Cancer Therapeutics Research Laboratory

Singapore, Singapore

Cancer Therapeutics Research Laboratory

Singapore, Singapore
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Mok T.S.K.,Chinese University of Hong Kong | Crino L.,Ospedale Santa Maria della Misericordia | Felip E.,University of Barcelona | Salgia R.,City of Hope | And 3 more authors.
Cancer Treatment Reviews | Year: 2017

The discovery of anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved—ceritinib and alectinib—and others that are in development—brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms. Ceritinib gained US Food and Drug Administration approval in 2014 following accelerated review for the treatment of patients with ALK-positive (ALK+) metastatic NSCLC who have progressed on or are intolerant to crizotinib. In pre-clinical studies, it demonstrated more potent inhibition of ALK than crizotinib in enzymatic assays, more durable responses in xenograft models and the ability to potently overcome crizotinib resistance mutations in vitro (including the gatekeeper mutation). There is also evidence for ceritinib penetration across the blood-brain barrier. In clinical trials, ceritinib has demonstrated durable responses and progression-free survival in ALK-inhibitor–pre-treated and –naïve NSCLC patients, including high overall and intracranial response rates in those with central nervous system metastases. Selective gastrointestinal toxicity of ceritinib, such as diarrhea, nausea and vomiting is generally manageable with prophylactic medication and prompt dose reduction or interruption. Future progress in treating ALK+ NSCLC will focus on determining the optimal sequencing of therapies and strategies to overcome acquired resistance, an ongoing challenge in treating ALK-mutation–driven tumors. © 2017 The Authors

Tan D.S.W.,National Cancer Center Singapore | Tan D.S.W.,Cancer Therapeutics Research Laboratory | Haaland B.,Quantitative Medicine | Haaland B.,National University of Singapore | And 15 more authors.
Molecular Cancer | Year: 2014

The advent of effective targeted therapeutics has led to increasing emphasis on precise biomarkers for accurate patient stratification. Here, we describe the role of ACK1, a non-receptor tyrosine kinase in abrogating migration and invasion in KRAS mutant lung adenocarcinoma. Bosutinib, which inhibits ACK1 at 2.7 nM IC50, was found to inhibit cell migration and invasion but not viability in a panel of non-small cell lung cancer (NSCLC) cell lines. Knockdown of ACK1 abrogated bosutinib-induced inhibition of cell migration and invasion specifically in KRAS mutant cells. This finding was further confirmed in an in vivo zebrafish metastatic model. Tissue microarray data on 210 Singaporean lung adenocarcinomas indicate that cytoplasmic ACK1 was significantly over-expressed relative to paired adjacent non-tumor tissue. Interestingly, ACK1 expression in " normal" tissue adjacent to tumour, but not tumour, was independently associated with poor overall and relapse-free survival. In conclusion, inhibition of ACK1 with bosutinib attenuates migration and invasion in the context of KRAS mutant NSCLC and may fulfil a therapeutic niche through combinatorial treatment approaches. © 2014 Tan et al.; licensee BioMed Central Ltd.

Jain A.,National Cancer Center Singapore | Lim C.,National Cancer Center Singapore | Gan E.M.,National University of Singapore | Ng D.Z.,National University of Singapore | And 24 more authors.
PLoS ONE | Year: 2015

Objectives This purpose of this study was to examine clinical-pathologic factors - particularly smoking and brain metastases - in EGFR mutation positive (M+) lung adenocarcinoma (ADC) to determine their impact on survival in patients treated with first line EGFR TKI. Methods A retrospective review of EGFR mutation reflex testing experience for all ADC diagnosed at a tertiary Asian cancer centre from January 2009 to April 2013. Amongst this cohort, patients with advanced EGFR M+ ADC treated with first line EGFR TKI were identified to determine factors that influence progression free and overall survival. Results 444/742 (59.8%) ADC reflex tested for EGFR mutations were EGFR M+. Amongst neversmokers (n=468), EGFR M+ were found in 74.5%of females and 76.3% of males, and amongst ever smokers (n=283), in 53.3% of females and 35.6%of males. Exon 20 mutations were found more commonly amongst heavy smokers (> 50 pack years and > 20 pack years, Pearson's chi square p=0.044, and p=0.038 respectively). 211 patients treated with palliative first line TKI had a median PFS and OS of 9.2 and 19.6 months respectively. 26% of patients had brain metastasis at diagnosis. This was significantly detrimental to overall survival (HR 1.85, CI 1.09-3.16, p=0.024) on multivariate analysis. There was no evidence that smoking status had a significant impact on survival. Conclusions The high prevalence of EGFR M+ in our patient population warrants reflex testing regardless of gender and smoking status. Smoking status and dosage did not impact progression free or overall survival in patients treated with first line EGFR TKI. The presence of brain metastasis at diagnosis negatively impacts overall survival. © 2015 Jain et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Tan D.S.W.,National Cancer Center | Tan D.S.W.,Cancer Therapeutics Research Laboratory | Tan D.S.W.,Genome Institute of Singapore | Camilleri-Broet S.,University of Paris Descartes | And 14 more authors.
International Journal of Cancer | Year: 2014

