Targeted therapies in the treatment of advanced/metastatic NSCLC

The treatment of advanced non-small cell lung cancer (NSCLC) has evolved substantially during the last years. Chemotherapy remains the cornerstone of treatment and prolongs survival with a positive impact on quality of life. However, we seem to have reached a plateau of activity in the treatment of NSCLC. Recently, the addition of bevacizumab or cetuximab to chemotherapy doublets has improved the outcome in selected patients with advanced NSCLC. Furthermore, the use of erlotinib and gefitinib is an alternative for second line treatment. Advances in our understanding of molecular biology of cancer and mechanisms of tumourigenesis have further enabled the discovery of several potential molecular targets and development of novel 'targeted therapies'. The purpose of this study is to review current data on the role of targeted therapies in the treatment of advanced NSCLC. (C) 2009 Elsevier Ltd. All rights reserved.

Recent Innovations in Antibody-Mediated, Targeted Particulate Nanotechnology and Implications for Advanced Visualisation and Drug Delivery

Research into the targeting of drug substances to a specific disease site has enjoyed sustained activity for many decades. The reason for such fervent activity is the considerable clinical advantages that can be gained when the delivery system plays a pivotal role in determining where the drug is deposited. When compared to conventional formulations where no such control exists, such as parenteral and oral systems, the sophisticated targeting device can reduce side effects and limit collateral damage to surrounding normal tissue. No more so is this important than in the area of oncology when dose-limiting side effects are often encountered as an ever present difficulty. In this review, the types of colloidal carrier commonly used in targeted drug delivery are discussed, such as gold and polymeric colloids. In particular, the process of attaching targeting capabilities is considered, with reference to antibody technologies used as the targeting motifs. Nanotechnology has brought together a means to carry both a drug and targeting ligand in self-contained constructs and their applications to both clinical therapy and diagnosis are discussed.

Conatumumab (AMG 655) coated nanoparticles for targeted pro-apoptotic drug delivery

Colloidal nanoparticle drug delivery systems have attracted much interest for their ability to enable effective formulation and delivery of therapeutic agents. The selective delivery of these nanoparticles to the disease site can be enhanced by coating the surface of the nanoparticles with targeting moieties, such as antibodies. In this current work, we demonstrate that antibodies on the surface of the particles can also elicit key biological effects. Specifically, we demonstrate the induction of apoptosis in colorectal HCT116 cancer cells using PLGA nanoparticles coated with Conatumumab (AMG 655) death receptor 5-specific antibodies (DR5-NP). We show that DR5-NP preferentially target DR5-expressing cells and present a sufficient density of antibody paratopes to induce apoptosis via DR5, unlike free AMG 655 or non-targeted control nanoparticles. We also demonstrate that DR5-targeted nanoparticles encapsulating the cytotoxic drug camptothecin are effectively targeted to the tumour cells, thereby producing enhanced cytotoxic effects through simultaneous drug delivery and apoptosis induction. These results demonstrate that antibodies on nanoparticulate surfaces can be exploited for dual modes of action to enhance the therapeutic utility of the modality. (C) 2011 Elsevier Ltd. All rights reserved.

Rescue of glandular dysmorphogenesis in PTEN-deficient colorectal cancer epithelium by PPARγ-targeted therapy

Disruption of glandular architecture associates with poor clinical outcome in high-grade colorectal cancer (CRC). Phosphatase and tensin homolog deleted on chromosome ten (PTEN) regulates morphogenic growth of benign MDCK (Madin Darby Canine Kidney) cells through effects on the Rho-like GTPase cdc42 (cell division cycle 42). This study investigates PTEN-dependent morphogenesis in a CRC model. Stable short hairpin RNA knockdown of PTEN in Caco-2 cells influenced expression or localization of cdc42 guanine nucleotide exchange factors and inhibited cdc42 activation. Parental Caco-2 cells formed regular hollow gland-like structures (glands) with a single central lumen, in three-dimensional (3D) cultures. Conversely, PTEN-deficient Caco-2 ShPTEN cells formed irregular glands with multiple abnormal lumens as well as intra- and/or intercellular vacuoles evocative of the high-grade CRC phenotype. Effects of targeted treatment were investigated. Phosphatidinylinositol 3-kinase (PI3K) modulating treatment did not affect gland morphogenesis but did influence gland number, gland size and/or cell size within glands. As PTEN may be regulated by the nuclear receptor peroxisome proliferator-activated receptor-? (PPAR?), cultures were treated with the PPAR? ligand rosiglitazone. This treatment enhanced PTEN expression, cdc42 activation and rescued dysmorphogenesis by restoring single lumen formation in Caco-2 ShPTEN glands. Rosiglitazone effects on cdc42 activation and Caco-2 ShPTEN gland development were attenuated by cotreatment with GW9662, a PPAR? antagonist. Taken together, these studies show PTEN-cdc42 regulation of lumen formation in a 3D model of human CRC glandular morphogenesis. Treatment by the PPAR? ligand rosiglitazone, but not PI3K modulators, rescued colorectal glandular dysmorphogenesis of PTEN deficiency.