Hong Kong Cancer Institute

Hong Kong, Hong Kong

Hong Kong Cancer Institute

Hong Kong, Hong Kong
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Ma B.,Hong Kong Cancer Institute | King A.D.,Chinese University of Hong Kong | Leung L.,Hong Kong Cancer Institute | Wang K.,Chinese University of Hong Kong | And 6 more authors.
Annals of Oncology | Year: 2017

Background: This study investigated the predictive and prognostic significance of assessing early drug response with both positron-emission computerized tomography (PET-CT) and circulating tumor cells (CTCs) in patients receiving first-line chemotherapy for metastatic colorectal cancer. Patients and methods: Eligible patients had PET-CT and CTC analysis at baseline and 4-6 weeks after starting chemotherapy, and then a CT scan at 10-12 weeks to assess the Response Evaluation Criteria In Solid Tumors (RECIST) response. Early response was defined as achieving a dual-endpoint consisting of PET-CT (30% drop in the sum of maximum standard uptake values- SUVmax-of target lesions) and CTC response (CTC<3 cells/7.5 ml blood) at 4-6 weeks after starting chemotherapy. Results: About 84 patients were enrolled with a median follow-up of 32.9months (95% confidence interval, CI, 24.5months-not reached, NR), and 70 patients (84.3%) completed all assessments. Achieving an early response based on the dual-endpoint was independently associated with progression-free survival (hazard ratio, HR=0.452, 95% CI 0.267-0.765). The median progression-free survival of early responders was 7.41months (95% CI, 6.05-9.11) compared with 5.37 months (95% CI, 4.68-6.24) in non-responders (log-rank, P=0.0167). RECIST response at 10 weeks was independently associated with overall survival (OS) (HR=0.484, 95% CI, 0.275-0.852). Early response based on the dual-endpoint could predict the subsequent RECIST response with a sensitivity, specificity and positive predictive value of 64%, 70% and 74%, respectively. Conclusions: Early response based on both PET-CT and CTC analysis has prognostic and probably predictive significance in patients undergoing first-line chemotherapy for metastatic colorectal cancer. Its utility as a new tool for assessing early drug response should be further validated. © The Author 2017.

Ma B.B.Y.,Sir Pao Center for Cancer | Ma B.B.Y.,Hong Kong Cancer Institute | Ma B.B.Y.,Chinese University of Hong Kong | Hui E.P.,Sir Pao Center for Cancer | And 5 more authors.
Expert Opinion on Investigational Drugs | Year: 2017

Introduction: Nasopharyngeal carcinoma (NPC) is endemic to Southern China and Asia and is etiologically associated with the Epstein Barr virus (EBV). Whole exome and genome sequencing (WES, WGS) studies of NPC have reported several actionable therapeutic targets, and that the mutational load of NPC maybe comparable to that of squamous head and neck cancer. These unique biological characteristics have been exploited as potential targets and a wide range of investigational drugs are being investigated in clinical trials. Area covered: This review focused on the latest clinical development of the most promising classes of investigational agents in the treatment of advanced NPC. These include inhibitors of tumor angiogenesis, kinase signaling pathways and immunotherapy. Expert opinion: Checkpoint inhibitors and EBV-specific T-cell therapy have shown promising activity in early phase clinical trials, and are being further evaluated in randomized studies. For patients whose tumors express genetic alterations that are known to predict response to kinase inhibitors, novel trial designs such as an ‘Umbrella’ study may be considered given the abundance of targeted agents that are now available for clinical evaluation. It is envisioned that regulatory approval for new drugs for advanced NPC will occur in the near future. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Cheng Y.,Hong Kong Cancer Institute | Geng H.,Hong Kong Cancer Institute | Cheng S.H.,Chinese University of Hong Kong | Liang P.,Chinese University of Hong Kong | And 8 more authors.
Cancer Research | Year: 2010

