Individualization of treatment in non-small cell lung cancer

Two recently reported randomized studies discussed below are paving the way for personalized treatment approaches for patients with non-small cell lung cancer (NSCLC). Both studies show that accurate subclassification of NSCLC will become necessary to prescribe chemotherapy doublets and epidermal growth factor receptor tyrosine kinase inhibitors. It is expected that the practice of the last 30 years of lumping all NSCLC subtypes together will soon come to an end

Photodynamic therapy: A promising new modality for the treatment of cancer

The first reports on photodynamic therapy (PDT) date back to the 1970s. Since then, several thousands of patients, both with early stage and advanced stage solid tumours, have been treated with PDT and many claims have been made regarding its efficacy. Nevertheless, the therapy has not yet found general acceptance by oncologists. Therefore it seems legitimate to ask whether PDT can still be described as "a promising new therapy in the treatment of cancer". Clinically, PDT has been mainly used for bladder cancer, lung cancer and in malignant diseases of the skin and upper aerodigestive tract. The sensitizer used in the photodynamic treatment of most patients is Photofrin, (Photofrin, the commercial name of dihematoporphyrin ether/ester, containing > 80% of the active porphyrin dimers/oligomers (A.M.R. Fisher, A.L. Murphee and C.J. Gomer, Clinical and preclinical photodynamictherapy, Review Series Article, Lasers Surg. Med., 17 (1995) 2-31). It is a complex mixture of porphyrins derived from hematoporphyrin. Although this sensitizer is effective, it is not the most suitable photosensitizer for PDT. Prolonged skin photosensitivity and the relatively low absorbance at 630 nm, a wavelength where tissue penetration of light is not optimal, have been frequently cited as negative aspects hindering general acceptance. A multitude of new sensitizers is currently under evaluation. Most of these "second generation photosensitizers" are chemically pure, absorb light at around 650 nm or greater and induce no or less general skin photosensitivity. Another novel approach is the photosensitization of neoplasms by the induction of endogenous photosensitizers through the application of 5-aminolevulinic acid (ALA). This article addresses the use of PDT in the disciplines mentioned above and attempts to indicate developments of PDT which could be necessary for this therapy to gain a wider acceptance in the various field

Novel active agents in patients with advanced NSCLC without driver mutations who have progressed after first-line chemotherapy

Despite the efficacy of a number of first-line treatments, most patients with advanced-stage non-small cell lung cancer (NSCLC) experience disease progression that warrants further treatment. In this review, we examine the role of novel active agents for patients who progress after first-line therapy and who are not candidates for targeted therapies. More therapeutic options are needed for the management of patients with NSCLC after failure of first-line chemotherapy. A PubMed search was performed for articles from January 2012 to May 2015 using the keywords NSCLC, antiangiogenic, immunotherapy, second-line, novel therapies and English language articles only. Relevant papers were reviewed; papers outside that period were considered on a case-by-case basis. A search of oncology congresses was performed to identify relevant abstracts over this period. In recent years, antiangiogenic agents and immune checkpoint inhibitors have been added to our armamentarium to treat patients with advanced NSCLC who have progressed on first-line chemotherapy. These include nintedanib, a triple angiokinase inhibitor; ramucirumab, a vascular endothelial growth factor receptor-2 antibody; and nivolumab, pembrolizumab and atezolizumab, just three of a growing list of antibodies targeting the programmed death receptor-1 (PD-1)/PD ligand-1 pathway. Predictive and prognostic factors in NSCLC treatment will help to optimise treatment with these novel agents. The approval of new treatments for patients with NSCLC after the failure of first-line chemotherapy has increased options after a decade of few advances, and holds promise for future evolution of the management of NSCLC

Integration of Gene Dosage and Gene Expression in Non-Small Cell Lung Cancer, Identification of HSP90 as Potential Target

