In vivo loss of expression of argininosuccinate synthetase in malignant pleural mesothelioma is a biomarker for susceptibility to arginine depletion.

PURPOSE: Malignant pleural mesothelioma (MPM) is an increasing health burden on many societies worldwide and, being generally resistant to conventional treatment, has a poor prognosis with a median survival of <1 year. Novel therapies based on the biology of this tumor seek to activate a proapoptotic cellular pathway. In this study, we investigated the expression and biological significance of argininosuccinate synthetase (AS), a rate-limiting enzyme in arginine production. EXPERIMENTAL DESIGN: Initially, we documented down-regulation of AS mRNA in three of seven MPM cell lines and absence of AS protein in four of seven MPM cell lines. We confirmed that the 9q34 locus, the site of the AS gene, was intact using a 1-Mb comparative genomic hybridization array; however, there was aberrant promoter CpG methylation in cell lines lacking AS expression, consistent with epigenetic regulation of transcription. To investigate the use of AS negativity as a therapeutic target, arginine was removed from the culture medium of the MPM cell lines. RESULTS: In keeping with the cell line data, 63% (52 of 82) of patients had tumors displaying reduced or absent AS protein, as assessed using a tissue microarray. Cell viability declined markedly in the AS-negative cell lines 2591 and MSTO but not in the AS-positive cell line, 28. This response was apparent by day 4 and maintained by day 9 in vitro. Arginine depletion induced BAX conformation change and mitochondrial inner membrane depolarization selectively in AS-negative MPM cells. CONCLUSIONS: In summary, we have identified AS negativity as a frequent event in MPM in vivo, leading to susceptibility to cytotoxicity following restriction of arginine. A phase II clinical trial is planned to evaluate the role of arginine depletion in patients with AS-negative MPM.

Prognostic factors in mesothelioma.

Prognostic factors can help clinicians and patients when deciding a treatment plan. Patients in the best prognostic groups can be considered for more intensive or experimental therapy. Alternatively, patients in the best prognostic groups might prefer a period of observation prior to commencement of therapy. For patients with mesothelioma prognostic factors are potentially especially important because of the lack of a widely applicable anatomical staging system. Both the International Mesothelioma Interest Group (IMIG) and Brigham staging systems are of limited relevance to patients not undergoing radical debulking surgery. Radiological prediction of IMIG or Brigham stage is of little value. Review of the best-known prognostic scoring systems from the EORTC and CALGB has shown that the most important predictors of poor prognosis are: poor performance status; non-epithelioid histology; male gender; low hemoglobin; high platelet count; high white blood cell count; and high lactate dehydrogenase (LDH). The EORTC model was validated at St Bartholomew's Hospital in a group of 145 patients treated in sequential phase II chemotherapy trials. For 70 patients treated with vinorelbine, those having the best EORTC prognosis had a median survival of 19.2 months [95% C.I.=14.7-23.7] compared to 9.9 months [95% C.I.=8.5-11.3] for those in the worst group. The suggestion is that all clinical and biological factors relevant to prognosis should be recorded prospectively in mesothelioma patients selected for clinical trials.