New advances in the second-line treatment of small cell lung cancer.

Lung cancer is the leading cause of cancer-related death in the U.K., with small cell histology accounting for 15%-20% of cases. Small cell lung cancer (SCLC) is initially a chemosensitive disease, but relapse is common, and in this group of patients it remains a rapidly lethal disease with a particularly poor prognosis. The choice of second-line chemotherapy for patients with relapsed SCLC has been an area of difficulty for oncologists, and until recently there was no randomized evidence for its use over best supportive care (BSC). Topotecan is currently the only drug licensed in Europe and the U.S. for this indication, having been shown in a phase III trial to lead to longer overall survival and better quality of life than with BSC. In this article, we review the current evidence for the use of second-line cytotoxic therapy and also the emerging role of novel agents and targeted therapies in this setting. In particular, we explore the role of the Bcl-2 protein family, which are key regulators of mitochondrial apoptosis and are implicated in resistance to anticancer therapies. SCLC overexpresses antiapoptotic members of the Bcl-2 family in approximately 80% of cases. Several Bcl-2 inhibitors, including obatoclax, are currently entering clinical trials in SCLC and are an exciting area of drug development in the relapsed setting.

Vorinostat/SAHA-induced apoptosis in malignant mesothelioma is FLIP/caspase 8-dependent and HR23B-independent.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rapidly fatal malignancy that is increasing in incidence. The caspase 8 inhibitor FLIP is an anti-apoptotic protein over-expressed in several cancer types including MPM. The histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) is currently being evaluated in relapsed mesothelioma. We examined the roles of FLIP and caspase 8 in regulating SAHA-induced apoptosis in MPM. METHODS: The mechanism of SAHA-induced apoptosis was assessed in 7 MPM cell lines and in a multicellular spheroid model. SiRNA and overexpression approaches were used, and cell death was assessed by flow cytometry, Western blotting and clonogenic assays. RESULTS: RNAi-mediated FLIP silencing resulted in caspase 8-dependent apoptosis in MPM cell line models. SAHA potently down-regulated FLIP protein expression in all 7 MPM cell lines and in a multicellular spheroid model of MPM. In 6/7 MPM cell lines, SAHA treatment resulted in significant levels of apoptosis induction. Moreover, this apoptosis was caspase 8-dependent in all six sensitive cell lines. SAHA-induced apoptosis was also inhibited by stable FLIP overexpression. In contrast, down-regulation of HR23B, a candidate predictive biomarker for HDAC inhibitors, significantly inhibited SAHA-induced apoptosis in only 1/6 SAHA-sensitive MPM cell lines. Analysis of MPM patient samples demonstrated significant inter-patient variations in FLIP and caspase 8 expressions. In addition, SAHA enhanced cisplatin-induced apoptosis in a FLIP-dependent manner. CONCLUSIONS: These results indicate that FLIP is a major target for SAHA in MPM and identifies FLIP, caspase 8 and associated signalling molecules as candidate biomarkers for SAHA in this disease.

Afatinib treatment in advanced non-small cell lung cancer.

Despite some recent advances in the management of advanced non-small cell lung cancer (NSCLC), prognosis for these patients remains poor. Small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have however provided a new therapeutic option in this disease setting and EGFR mutation testing is now routine practice for newly diagnosed NSCLC patients. A proportion of patients will not respond to first-generation EGFR-TKIs however, and those who do will ultimately develop resistance and disease relapse. Next-generation EGFR-TKIs which inhibit multiple members of the EGFR family are being developed in order to increase sensitivity and overcome resistance to existing agents. Afatinib (BIBW 2992) is an oral, irreversible inhibitor of EGFR and HER2 tyrosine kinases and is the most advanced of these agents in clinical development. Pre-clinical and early-phase clinical trials have demonstrated a favorable safety profile as a single agent and in combination with other anti-cancer agents, and provide evidence of clinical activity in advanced NSCLC. The LUX-Lung trials suggest that for selected patients, afatinib offers symptomatic improvement and prolonged progression-free survival, although this has not yet translated into improved overall survival. This article aims to review the use of EGFR-TKIs in the management of advanced NSCLC and the mechanisms underlying resistance to these agents. We will discuss the current pre-clinical and clinical data regarding afatinib, its potential to overcome resistance to first-generation TKIs, and its emerging role in advanced NSCLC treatment.