Targeting hypoxia in the treatment of small cell lung cancer.

Small cell lung cancer (SCLC) is an extremely aggressive disease for which minimal therapeutic improvements have been made over the last few decades. Patients still rely on non-targeted, chemotherapeutic drugs complemented by irradiation. Although initial response is very good, the majority of SCLC patients invariably relapse with therapy-resistant tumours. Despite the link between pathologically low oxygen levels and therapy resistant tumours, hypoxia has gained little attention in the development of novel therapies for SCLC. In contrast, the advantages of targeting hypoxic cells in many other cancer types have been studied extensively. This review describes the reasons for targeting hypoxia in SCLC and outlines strategies undertaken to enhance hypoxic tumour cell death, including the use of bioreductive prodrugs, the targeting of HIF-1α and the induction of cell death through acidosis. Therapy directed towards hypoxic tumour regions has the potential to greatly enhance the response of SCLC tumours to current treatment regimens and represents an area of research in need of greater attention. Such research could lead to the much sought after development of targeted drugs against SCLC tumours.

Neuroendocrine and epithelial phenotypes in small-cell lung cancer: implications for metastasis and survival in patients.

BACKGROUND: Small-cell lung cancer (SCLC) has a very aggressive clinical course with early metastasis. This study investigated how the distinctive neuroendocrine characteristics contribute to disease progression and invasion in human SCLC. METHODS: The neuroendocrine phenotype (pro-opiomelanocortin (POMC)) was quantified by ELISA in blood samples from 43 SCLC patients. The neuroendocrine (POMC, chromogranin A, neuron-specific enolase, NCAM) and epithelial (cytokeratin and E-cadherin) phenotypes were investigated, using ELISA and immunocytochemistry/immunohistochemistry. RESULTS: In SCLC patients, 16% had elevated circulating POMC, which was associated with significantly worse survival (P=0.02) and liver metastases (P=0.004). In addition, POMC correlated with epithelial-positive circulating tumour cells (P=0.0002). In a panel of SCLC cell lines, all POMC-secreting cell lines expressed cytokeratin (40% of total). Even after cloning, DMS 79 cells expressed both neuroendocrine and epithelial markers. DMS 79 xenografts secreted POMC into the blood, which mirrored the tumour volume. These xenografts expressed both neuroendocrine and epithelial phenotypes in all tumours, with both phenotypes prevalent in cells invading the surrounding tissue. CONCLUSION: Both neuroendocrine and epithelial phenotypes coexist in human SCLC tumours in vitro and in vivo and this persists in invading tumour cells. In patients, POMC secretion predicts poor survival and liver metastases, suggesting a crucial role of the neuroendocrine phenotype.