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Mok T.,Hong Kong Cancer Institute | Gorbunova V.,Russian Academy of Medical Sciences | Juhasz E.,Orszagos Koranyi Tbc es Pulmonologiai Intezet | Szima B.,Markusovszky University Hospital | And 8 more authors.
Journal of Thoracic Oncology | Year: 2014

INTRODUCTION:: Avastin Biomarkers In lunG And 3D Innovative anaLysis (ABIGAIL), which is a phase II, open-label, randomized study, investigated correlations between biomarkers and best overall response to bevacizumab plus platinum-doublet chemotherapy for patients with advanced/recurrent non-small-cell lung cancer. METHODS:: Patients received bevacizumab (7.5 or 15 mg/kg, 3-weekly until disease progression/unacceptable toxicity) plus carboplatin/gemcitabine or carboplatin/paclitaxel (maximum six cycles). Plasma samples (baseline/throughout treatment) were analyzed for vascular endothelial growth factor (VEGF)-A (baseline only), VEGF receptors (VEGFR-1/VEGFR-2), basic fibroblast growth factor, E-selectin, intercellular adhesion molecule-1, and placental growth factor (baseline only). Tumor samples (primary specimen) were analyzed for VEGF-A, VEGFR-1/VEGFR-2, neuropilin (NRP), and CD31. Response was evaluated at baseline and every 6 weeks (Response Evaluation Criteria in Solid Tumors). RESULTS:: Patients were randomized to receive chemotherapy plus 7.5 mg/kg (n =154) or 15 mg/kg (n =149) bevacizumab. For the primary analysis, none of the baseline plasma biomarkers correlated with best overall response. Exploratory analyses showed that low VEGF-A levels were associated with longer progression-free survival (7.4 versus 6.1 months; hazard ratio, 1.57; 95% confidence intervals, 1.17 to 2.09; p = 0.002) and overall survival (19.8 versus 11.1 months; hazard ratio, 1.57; 95% confidence interval, 1.15-2.13; p = 0.004) compared with these in high baseline plasma VEGF-A levels. No plasma biomarkers changed significantly over time. No significant correlations were observed between tumor biomarkers and clinical outcomes. No new safety signals were observed. CONCLUSION:: Baseline and/or dynamic changes in plasma basic fibroblast growth factor, E-selectin, intercellular adhesion molecule-1, placental growth factor, VEGFR-1 and VEGFR-2, and tumor biomarkers did not correlate statistically with treatment outcomes for bevacizumab plus chemotherapy. Only baseline plasma VEGF-A was significantly correlated with progression-free survival/overall survival. Copyright © 2014 by the International Association for the Study of Lung Cancer. Source


Li L.,Hong Kong Cancer Institute | Li L.,Li Ka Shing Institute of Health science | Li L.,Central South University | Tao Q.,Hong Kong Cancer Institute | And 14 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Nasopharyngeal carcinoma is prevalent in southern China and Southeast Asia, with distinct geographic and ethnic distribution. One candidate susceptibility locus has been identified at 4p11-14, with the associated candidate gene(s) not identified yet. This study investigated the role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in nasopharyngeal carcinoma pathogenesis. Experimental Design: UCHL1 expression and methylation were examined in nasopharyngeal carcinoma. Furthermore, the mechanism of its tumor-suppressive function was elucidated in nasopharyngeal carcinoma cells. Results: Through genomewide expression profiling, we identified UCHL1, a 4p14 gene normally expressed in normal upper respiratory tract tissues, being silenced in all nasopharyngeal carcinoma cell lines. Its silencing is mediated by CpG methylation because UCHL1 promoter methylation was detected in all silenced cell lines, and pharmacologic demethylation reactivated UCHL1 expression along with concomitant promoter demethylation. UCHL1 methylation was also frequently detected in primary tumors but only weakly detected in few normal nasopharyngeal tissues, indicating that the methylation-mediated silencing of UCHL1 is important in nasopharyngeal carcinoma pathogenesis. Ectopic UCHL1 expression dramatically inhibited the growth of nasopharyngeal carcinoma cells through promoting tumor cell apoptosis. We further found that UCHL1 formed a complex with p53/p14ARF/Mdm2 p53 binding protein homolog (mouse), MDM2 and activated the p53 signaling pathway. UCHL1 expression extended p53 and p14ARF protein half-life and shortened MDM2 protein half-life. Conclusions: These results indicate that UCHL1 could deubiquitinate p53 and p14ARF and ubiquitinate MDM2 for p53 stabilization to promote p53 signaling, thus involved in nasopharyngeal carcinoma pathogenesis, whereas it is frequently silenced in this tumor. ©2010 AACR. Source


