derived tumors (patient-derived xenografts), randomized to treatment groups
• Who was studied: Malignant pleural mesothelioma cells from tumor samples of 12 patients (epithelioid, sarcomatoid and biphasic; BAP1-positive and BAP1-negative), obtained at three hospitals in Italy. Tumors from two of these patients (MPM#1, epithelioid, BAP1-positive; MPM#7, sarcomatoid, BAP1-negative) were implanted under the skin of female NSG mice and of NSG mice engrafted with human immune stem cells, 4 mice per group. Study dates not given.
• Exposure: No asbestos exposure was studied. The exposures were drug treatments: lurbinectedin, ecubectedin and PM54, compared with cisplatin plus pemetrexed. In mice, the immune checkpoint inhibitor atezolizumab was given alone or combined with each drug. Mouse doses: lurbinectedin 0.18 mg/kg, ecubectedin 1.2 mg/kg, PM54 0.9 mg/kg, cisplatin 5 mg/kg plus pemetrexed 100 mg/kg, atezolizumab 10 mg/kg.
• Main results:
  • In 12 patient-derived mesothelioma cultures, the median IC50 (concentration reducing viability by half) for cisplatin plus pemetrexed was 6.0 nM.
  • In the same cultures, the median IC50 was 0.1 nM for lurbinectedin, 0.15 nM for ecubectedin and 0.17 nM for PM54.
  • In 10-week long-term tests, most cultures treated with cisplatin plus pemetrexed showed a rebound in cell viability after the 2-week treatment break.
  • In the same long-term tests, median viability was 12 ± 4% with lurbinectedin, 3 ± 4% with ecubectedin and 5 ± 4% with PM54.
  • In the invasion assay, migrated cells per field were 108 ± 25 with lurbinectedin, 27 ± 6 with ecubectedin and 15 ± 5 with PM54, versus 786 ± 205 in untreated cells.
  • After 24 hours, the three drugs significantly increased the percentage of mesothelioma cells arrested in the S phase of the cell cycle.
  • The three drugs significantly increased DNA damage in the mesothelioma cells, regardless of BAP1 status.
  • The three drugs increased all three measured markers of immunogenic cell death (calreticulin exposure, ATP release and HMGB1 release). Cisplatin plus pemetrexed produced only a small increase in HMGB1.
  • When treated mesothelioma cells were cultured with blood immune cells from healthy donors, lurbinectedin and ecubectedin increased natural killer cells and decreased T-regulatory cells and monocyte-derived suppressor cells. The decrease was statistically significant with PM54.
  • In both mouse strains, cisplatin plus pemetrexed did not reduce tumor growth compared with the inactive control (vehicle).
  • In NSG mice with tumor PDX#1, final median tumor volume was 926.8 ± 58.9 cubic millimetres with vehicle, 542.5 ± 16.6 with lurbinectedin, 513.5 ± 24.1 with ecubectedin and 520 ± 11.7 with PM54. The reductions were statistically significant.
  • In mice with a human immune system, atezolizumab alone significantly reduced tumor volume compared with vehicle. Combining it with lurbinectedin, ecubectedin or PM54 significantly enhanced this effect.
  • In immune-deficient mice, the combination with atezolizumab gave no additional benefit over each drug alone. In immunocompetent (human-immune) mice, the combination was significantly stronger than atezolizumab alone.
  • In tumors of mice treated with atezolizumab plus one of the three drugs, the authors reported a decrease in two immune-suppressive cell types infiltrating the tumor (Mo-MDSC and TAM2).
• The authors' conclusion: The authors concluded that the three drugs caused DNA damage and mesothelioma cell death and shifted the tumor immune environment toward anti-tumor cells. They suggested these agents be evaluated clinically in malignant pleural mesothelioma patients, alone or combined with an immune checkpoint inhibitor.
• Limitations the authors state:
  • The authors stated that the number of patient-derived cell lines and mouse tumor models was small.
  • The authors stated that the drugs' potential to block mesothelioma invasion still needs testing in proper orthotopic animal models. The mouse tumors here were implanted under the skin.
  • Calreticulin, the key marker of immunogenic cell death, did not change in the mouse tumors. The authors attributed this to the staining method being unable to separate surface calreticulin from total calreticulin.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Median Overall Survival, Chemotherapy, Immunotherapy, Apoptosis, Pemetrexed (Alimta), Cytokine, Mesothelioma.

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