Drug repurposing in malignant pleural mesothelioma: a breath of fresh air?

Our plain-English summary of Drug repurposing in malignant pleural mesothelioma: a breath of fresh air?, by A. Boyer, E. Pasquier, P. Tomasini, et al (European Respiratory Review, 2018).

The study

• Authors: A. Boyer, E. Pasquier, P. Tomasini, J. Ciccolini, L. Greillier, N. Andre, F. Barlesi, C. Mascaux
• Journal: European Respiratory Review
• Published: 2018;27(147)
• Type of article: Review
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Drug repurposing is the use of known drugs for new indications. Malignant pleural mesothelioma (MPM) is a rare cancer with a poor prognosis. So far, few treatments have been approved in this disease. However, its incidence is expected to increase significantly, particularly in developing countries. Consequently, drug repurposing appears as an attractive strategy for drug development in MPM, since the known pharmacology and safety profile based on previous approvals of repurposed drugs allows for faster time-to-market for patients and lower treatment cost. This is critical in low- and middle-income countries where access to expensive drugs is limited. This review assesses the published preclinical and clinical data about drug repurposing in MPM.In this review, we identified 11 therapeutic classes that could be repositioned in mesothelioma. Most of these treatments have been evaluated in vitro, half have been evaluated in vivo in animal models of MPM and only three (i.e. valproate, thalidomide and zoledronic acid) have been investigated in clinical trials, with limited benefits so far. Efforts could be coordinated to pursue further investigations and test promising drugs identified in preclinical experiments in appropriately designed clinical trials.

Copyright ©ERS 2018.

In plain English

This was a review by researchers in Marseille, France, of published laboratory, animal and clinical studies on drug repurposing in malignant pleural mesothelioma. Drug repurposing means using drugs already approved for other illnesses. The authors searched PubMed for English-language studies up to November 2016. They identified 11 therapeutic classes. Among the drugs covered were the epilepsy drug valproate, statins, the antifungal itraconazole, arsenic trioxide, disulfiram, aspirin, celecoxib, metformin, tocotrienol (a form of vitamin E), thalidomide, the antibiotic anisomycin and zoledronic acid. Most had been tested on cells in the laboratory, half in animal models, and only three (valproate, thalidomide and zoledronic acid) in clinical trials, with limited benefits so far. In one phase III trial they reviewed, median overall survival was 10.6 months with thalidomide and 12.9 months with active supportive care. The authors noted that repurposed drugs are rarely effective alone, attract little commercial interest, and may have unknown toxicity alongside chemotherapy. They concluded that repurposing could offer cheaper treatment options in developing countries and that clinical trials are needed. The review did not study asbestos exposure itself.

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: Review of published preclinical (laboratory and animal) and clinical studies, based on a PubMed search
• Who was studied: Published English-language studies on repurposed drugs in malignant pleural mesothelioma, including studies of cell lines, mouse models and patients; the search ended in November 2016
• Exposure: Drugs approved for non-cancer conditions, tested against mesothelioma. These included valproate, statins, itraconazole, arsenic trioxide, disulfiram, aspirin, celecoxib, metformin, tocotrienol, thalidomide, anisomycin and zoledronic acid. Asbestos appears only as background on the cause of the disease and was not studied.
• Main results:
  • Of the drug classes identified, most had been evaluated in vitro, half in animal models, and only three (valproate, thalidomide and zoledronic acid) in clinical trials in mesothelioma patients, with limited benefits so far
  • In a cited randomised phase III trial in patients with mesothelioma after first-line therapy, median overall survival was 10.6 months in the thalidomide group and 12.9 months in the active supportive care group (HR 1.2, p=0.21)
  • In a cited phase II trial of valproate with doxorubicin, 7 of 45 heavily pretreated patients (16%) had a partial response. Median progression-free survival was 2.5 months and median overall survival was 6.7 months.
  • In a cited single-arm trial of zoledronic acid in eight pretreated patients with unresectable mesothelioma, median progression-free survival was 2 months and median overall survival was 7 months, without significant toxicity
  • In a cited retrospective analysis of 300 patients with type 2 diabetes and mesothelioma, median overall survival was 8.8 months for metformin users and 6.5 months for nonusers (p=0.37). The authors described this as no evidence that metformin improved survival.
  • Several drugs (statins, itraconazole, arsenic trioxide, aspirin) had shown effects on mesothelioma cells or in mice but had not been tested in mesothelioma patients
• The authors' conclusion: The authors concluded that drug repurposing could provide cheaper and more accessible treatment options for mesothelioma patients in developing countries. They called for clinical trials of the most relevant drugs, selected in preclinical models.
• Limitations the authors state:
  • The authors stated that repurposed drugs are rarely effective on their own
  • The authors stated that low cost and lack of patent protection make commercial interest very low
  • The authors stated that the toxicity of these drugs in cancer patients also receiving cytotoxic drugs is not known. As an example, they cited two toxic deaths among 16 patients treated with valproate and doxorubicin.
  • The authors stated that promising preclinical results often fail to translate to patients

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: Pleural Mesothelioma, Prognosis, Mesothelioma, Clinical Trial.

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