Preclinical emergence of vandetanib as a potent antitumour agent in mesothelioma: molecular mechanisms underlying its synergistic interaction with pemetrexed and carboplatin

Our plain-English summary of Preclinical emergence of vandetanib as a potent antitumour agent in mesothelioma: molecular mechanisms underlying its synergistic interaction with pemetrexed and carboplatin, by E. Giovannetti, P.A. Zucali, Y.G. Assaraf, et al (British Journal of Cancer, 2011).

The study

• Authors: E. Giovannetti, P.A. Zucali, Y.G. Assaraf, L.G. Leon, K. Smid, C. Alecci, F. Giancola, A. Destro, L. Gianoncelli, E. Lorenzi, M. Roncalli, A. Santoro, G.J. Peters
• Journal: British Journal of Cancer
• Published: 2011;105(10):1542-53
• Cited by: 40 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Although pemetrexed, a potent thymidylate synthase (TS) inhibitor, enhances the cytoytoxic effect of platinum compounds against malignant pleural mesothelioma (MPM), novel combinations with effective targeted therapies are warranted. To this end, the current study evaluates new targeted agents and their pharmacological interaction with carboplatin-pemetrexed in human MPM cell lines.

Methods: We treated H2052, H2452, H28 and MSTO-211H cells with carboplatin, pemetrexed and targeted compounds (gefitinib, erlotinib, sorafenib, vandetanib, enzastaurin and ZM447439) and evaluated the modulation of pivotal pathways in drug activity and cancer cell proliferation.

Results: Vandetanib emerged as the compound with the most potent cytotoxic activity, which interacted synergistically with carboplatin and pemetrexed. Drug combinations blocked Akt phosphorylation and increased apoptosis. Vandetanib significantly downregulated epidermal growth factor receptor (EGFR)/Erk/Akt phosphorylation as well as E2F-1 mRNA and TS mRNA/protein levels. Moreover, pemetrexed decreased Akt phosphorylation and expression of DNA repair genes. Finally, most MPM samples displayed detectable levels of EGFR and TS, the variability of which could be used for patients' stratification in future trials with vandetanib-pemetrexed-carboplatin combination.

Conclusion: Vandetanib markedly enhances pemetrexed-carboplatin activity against human MPM cells. Induction of apoptosis, modulation of EGFR/Akt/Erk phosphorylation and expression of key determinants for pemetrexed and carboplatin activity contribute to this synergistic interaction, and, together with the expression of these determinants in MPM samples, warrant further clinical investigation.

2011 Cancer Research UK

In plain English

This was a laboratory study of human malignant pleural mesothelioma (MPM) cells grown in culture. No patients were treated, and asbestos exposure was not studied. The authors tested the chemotherapy drugs carboplatin and pemetrexed and six targeted drugs on four MPM cell lines. Vandetanib was the targeted drug that most strongly inhibited cell growth. In two cell lines (H28 and H2452), vandetanib combined with carboplatin, pemetrexed or both was synergistic. By the authors' combination index, the drugs together had more effect than expected from adding their separate effects. In all four lines, the three-drug combination caused significantly more apoptosis (programmed cell death) than pemetrexed plus carboplatin. Vandetanib reduced activation of the EGFR growth signal and lowered levels of thymidylate synthase, the main target of pemetrexed. It did not change VEGF levels. In tumour samples from 44 patients who had not received chemotherapy, EGFR and thymidylate synthase were detectable in most samples. The authors noted that two cell lines cannot represent the variety of human MPM. They concluded that vandetanib markedly enhanced pemetrexed–carboplatin activity against MPM cell lines and that further preclinical and clinical studies are warranted.

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 (in vitro) drug study on human mesothelioma cell lines, with additional analysis of patient tumour tissue samples
• Who was studied: Four human malignant pleural mesothelioma cell lines: NCI-H28 and NCI-H2052 (sarcomatoid), NCI-H2452 (epithelioid) and MSTO-211H (biphasic). Also 44 paraffin-embedded MPM tissue samples from patients who had not received chemotherapy (36 epithelioid, 7 biphasic, 1 sarcomatoid).
• Exposure: No asbestos exposure was studied. Cells were exposed for 72 hours to carboplatin, pemetrexed and the targeted drugs gefitinib, erlotinib, sorafenib, vandetanib, enzastaurin and ZM447439, alone and in combination.
• Main results:
  • Vandetanib was the most potent targeted drug across the four cell lines. The concentration halving cell growth (IC50) ranged from 0.32±0.07 in H28 cells to 3.52±1.13 in H2452 cells; the unit is printed as 'mM' in the text.
  • In H28 and H2452 cells, all two-drug and three-drug combinations of carboplatin, pemetrexed and vandetanib were synergistic. The authors measured this with a combination index (CI): below 0.9 means synergistic, 0.9 to 1.1 additive, and above 1.1 antagonistic.
  • The three-drug combination significantly increased apoptosis compared with controls and with pemetrexed-treated or carboplatin-treated cells in all cell lines. Apoptotic index with the triple combination: 19.4% in H2052, 20.5% in H2452, 18.2% in H28 and 26.4% in MSTO-211H. Control cells were 1.1% to 1.5%. Each triple-combination value was significant (p less than 0.05) against pemetrexed plus carboplatin.
  • Vandetanib reduced EGFR phosphorylation (activation) by up to 74.3% in H28 cells.
  • Akt phosphorylation was inhibited by up to 80.4% in H28 cells and 65.7% in H2452 cells after the triple combination.
  • Vandetanib decreased thymidylate synthase (TS) mRNA 2.3-fold in H2452 cells and 4.8-fold in H28 cells. Pemetrexed significantly increased it.
  • Pemetrexed plus vandetanib almost completely blocked TS activity. The reduction was significant compared with pemetrexed alone (p less than 0.037 in H28 and p less than 0.027 in H2452 cells).
  • Vandetanib did not affect VEGF mRNA levels or VEGF secretion.
  • In the 44 patient samples, EGFR membrane staining was seen in 23 of 44 cases (52.3%), and intense TS staining in 8 of 44 samples. EGFR and TS levels were not statistically associated with tumour histology, stage or grade.
  • No clear relationship was found between the gene variants (polymorphisms) studied and the cells' sensitivity to chemotherapy.
• The authors' conclusion: The authors concluded that vandetanib markedly enhanced pemetrexed and carboplatin activity against established MPM cell lines. They also concluded that the findings, together with detection of these markers in MPM samples, warrant further preclinical and clinical studies.
• Limitations the authors state:
  • The combination experiments used only two cell lines, which the authors state cannot represent the variety and complexity of human MPM.

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, Pemetrexed (Alimta), Carboplatin, Pleural Mesothelioma, Sorafenib (Nexavar), Apoptosis, EGFR.

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• Molecular mechanism implicated in Pemetrexed-induced apoptosis in human melanoma cells — A. Buqué, J.S.H. Muhialdin, et al. (2012)
• Synergistic antitumor activity of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in combination with carboplatin and pemetrexed in malignant pleural mesothelioma — G. Pasello, L. Urso, et al. (2014)
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