Mesothelioma is a largely incurable disease for which no effective systemic treatment exists. Since 1984 the Cancer and leukemia Group B (CALGB) has enrolled almost 400 patients on treatment studies for mesothelioma with extremely limited success. Two studies carried out almost a decade ago, CALGB 9031 and CALGB 8833, used the novel cytidine analog, dihydro-5-azacytidine (DHAC). Although the response rates to this drug was disappointing low (17%), the cohort of patients who did respond often had prolonged partial responses or even long term complete responses. One patient remains in remission almost a decade later. The mechanism of action of azacytidine analogs is felt to be through inhibition of DNA hypermethylation. Methylation of DNA resulting in suppression of expression is increasingly being found to be a common mechanism for silencing tumor suppressor genes in a variety of cancers. One common target for hypermethylation appears to be the cyclin-dependent kinase (Cdk) inhibitor p16INK4a (CDKN2, MST). Based on a relatively small number of samples, he has previously identified loss of p16INK4a expression in virtually all mesothelioma tumors and cell lines examined, while these tumors retain the inversely correlated Rb gene product (pRB). In a subset of these tumors and cell lines, loss of p16INK4a gene product expression is mediated through hypermethylation of 5' DNA. This process can be reversed with azacytidine drugs in vitro and in vivo. Dr. Kratzke has previously demonstrated that re-expression of p16INK4a protein in mesothelioma cells results in cell death, and can be used to shrink existing xenografts in vivo. Based on these observations, he intend to examine a large cohort of patients (n=77) who were diagnosed with mesothelimoa and treated with azacytidine drugs in order to examine the following hypothesis: 1) All mesothelioma tumors lack expression of the p16INK4a gene product while maintaining wild-type expression of pRB. 2) Expression of the p16INK4A gene product is regulated by hypermethylation in a minority of mesothelioma tumors. 3) Response to azacytidine based therapy correlates with the presence of hypermethylation of the p16INK4a gene. 4) Response to azacytidine based therapy is inversely correlated with gene rearrangement of p16INK4a in mesothelioma tumors.