Zinc finger transcription factors are involved broadly in development and tumorigenesis. Here, we report that the little studied zinc finger transcription factor ZNF382 functions as a tumor suppressor in multiple carcinomas. Although broadly expressed in normal tissues, ZNF382 expression was attenuated in multiple carcinoma cell lines due to promoter CpG methylation. ZNF382 was also frequently methylated in multiple primary tumors (nasopharyngeal, esophageal, colon, gastric, and breast). Ectopic expression of ZNF382 in silenced tumor cells significantly inhibited their clonogenicity and proliferation and induced apoptosis. We further found that ZNF382 inhibited NF-κB and AP-1 signaling and downregulated the expression of multiple oncogenes including MYC, MITF, HMGA2, and CDK6, as well as the NF-κB upstream factors STAT3, STAT5B, ID1, and IKBKE, most likely through heterochromatin silencing. ZNF382 could suppress tumorigenesis through heterochromatin-mediated silencing, as ZNF382 was colocalized and interacted with heterochromatin protein HP1 and further changed the chromatin modifications of ZNF382 target oncogenes. Our data show that ZNF382 is a functional tumor suppressor frequently methylated in multiple carcinomas. ©2010 AACR.

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.

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.

Lau P.C.,Hong Kong Cancer Institute | Lau P.C.,Chinese University of Hong Kong | Lau P.C.,Prince of Wales Hospital | 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.

Lui V.W.Y.,Chinese University of Hong Kong | Lui V.W.Y.,Prince of Wales Hospital | Lau C.P.Y.,Hong Kong Cancer Institute | Ho K.,Hong Kong Cancer Institute | And 7 more authors.
Investigational New Drugs | Year: 2011

Nasopharyngeal cancer (NPC) is a highly prevalent and invasive head and neck cancer in Asia. Disease recurrence and distant metastasis account for major NPC deaths. Therefore, more effective therapy is needed. Lapatinib, a dual tyrosine kinase inhibitor (TKI) against both EGFR and HER-2, has been known to exert potent antitumor activity against several cancer models. Given that both EGFR and HER-2 are co-expressed in NPC, we hypothesized that dual targeting of EGFR and HER-2 by this small molecule EGFR/HER-2 TKI would elicit antitumor activity in NPC. Using in vitro models of NPC, we demonstrated that lapatinib was able to efficiently inhibit the phosphorylation of both EGFR and HER-2. This was accompanied by significant growth inhibition of NPC cells (with maximal growth inhibition >90%). For the most lapatinib-sensitive cell line (HK1-LMP1, with IC 50∼600 nM), which harbored the highest levels of both EGFR and HER-2, inhibition of cell growth was associated G 0/G 1 cell cycle arrest, marked PARP cleavage, caspase-3 cleavage, as well as significant downregulation of several important survival proteins (e.g. survivin, Mcl-1 and cyclin D1). NPC cells are intrinsically invasive. We found that lapatinib was able to inhibit cellular invasion of both HK1-LMP1 and HONE-1 cells. Furthermore, our data demonstrated for the first time that lapatinib harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced apoptosis) in human cancer cells overexpressing both EGFR and HER-2 (HK1-LMP1 and HK1). Taken together, our findings suggest that lapatinib is a promising anti-cancer agent for NPC with anti-invasion and anoikis-sensitization activities. © Springer Science+Business Media, LLC 2010.

Chan S.L.,Hong Kong Cancer Institute | Mo F.,Hong Kong Cancer Institute | Johnson P.J.,University of Liverpool | Siu D.Y.W.,Interventional Imaging | And 6 more authors.
HPB | Year: 2014

Objectives The role of serum α-fetoprotein (AFP) measurements in the diagnosis of hepatocellular carcinoma (HCC) remains controversial. Some guidelines have advised against the use of AFP in the diagnosis of HCC. This study was conducted to evaluate the performance of AFP in the diagnosis of HCC, and to identify the optimal cut-off value of serum AFP in the diagnosis of HCC in patients with a hepatic mass. Methods Patients who presented during the period from May 1997 to March 2003 with hepatic lesions, for whom paired data on serum AFP values at baseline and lesion histology were available, were reviewed. The performance of AFP in the diagnosis of HCC was determined using receiver operating characteristic curve analysis. Results Data for a total of 805 patients were evaluated. The mean AFP value was 26 900 ng/ml (range: 0-1 965 461 ng/ml). The histological diagnosis was HCC in 557 patients. The optimal AFP cut-off value was 10 ng/ml (for sensitivity of 82.6% and specificity of 70.4%). At a cut-off level of 200 ng/ml, sensitivity, specificity, and positive and negative predictive values were 47.7%, 97.1%, 97.5% and 44.4%, respectively. The diagnostic performance of AFP remains similar in patients with chronic hepatitis B virus infection, despite a lower negative predictive value. Common aetiologies of liver lesions associated with elevated AFP include cholangiocarcinoma and neuroendocrine tumours. Conclusions In Asian patients with suspicious liver lesions, the cut-off AFP level of 200 ng/ml is useful to achieve a diagnosis of HCC with high specificity and reasonable sensitivity. The measurement of serum AFP should not be excluded from guidelines for the diagnosis of HCC. © 2013 International Hepato-Pancreato-Biliary Association.

