Targeted agents in the management of small cell lung cancer - present and future.

Lung cancer is the leading cause of cancer-related mortality worldwide and is the second most common cancer in both sexes. The small cell lung cancer (SCLC) subtype constitutes about 13% to 15% of all diagnosed lung cancers with an expected 5-year mortality of about 90%. In the past decades, various strategies used to treat newly diagnosed, relapsed or refractory SCLC have shown no significant improvement in clinical outcomes. In the genomic era of oncology, with a better understanding of tumor biology and pathway specific investigations, multiple investigational agents have been studied with the aim to improve clinical outcomes. Some of them include epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), BCR-ABL TKIs, mammalian target of rapamycin (mTOR) inhibitors, vascular endothelial growth factor (VEGF) inhibitors, etc. All of them have been unsuccessful in adding any survival advantage. DNA repair inhibitors, immunotherapies and anti-delta-like protein 3 (DLL3) antibody-drug conjugates have also been tested so far. This article aims to review the current literature and investigational approaches to improving clinical outcomes of SCLC.

ALK5 inhibition maintains islet endothelial cell survival but does not enhance islet graft revascularisation or function.

Islet transplantation is a potential treatment for Type 1 diabetes but long term graft function is suboptimal. The rich supply of intraislet endothelial cells diminishes rapidly after islet isolation and culture, which affects the revascularisation rate of islets after transplantation. The ALK5 pathway inhibits endothelial cell proliferation and thus inhibiting ALK5 is a potential target for improving endothelial cell survival. The aim of the study was to establish whether ALK5 inhibition prevents the loss of intraislet endothelial cells during islet culture and thus improves the functional survival of transplanted islets by enhancing their subsequent revascularisation after implantation. Islets were cultured for 48 h in the absence or presence of 2 different ALK inhibitors: SB-431542 or A-83-01. Their vascular density after culture was analysed using immunohistochemistry. Islets pre-cultured with the ALK5 inhibitors were implanted into streptozotocin-diabetic mice for either 3 or 7 days and blood glucose concentrations were monitored and vascular densities of the grafts were analysed. Islets cultured with ALK5 inhibitors had higher vascular densities than control-cultured islets. Three days after implantation, endothelial cell numbers in islet grafts were minimal, irrespective of treatment during culture. Seven days after implantation, endothelial cells were evident within the islet grafts but there was no difference between control-cultured islets and islets pre-treated with an ALK5 inhibitor. Blood glucose concentrations were no different between the treatment groups. In conclusion, inhibition of ALK5 improved intraislet endothelial cell numbers after islet culture, but this effect was lost in the early post-transplantation period.