Histone deacetylase inhibitors in malignant pleural mesothelioma: preclinical rationale and clinical trials

Our plain-English summary of Histone deacetylase inhibitors in malignant pleural mesothelioma: preclinical rationale and clinical trials, by P.K. Paik, L.M. Krug (Journal of Thoracic Oncology, 2010).

The study

• Authors: P.K. Paik, L.M. Krug
• Journal: Journal of Thoracic Oncology
• Published: 2010;5(2):275-9
• Type of article: Review
• Cited by: 47 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer of the mesothelium with only a limited range of treatment options that are largely ineffective in improving survival. Recent efforts have turned toward the analysis of specific, dysregulated biologic pathways for insight into new treatment targets. Epigenetic regulation of tumor suppressor genes through chromatin condensation and decondensation has emerged as an important mechanism that leads to tumorogenesis. A family of histone acetyltransferases and deacetylases regulates this balance, with the latter facilitating chromatin condensation, thus preventing gene transcription, resulting in the loss of heterozygosity of tumor suppressors. Inhibition of this process, coupled with a similar inhibition of nonhistone protein deacetylation, ultimately leads to the promotion of apoptosis, cell cycle arrest, and inhibition of angiogenesis. An increasing amount of preclinical data highlighting the effectiveness of histone deacetylase inhibition in MPM cell lines and mouse xenograft models has led to a number of early phase clinical trials in patients with MPM. The results of these efforts have led to a multicenter, randomized, placebo-controlled phase III study of the histone deacetylase inhibitor vorinostat in patients with advanced MPM, offering hope for a new and effective therapy in patients with this disease.

In plain English

This article was a concise review, not a new study. The authors reviewed published laboratory and clinical research on histone deacetylase inhibitors as a possible treatment for malignant pleural mesothelioma. These are drugs that affect how genes are switched on and off. In laboratory work by other researchers, one of these drugs, sodium butyrate, triggered cell death in mesothelioma cell lines. In one mouse study, valproic acid combined with chemotherapy completely suppressed the growth of human mesothelioma tumors. In an earlier phase I trial of vorinostat, 13 of 73 patients had mesothelioma. Two of them had partial responses on scans that were ultimately unconfirmed. In a phase II trial of belinostat in 13 patients, two had stable disease and none responded. The authors described an ongoing phase III trial comparing vorinostat with placebo in previously treated patients, planned for 660 patients. The article did not study asbestos exposure. The authors concluded that preclinical studies provide a rationale for this treatment approach and that clinical data are emerging.

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: Concise review of preclinical studies and clinical trials of histone deacetylase inhibitors in malignant pleural mesothelioma
• Who was studied: Published studies in mesothelioma cell lines and mouse xenograft models, and early-phase clinical trials that included patients with malignant pleural mesothelioma or other advanced solid tumors
• Exposure: Not an asbestos exposure study. The review concerns drug treatment with histone deacetylase inhibitors (such as vorinostat, belinostat, valproic acid, sodium butyrate), alone or with chemotherapy.
• Main results:
  • Cited laboratory work (Cao et al.) found induction of apoptosis (cell death) in mesothelioma cell lines treated with sodium butyrate
  • A cited mouse xenograft study (Vandermeers et al.) showed complete suppression of human epithelioid mesothelioma growth after valproic acid plus chemotherapy, a response not seen with either alone
  • In a cited phase I trial of vorinostat in advanced solid tumors, 13 of the 73 patients treated had mesothelioma
  • In that phase I trial, two mesothelioma patients met criteria for a radiographic partial response, but these were ultimately unconfirmed. At the time of analysis these two patients were alive 27 and 21 months after starting treatment.
  • In a cited phase II trial of belinostat in 13 patients with advanced pleural mesothelioma, two patients (15%) had stable disease as best response, with no partial or complete responders
  • An ongoing phase III trial randomized previously treated mesothelioma patients 1:1 to vorinostat 300 mg twice daily or placebo
  • The planned target enrollment for the phase III vorinostat trial was 660 patients
  • In a cited phase I trial of vorinostat with cisplatin and pemetrexed in advanced solid tumors, three of five patients (60%) with mesothelioma had stable disease
• The authors' conclusion: The authors concluded that several preclinical studies provide a rationale for pursuing HDAC inhibition to treat malignant pleural mesothelioma, and that clinical data are emerging
• Limitations the authors state:
  • The authors noted that no study combining HDAC inhibitors with chemotherapy had yet been conducted in mesothelioma
  • The authors stated that further studies are needed to determine the optimal dosing schedule for combining vorinostat with cisplatin and pemetrexed

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, Clinical Trial, Mesothelium, Tumor Suppressor Gene, Apoptosis, Angiogenesis.

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• The levels of HDAC1 and thioredoxin1 are related to the death of mesothelioma cells by suberoylanilide hydroxamic acid — B.R. You, W.H. Park (2016)
• Assessment of new HDAC inhibitors for immunotherapy of malignant pleural mesothelioma — D. Bensaid, T. Blondy, et al. (2018)
• CAR T-cell therapy for pleural mesothelioma: Rationale, preclinical development, and clinical trials — N.K. Chintala, D. Restle, et al. (2021)
• Mesothelin-targeted agents in clinical trials and in preclinical development — R.J. Kelly, E. Sharon, et al. (2012)
• Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial — L.M. Krug, H.L. Kindler, et al. (2015)

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