BACKGROUND: Lung cancer causes approximately 1.2 million deaths per year worldwide, and non-small cell lung cancer (NSCLC) represents 85% of all lung cancers. Understanding the molecular events in non-small cell lung cancer (NSCLC) is essential to improve early diagnosis and treatment for this disease. METHODOLOGY AND PRINCIPAL FINDINGS: In an attempt to identify novel NSCLC related genes, we performed a genome-wide screening of chromosomal copy number changes affecting gene expression using microarray based comparative genomic hybridization and gene expression arrays on 32 radically resected tumor samples from stage I and II NSCLC patients. An integrative analysis tool was applied to determine whether chromosomal copy number affects gene expression. We identified a deletion on 14q32.2-33 as a common alteration in NSCLC (44%), which significantly influenced gene expression for HSP90, residing on 14q32. This deletion was correlated with better overall survival (P = 0.008), survival was also longer in patients whose tumors had low expression levels of HSP90. We extended the analysis to three independent validation sets of NSCLC patients, and confirmed low HSP90 expression to be related with longer overall survival (P = 0.003, P = 0.07 and P = 0.04). Furthermore, in vitro treatment with an HSP90 inhibitor had potent antiproliferative activity in NSCLC cell lines. CONCLUSIONS: We suggest that targeting HSP90 will have clinical impact for NSCLC patients

Haemolysis during Sample Preparation Alters microRNA Content of Plasma

The presence of cell-free microRNAs (miRNAs) has been detected in a range of body fluids. The miRNA content of plasma/serum in particular has been proposed as a potential source of novel biomarkers for a number of diseases. Nevertheless, the quantification of miRNAs from plasma or serum is made difficult due to inefficient isolation and lack of consensus regarding the optimal reference miRNA. The effect of haemolysis on the quantification and normalisation of miRNAs in plasma has not been investigated in great detail. We found that levels of miR-16, a commonly used reference gene, showed little variation when measured in plasma samples from healthy volunteers or patients with malignant mesothelioma or coronary artery disease. Including samples with evidence of haemolysis led to variation in miR-16 levels and consequently decreased its ability to serve as a reference. The levels of miR-16 and miR-451, both present in significant levels in red blood cells, were proportional to the degree of haemolysis. Measurements of the level of these miRNAs in whole blood, plasma, red blood cells and peripheral blood mononuclear cells revealed that the miRNA content of red blood cells represents the major source of variation in miR-16 and miR-451 levels measured in plasma. Adding lysed red blood cells to non-haemolysed plasma allowed a cut-off level of free haemoglobin to be determined, below which miR-16 and miR-451 levels displayed little variation between individuals. In conclusion, increases in plasma miR-16 and miR-451 are caused by haemolysis. In the absence of haemolysis the levels of both miR-16 and miR-451 are sufficiently constant to serve as normalisers

Cilengitide Inhibits Attachment and Invasion of Malignant Pleural Mesothelioma Cells through Antagonism of Integrins αvβ3 and αvβ5

<div><p>Malignant pleural mesothelioma (MPM) is an almost invariably fatal, asbestos-related malignancy arising from the mesothelial membrane lining the thoracic cavities. Despite some improvements in treatment, therapy is not considered curative and median survival following diagnosis is less than 1 year. Although still classed as a rare cancer, the incidence of MPM is increasing, and the limited progress in treating the disease makes the identification of new therapies a priority. As there is evidence for expression of the integrins αvβ3 and αvβ5 in MPM, there is a rationale for investigating the effects on MPM of cilengitide, a synthetic peptide inhibitor of integrin αv heterodimer with high specificity for αvβ3 and αvβ5. In mesothelial cells (MC) and 7 MPM cell lines, growth inhibition by cilengitide was associated with the expression level of its target integrins. Furthermore, cilengitide caused cell detachment and subsequent death of anoikis-sensitive cells. It also suppressed invasion of MPM cells in monolayer and three-dimensional cultures. Gene knockdown experiments indicated that these effects of cilengitide were, at least partly, due to antagonism of αvβ3 and αvβ5.</p></div