Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma

Our plain-English summary of Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma, by R.E. Favoni, A. Daga, P. Malatesta, et al (British Journal of Pharmacology, 2012).

The study

• Authors: R.E. Favoni, A. Daga, P. Malatesta, T. Florio
• Journal: British Journal of Pharmacology
• Published: 2012;166(2):532-53
• Type of article: Review
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth.

© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

In plain English

This article was a narrative review, not a new study of patients or workers. The authors described the reported activity of older chemotherapy drugs and newer 'targeted' drugs against human malignant pleural mesothelioma. The reviewed work mostly used established tumour cell lines, surgical tumour samples and animal models. The newer drugs covered included agents that block growth-factor receptors on tumour cells. The authors wrote that even with current first-line chemotherapy, a response rate above 20% is rare. They reported that disappointing trial results led to the idea that several receptors are active together in tumours and compensate for one another. Based on cell-line findings, they suggested that EGFR alone is a treatment target for only a minority of these tumours. They noted that long-cultured cell lines are more likely than real tumours to respond to anti-growth drugs. They said clear evidence had not yet been found that mesothelioma contains a subgroup of cells unable to form tumours. The authors concluded that tumour-initiating cells isolated from mesothelioma and grown in stem cell-permissive medium were highly advisable for drug studies.

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: Narrative review of preclinical (laboratory and animal) studies and some clinical studies of drug treatment for human malignant pleural mesothelioma
• Who was studied: No new population was studied. The review covered research using established mesothelioma cell lines, post-surgical human tumour samples and animal models (mainly immunodeficient mice with transplanted human tumour cells).
• Exposure: Drug treatments, not asbestos exposure. These were cytotoxic chemotherapy drugs (such as cisplatin, doxorubicin, pemetrexed and gemcitabine) and targeted inhibitors of growth-factor receptor tyrosine kinases (EGFR, PDGFR, VEGFR, c-Met) and of other signalling pathways (mTOR, NF-kB, COX-2, HDAC).
• Main results:
  • According to the authors, current first-line combinations work better than older regimens, but a response rate above 20% is rare, so their activity remains modest.
  • The authors reported that discouraging clinical trial results, despite good laboratory results, led to the hypothesis that in the body several receptor tyrosine kinases are activated at once and compensate for one another.
  • From the reviewed lapatinib cell-line studies, the authors suggested that EGFR alone is a treatment target for only a minority of mesotheliomas, and that combining EGFR inhibitors with other signalling inhibitors may increase effectiveness.
  • The authors noted that long-established cell lines grow much faster than real tumours and are therefore more likely to respond to anti-growth drugs than the original tumours in the body.
  • Reviewing attempts to isolate tumour-initiating (cancer stem) cells from mesothelioma, the authors stated that no clear evidence had yet been found that mesothelioma contains a non-tumour-forming subpopulation of cells.
• The authors' conclusion: The authors concluded that, whether or not mesothelioma follows the cancer stem cell model, tumour-initiating cells isolated from mesothelioma and grown in stem cell-permissive medium are highly advisable for drug studies. They wrote that such cultures could be added to classical cell lines as experimental models.

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, Prognosis, Median Survival, Chemotherapy, Pemetrexed (Alimta), Raltitrexed, STEM, Carcinogenesis.

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