Li L.,Prince of Wales Hospital | Ma B.B.Y.,Prince of Wales Hospital | Ma B.B.Y.,Hong Kong Cancer Institute
OncoTargets and Therapy | Year: 2014

Colorectal cancer is the second most common cancer in Hong Kong and its incidence is rising in economically developed Chinese cities, including Hong Kong and Shanghai. Several studies conducted in the People's Republic of China have characterized the unique molecular epidemiology of familial colorectal cancer syndromes and molecular biomarkers such as microsatellite instability and genetic mutations (eg, KRAS, NRAS, BRAF, PIK3CA, ERCC1) in Chinese populations. Interethnic differences in anticancer drug response and toxicity have been well described in many cancers, and this review examined the literature with regard to the tolerance of Chinese patients to commonly used chemotherapeutic regimens and targeted therapies for metastatic colorectal cancer. Studies on the pharmacogenomic differences in drug metabolizing and DNA repair enzymes between Chinese, North Asians, and Caucasian patients were also reviewed. © 2014 Li and Ma. Source


Chan S.L.,Chinese University of Hong Kong | Chan S.L.,Hong Kong Cancer Institute | Wong A.M.,Chinese University of Hong Kong | Lee K.,Hong Kong Cancer Institute | And 2 more authors.
Cancer Treatment Reviews | Year: 2016

Following the approval of sorafenib, a large number of molecular targeted agents have been tested clinically for advanced hepatocellular carcinoma (HCC), but all have failed to demonstrate significant efficacy in clinical trials. Multiple reasons for this phenomenon have been discussed in the literature, with one reason being the lack of patient selection on the basis of molecular profile in clinical trials. The concept of drug testing in selected populations has been recently suggested by retrospective analyses of HCC clinical trials in which a particular subgroup of patients, either enriched by clinical factors or by tissue biomarkers, derived more benefits from the novel drug. In addition, recent advances in genomic medicine have enhanced the understanding of genetic and epigenetic events occurring in HCC, raising the possibility of personalizing targeted agents in accordance with the genetic make-up of the tumors. The development of 'personalized' treatment for HCC is, however, hindered by the lack of fresh biopsy of advanced HCC, the low incidence of genetic driver mutations in HCC and the tumor heterogeneity. These limitations may be overcome by sequencing cell-free DNA in plasma, frequently known as liquid biopsy, and revolution in the concept of the design of clinical trials. In this review article, we aim to: (1) give a summary of the recent sequencing results of HCC and the related implications for drug development; (2) highlight potential individual targeted agents and existing research on biomarker selection in clinical trials; and (3) discuss future directions, including the potential of liquid biopsy and umbrella clinical trials, to enhance personalized drug testing for HCC. © 2016. Source


Lau P.C.,Hong Kong Cancer Institute | Lau P.C.,Chinese University of Hong Kong | Wong E.Y.,Hong Kong Cancer Institute | Wong E.Y.,Chinese University of Hong Kong
Pathology and Oncology Research | Year: 2012

Nasopharyngeal carcinoma (NPC) represents a common cancer in endemic areas with high invasive and metastatic potential. It is now known that the HGF-MET signaling pathway plays an important role in mediating the invasive growth of many different types of cancer, including head and neck squamous cell carcinoma. HGF has been shown to stimulate NPC cell growth and invasion in cell line model. The current study aims at demonstrating the effect of MET inhibition by small molecule tyrosine kinase inhibitor PHA665752 on the growth and invasive potential of NPC cell lines. NPC cell lines were used for immunohistochemistry for the MET protein, as well as western blot analysis on MET together with its downstream cascade signaling proteins after treatment with PHA665752. The effect on cell growth, migration and invasion after PHA665752 treatment was also studied. MET inhibition by PHA665752 resulted in highly significant inhibition on NPC cell growth, migration and invasion in vitro. Down-regulation of phospho-MET, phospho-Akt, phospho-MAPK, phospho-STAT3, cyclin D1, β-catenin and PCNAwas detected in NPC cells after PHA665752 treatment. MET inhibition with tyrosine kinase inhibitor resulted in suppression of NPC cell growth and invasive potential via down-regulation of a variety of signaling onco-proteins. MET is an important therapeutic target for NPC that warrants further studies and clinical trials. © Arányi Lajos Foundation 2011. Source

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