Hong B.,Chinese University of Hong Kong | Lui V.W.Y.,Chinese University of Hong Kong | Lui V.W.Y.,Cancer Drug Testing Unit | Hui E.P.,Hong Kong Cancer Institute | And 7 more authors.
Biochemical Pharmacology | Year: 2010

YC-1 has recently been demonstrated to have potent anti-invasion and anti-metastatic activity in several cancer models, in addition to its anti-proliferation activity. However, the mechanism underlying its anti-invasion/anti-metastatic activity is largely unknown. Nasopharyngeal carcinoma (NPC) is a highly metastatic head and neck cancer in Southeast Asia. Here, we demonstrated that YC-1 inhibited invasiveness and proliferation of NPC cells, with the latter being accompanied by PARP cleavage, S-phase arrest and activation of Chk1/Chk2. We aimed at identifying novel anti-invasion mechanisms of YC-1 in NPC by a functional proteomic platform, the reverse phase protein array (RPPA). Our study revealed for the first time that multiple invasion-related signaling proteins (β-catenin, caveolin, Src and EGFR), as well as several growth-related proteins (AMPKα, phospho-acetyl-CoA carboxylase (p-ACC), HER-2 and mTOR), which were previously un-described signaling proteins altered by YC-1, were found to be down-modulated by YC-1 in NPC cells. We hypothesized that YC-1-mediated downregulation of these invasion proteins contributed to its anti-invasion activity in NPC cells. Overexpression of EGFR, activated Src or caveolin, but not β-catenin reversed the inhibitory effects of YC-1 on NPC cell invasion, with EGFR and activated Src having additional effects on rescuing NPC cells from YC-1-mediated growth inhibition. In summary, we have identified several novel anti-invasion mechanisms of YC-1 that could impact NPC, and possibly other cancers as well. © 2009.

Poon D.M.C.,Hong Kong Cancer Institute | Poon D.M.C.,Chinese University of Hong Kong | Ng J.,Hong Kong Cancer Institute | Ng J.,Chinese University of Hong Kong | Chan K.,Pamela Youde Nethersole Eastern Hospital
Prostate International | Year: 2015

Abstract Purpose With the emergence of various novel therapies including new generation taxane and androgen-targeted therapies, the optimal sequence of systemic treatment in metastatic castration-resistant prostate cancer (mCRPC) patients remains to be defined. Our aim is to investigate the impact of duration of docetaxel-based chemotherapy and postdocetaxel treatment in mCRPC patients. Methods The medical data of 57 Chinese mCRPC patients who received docetaxel-based chemotherapy in two oncology centers between 2003 and 2012 were reviewed. The treatment efficacy and toxicity were determined. The potential determinants of efficacy were also determined. Results Fifty-seven patients (median age 66 years, range 51-82 years) were given docetaxel-based chemotherapy, of whom 48 (84.2%) received 3-weekly docetaxel (52.5-75 mg/m2) and nine (15.8%) received weekly docetaxel (35 mg/m2). Postdocetaxel treatments were received by 31 (57.4%) patients, including abiraterone in 13 patients and cabazitaxel in one patient. The median follow-up time was 14.3 months. The median overall survival (OS) and progression-free survival were 20.8 months and 5.8 months, respectively. In multivariate analysis, eight cycles or more of chemotherapy [hazard ratio (HR) = 0.151, P < 0.0358], use of postdocetaxel treatment (HR = 0.346, P = 0.0005), and hemoglobin level of <10 (HR = 5.224, P < 0.0001) were independent determinants of OS. Patients who had received abiraterone and cabazitaxel as postdocetaxel treatment had significantly longer OS compared with those who received other postdocetaxel treatments (including rechallenge of docetaxel) and those who did not receive any postdocetaxel treatment (35.3 months vs. 20.8 months vs. 15.3 months, P = 0.00057). Conclusions The results suggest that maximizing exposure to docetaxel-based chemotherapy followed by novel therapies would have a favorable survival impact on mCRPC patients. © 2015 Published by Elsevier B.V. on behalf of Prostate International.

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