New Treatment Options for Malignant Pleural Mesothelioma

 

Chemie  |  Biochemie  |  Medizin

 

Corsin Casty, 2004 | Bern, BE

 

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer, primarily caused by asbestos exposure, with limited treatment options and poor prognosis. 5 years after diagnosis and trimodality treatment only 15% of the patients are alive. Chemotherapy with Cisplatin and Pemetrexed (MTA) is the current standard therapy, but resistance remains a significant challenge. Pyrimidines are fundamental nucleotide building blocks in our DNA. They are necessary for cell replication and to produce RNA transcripts. Pyrimidines are produced by two pathways called de novo and Pyrimidine Salvage pathway. I showed that Pemetrexed leads to an upregulation of the Pyrimidine Salvage pathway because it blocks the de novo pathway. The chemotherapy drug Capecitabine (5’DFCR) is activated by the Pyrimidine Salvage pathway and inhibits this pathway. Testing the sensitivity of MPM cells to Capecitabine revealed that the needed dose would be too high for firstline clinical application. However, the results suggest that upon first-line treatment with Pemetrexed and Cisplatin, the upregulation of key enzymes in the Pyrimidine Salvage pathway after several days would lead to a higher activation of Capecitabine. A later second treatment with Capecitabine could increase the conversion and efficiency of the inhibitor in the cancer cells.

Introduction

Malignant pleural mesothelioma (MPM) is a rare and extremely aggressive cancer that grows in the pleura layer surrounding the lungs. MPM is usually a result of asbestos exposure, nevertheless, there are other causes such as the Simian Virus (SV40) or BAP1 Syndrome. The median survival is nine to twelve months, if untreated. Until now, the golden standard systemic therapy is chemotherapy with Cisplatin and Pemetrexed (MTA), which induce DNA damage and inhibit DNA synthesis, respectively. Chemotherapy resistance is one of the biggest challenges in clinical practice and research. Two pathways synthesize the pyrimidine nucleotide building blocks which are essential for DNA and RNA synthesis; the de novo and the Salvage Pyrimidine pathway. Pemetrexed blocks three enzymes of the de novo synthesis pathway. Cytidine Deaminase (CDA) is a key enzyme of the Pyrimidine Salvage pathway. The first experiment tested whether Pemetrexed treatment leads to an upregulation of CDA and thus of the Salvage Pyrimidine pathway. Capecitabine (5’DFCR) is a chemotherapeutic agent activated by CDA. Once activated, it inhibits this pathway. Its inhibitory activity is therefore dependent on CDA expression in the cells. In the second experiment the effect of Capecitabine on untreated MPM cells was tested, because that has never been tested before.

Methods

In the first experiment, cell viability assays for 5’DFCR treatment were performed on H2452 and MESO1 MPM cell lines to test their sensitivity to the treatment. In the second experiment, the cell line MESO1 was treated with Pemetrexed and Cisplatin for 24h. CDA expression was then monitored over several days by Western Blot. The cell line H358 was used as a positive control since it displays a high basic level of CDA.

Results

The cell viability assay showed that viability decreased only at a dose between 10² and 10^4 mikro-molar of 5’DFCR. This indicates that mesothelioma cells are not sufficiently sensitive to 5’DFCR as first-line therapy. In the second experiment, the Western Blot method revealed that CDA levels increased after 24h of Pemetrexed and Cisplatin treatment. The highest expression of CDA was observed on recovery day 7, the last time point.

Discussion

This study suggests that with further investigation, the combination of Pemetrexed and Cisplatin as a first-line treatment with a subsequent treatment of 5’DFCR could be used for the treatment of MPM. First, cells are treated with standard chemotherapy. This leads to the upregulation of the Pyrimidine Salvage pathway. On recovery day 7, when CDA concentrations are the highest, the second-line treatment should block the Pyrimidine Salvage pathway, and this would lead to the cell cycle arrest of MPM cells. The higher the CDA concentration is, the more 5’DFCR can be activated and the more apoptosis of MPM cells occurs.

Conclusions

Our results suggest that due to the Pemetrexed treatment, de novo pyrimidine synthesis is blocked. The cancer cells, therefore, started to upregulate the Pyrimidine Salvage pathway and thus the CDA concentration rises, as a process of resistance. The viability assay shows that 5’ DFCR is not a promising first-line therapy for MPM, because the dosages would be too high, and this could have fatal consequences for the patient.

 

 

Würdigung durch den Experten

Prof. Beat Suter

Der Brustfellkrebs, das maligne Mesotheliom, ist nicht heilbar. Bestehende Therapien verlängern das Leben der Patienten nur für relativ kurze Zeit und sind mit Nebenwirkungen verbunden. Im Rahmen eines Forschungsprojekts am Inselspital untersuchte Corsin Casty einen neuen Therapieansatz. Dazu setzte er sich intensiv mit dem Thema auseinander und führte anspruchsvolle Laborexperimente durch. Einerseits zeigte er, dass Versuche zur neuen Therapiemethode in Zellkulturen noch nicht die gewünschte Wirkung erzielten. Andererseits erarbeitete er aber auch Grundlagen für eine verbesserte Anwendung.

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Gymnasium Kirchenfeld, Bern
Lehrerin: Marianne Steiner