Correlation of Angiogenic Biomarker Signatures With Clinical Outcomes in Metastatic Colorectal Cancer Patients Receiving Capecitabine, Oxaliplatin, and Bevacizumab.

Correlation of angiogenic biomarker signatures with clinical outcomes in metastatic colorectal cancer patients receiving capecitabine, oxaliplatin, and bevacizumab.

Cancer Med. 2013 Apr; 2(2): 234-42
Liu Y, Starr MD, Bulusu A, Pang H, Wong NS, Honeycutt W, Amara A, Hurwitz HI, Nixon AB

A novel combination of capecitabine, oxaliplatin, and bevacizumab was evaluated in colorectal cancer patients enrolled in a phase II clinical trial. In this retrospective analysis, plasma samples from patients receiving capecitabine, oxaliplatin, and bevacizumab were analyzed to investigate biomarkers of clinical benefit. Forty-one protein biomarkers were tested in 38 patients at baseline and after two cycles of drug administration. Correlations among analytes were evaluated by Spearman analysis. Analyte levels at baseline and changes on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) by univariate analysis. Multivariate analyses were determined using the Cox proportional hazard model. Time to event analyses were evaluated by Kaplan-Meier analysis and compared by log-rank test. Baseline levels of vWF and Ang-2 significantly correlated with PFS, while levels of VCAM-1, vWF, TSP-2, IL-8, MMP-2, and Ang-2 correlated with OS (P < 0.05). The fold change of IGF-1 levels from baseline to the end of cycle 2 was correlated with PFS, while fold changes of Ang-2, TSP-2, and TGF-?2 correlated with OS. A baseline signature of Ang-2, IGFBP-3, IL-6, and VCAM-1 identified a low-risk and high-risk group of patients (OS: 33.9 months vs. 18.1 months, respectively, P = 0.016). For treatment-related changes, a signature consisting of Ang-2, E-Cadherin, IL-6, MCP-1, OPN, and TGF-?1 was able to stratify patients into high- and low-risk groups (PFS: 7.7 months vs. 15.5 months, P = 0.004). Multiplex analysis of patient plasma in this trial identified several baseline- and treatment-related biomarkers associated with clinical outcome. These findings merit further exploration in larger, controlled clinical trials. HubMed – drug


Slug increases sensitivity to tubulin-binding agents via the downregulation of ?III and ?IVa-tubulin in lung cancer cells.

Cancer Med. 2013 Apr; 2(2): 144-54
Tamura D, Arao T, Nagai T, Kaneda H, Aomatsu K, Fujita Y, Matsumoto K, De Velasco MA, Kato H, Hayashi H, Yoshida S, Kimura H, Maniwa Y, Nishio W, Sakai Y, Ohbayashi C, Kotani Y, Nishimura Y, Nishio K

Transcription factor Slug/SNAI2 (snail homolog 2) plays a key role in the induction of the epithelial mesenchymal transition in cancer cells; however, whether the overexpression of Slug mediates the malignant phenotype and alters drug sensitivity in lung cancer cells remains largely unclear. We investigated Slug focusing on its biological function and involvement in drug sensitivity in lung cancer cells. Stable Slug transfectants showed typical morphological changes compared with control cells. Slug overexpression did not change the cellular proliferations; however, migration activity and anchorage-independent growth activity with an antiapoptotic effect were increased. Interestingly, stable Slug overexpression increased drug sensitivity to tubulin-binding agents including vinorelbine, vincristine, and paclitaxel (5.8- to 8.9-fold increase) in several lung cancer cell lines but did not increase sensitivity to agents other than tubulin-binding agents. Real-time RT-PCR (polymerase chain reaction) and western blotting revealed that Slug overexpression downregulated the expression of ?III and ?IVa-tubulin, which is considered to be a major factor determining sensitivity to tubulin-binding agents. A luciferase reporter assay confirmed that Slug suppressed the promoter activity of ?IVa-tubulin at a transcriptional level. Slug overexpression enhanced tumor growth, whereas Slug overexpression increased drug sensitivity to vinorelbine with the downregulation of ?III and ?IV-tubulin in vivo. Immunohistochemistry of Slug with clinical lung cancer samples showed that Slug overexpression tended to be involved in response to tubulin-binding agents. In conclusion, our data indicate that Slug mediates an aggressive phenotype including enhanced migration activity, anoikis suppression, and tumor growth, but increases sensitivity to tubulin-binding agents via the downregulation of ?III and ?IVa-tubulin in lung cancer cells. HubMed – drug


Alemtuzumab in multiple sclerosis: latest evidence and clinical prospects.

Ther Adv Chronic Dis. 2013 May; 4(3): 97-103
Kousin-Ezewu O, Coles A

Alemtuzumab was first used in multiple sclerosis in 1991. It is a monoclonal antibody which is directed against CD52, a protein of unknown function on lymphocytes. Alemtuzumab causes a lymphopenia, following which homeostatic reconstitution leads to prolonged alteration of the immune repertoire. This reduces the risk of relapse and disability accumulation in multiple sclerosis; it is the only drug to show superiority over interferon ?-1a in disability outcomes in a monotherapy phase III trial. It should be used with a parallel risk management programme to identify the principal adverse effects of alemtuzumab, especially secondary autoimmunity months or years later, mainly against the thyroid but also immune thrombocytopenia. This review charts the development of alemtuzumab as a drug for multiple sclerosis and summarizes the latest clinical trial data. HubMed – drug