Novel Agents in the Management of Lung Cancer

B.      Kennedy; F.      Gargoum; B.      Bystricky; D.      R. Curran; T.      M. O'Connor

Abstract

Lung cancer is the leading cause of cancer death worldwide. Survival remains poor as approximately 80% of cases present with advanced stage disease. However, new treatments are emerging which offer hope to patients with advanced disease. Insights into cell biology have identified numerous intracellular and extracellular peptides that are pivotal in cancer cell signalling. Disrupting the function of these peptides inhibits intracellular signal transduction and diminishes uncontrolled proliferation, resistance to apoptosis and tumour angiogenesis. The most widely studied signalling pathway is the Epidermal Growth Factor (EGF) pathway. EGF signalling can be disrupted at numerous points. Blockade of the cell surface receptor is achieved by the monoclonal antibody cetuximab; intracellular tyrosine kinase activity is inhibited by erlotinib. Vascular Endothelial Growth Factor (VEGF) regulates another pathway important for tumour growth. Inhibition of VEGF impairs angiogenesis and disrupts metastatic spread. Bevacizumab is a monoclonal antibody that binds to VEGF and blocks interaction with its cell surface receptor. Clinical trials have demonstrated that disruption of these signalling pathways can improve survival in advanced lung cancer. New compounds including folate antimetabolites such as pemetrexed, proteasome inhibitors such as bortezomib, modified glutathione analogues such as TLK286, and other agents such as epothilones and other small molecules are currently being evaluated in patients with lung cancer. As more and more signalling peptides are targeted for manipulation, it is hoped that a new era is dawning in the treatment of advanced stage lung cancer. This review will focus on emerging new therapies in the management of lung cancer.

Keywords: Lung cancer, new treatments, tyrosine kinase inhibitors, growth factors, VEGF, EGF, TLK286, epothilones, Mortality, ACCP, NSCLC, DNA replication, Radiotherapy, GF, chemotherapy, RECEPTORS, cellular proliferation, GFR, TKD, SH2, PTB, PLC, PI3K, Fibroblast, differentiation, proliferation, apoptosis, GFs, TGF-, EGF-R, IGF, ErbB, MAPK, Src kinases, signal transduction, transcription, TKIs, CET, adenocarcinoma, Akt, STAT, Gefitinib, ATP, IDEAL-1, INTEREST, INTACT-2, EGFR, FISH, mutation, methionine, threonine, T790M, MET, erbB3, EKB-569, HER-2, Neratinib, BT474, G1-S cell cycle, NCIH1975 cell line, BIBW 2992, Lapatinib, Cetuximab, IRRC, FLEX, hypomagnesemia, colorectal cancer, paclitaxel, Bevacizumab, Leucopenia, diarrhoea, fever, headache, carboplatin, Cerebral Metastases, Sunitinib, pulmonary haemorrhage, Sorafenib, Vandetanib, xenografts, docetaxel, ZEAL, Cediranib, Pazopanib, Axitinib, Motesanib, XL647, Enzastaurin, Vatalanib, YH-16, Aflibercept, Pemetrexed, PROCLAIM trial, Bortezomib, Canfosfamide, Taxanes, Ixabepilone, Patupilone, EML4