Non-small-cell lung cancer (NSCLC) is a heterogeneous disease, with a burden of genomic alterations exceeding most other tumors. The goal of our study was to evaluate the frequencies of co-occurring mutations and copy-number aberrations (CNAs) within the same tumor and to evaluate their potential clinical impact. Mass-spectrometry based mutation profiling using a customized lung cancer panel evaluating 214 mutations across 26 key NSCLC genes was performed on 230 nonsquamous NSCLC and integrated with genome-wide CNAs and clinical variables. Among the 138 cases having at least one mutation, one-third (41, 29.7%) showed two or more mutations, either in the same gene (double mutation) or in different genes (co-mutations). In epidermal growth factor receptor (EGFR) mutant cancers, there was a double mutation in 18% and co-mutations in the following genes: TP53 (10%), PIK3CA (8%), STK11 (6%) and MET (4%). Significant relationships were detected between EGFR mutation and 1p, 7p copy gains (harboring the EGFR gene) as well as 13q copy loss. KRAS mutation was significantly related with 1q gain and 3q loss. For Stage I, tumors harboring at least one mutation or PIK3CA mutation were significantly correlated with poor prognosis (p-value = 0.02). When combining CNAs and mutational status, patients having both KRAS mutation and the highest related CNA (3q22.3 copy loss) showed a significant poorer prognosis (p-value = 0.03). Our study highlights the clinical relevance of studying tumor complexity by integrative genomic analysis and the need for developing assays that broadly screen for both "actionable" mutations and copy-number alterations to improve precision of stratified treatment approaches. What's New? Personalized therapy in non-small cell lung cancer (NSCLC) is underpinned by the fact that tumor cell growth and survival depends on single gene alterations, that have become prime candidates for targeted therapeutics. Here, high-sensitivity multiplexed mutation profiling and integration of whole genome SNP array analysis were used to examine mutational status and molecular heterogeneity in NSCLC. The findings show high frequencies of co-existing mutations and copy-number aberrations within the same tumor. This complex pattern potentially influences clinical outcomes and highlights the challenges in targeting a single-driver event. The results further indicate that future tumor profiling should account for molecular heterogeneity. © 2014 UICC.

Khoo B.L.,National University of Singapore | Warkiani M.E.,Singapore Alliance for Research and Technology Center | Guan G.,Singapore Alliance for Research and Technology Center | Guan G.,National University of Singapore | And 12 more authors.
IFMBE Proceedings | Year: 2014

Detection, enumeration and characterization of rare circulating tumor cells (CTCs) from the peripheral blood of cancer patients potentially provide critical insights into tumor biology and is promising for cancer diagnosis and prognosis. Here, we present a novel multiplexed spiral microfluidic device for ultra-high throughput, label-free enrichment of CTCs from clinically relevant blood volumes. The fast processing time of the technique (7.5 mL blood in < 5 min) and high sensitivity of the device lends itself to a broad range of potential genomic and transcriptomic applications. The method can specifically separate and preserve all fractions of blood (i.e., plasma, CTCs and PBMC) for diverse downstream analysis. CTCs were detected from 100% (10/10) of blood samples collected from patients with advanced stage metastatic breast (12- 56 CTC/ml) or lung cancer (30-153 CTC/ml). Cancer cells were characterized with immunostaining and fluorescence in situ hybridization (FISH) (HER2/neu). Retrieved cells were unlabelled and hence more viable for propagation and other informative analysis such as the next generation sequencing (NGS) to guide treatment and individualized patient care. © Springer International Publishing Switzerland 2014.

Khoo B.L.,National University of Singapore | Warkiani M.E.,Singapore Alliance for Research and Technology Center | Tan D.S.-W.,National Cancer Center Singapore | Tan D.S.-W.,Cancer Therapeutics Research Laboratory | And 17 more authors.
PLoS ONE | Year: 2014

Background: Circulating tumor cells (CTCs) are cancer cells that can be isolated via liquid biopsy from blood and can be phenotypically and genetically characterized to provide critical information for guiding cancer treatment. Current analysis of CTCs is hindered by the throughput, selectivity and specificity of devices or assays used in CTC detection and isolation. Methodology/Principal Findings: Here, we enriched and characterized putative CTCs from blood samples of patients with both advanced stage metastatic breast and lung cancers using a novel multiplexed spiral microfluidic chip. This system detected putative CTCs under high sensitivity (100%, n = 56) (Breast cancer samples: 12-1275 CTCs/ml; Lung cancer samples: 10-1535 CTCs/ml) rapidly from clinically relevant blood volumes (7.5 ml under 5 min). Blood samples were completely separated into plasma, CTCs and PBMCs components and each fraction were characterized with immunophenotyping (Pan-cytokeratin/CD45, CD44/CD24, EpCAM), fluorescence in-situ hybridization (FISH) (EML4-ALK) or targeted somatic mutation analysis. We used an ultra-sensitive mass spectrometry based system to highlight the presence of an EGFR-activating mutation in both isolated CTCs and plasma cell-free DNA (cf-DNA), and demonstrate concordance with the original tumor-biopsy samples. Conclusions/Significance: We have clinically validated our multiplexed microfluidic chip for the ultra high-throughput, lowcost and label-free enrichment of CTCs. Retrieved cells were unlabeled and viable, enabling potential propagation and realtime downstream analysis using next generation sequencing (NGS) or proteomic analysis.

PubMed | Agency for Science, Technology and Research Singapore, Singapore General Hospital, National University of Singapore, Cancer Therapeutics Research Laboratory and National Cancer Center Singapore
Type: Journal Article | Journal: The Lancet. Oncology | Year: 2016

Lung cancer is a leading cause of cancer-related mortality worldwide, and is classically divided into two major histological subtypes: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Although NSCLC and SCLC are considered distinct entities with different genomic landscapes, emerging evidence highlights a convergence in therapeutically relevant targets for both histologies. In adenocarcinomas with defined alterations such as EGFR mutations and ALK translocations, targeted therapies are now first-line standard of care. By contrast, many experimental and targeted agents remain largely unsuccessful for SCLC. Intense preclinical research and clinical trials are underway to exploit unique traits of lung cancer, such as oncogene dependency, DNA damage response, angiogenesis, and cellular plasticity arising from presence of cancer stem cell lineages. In addition, the promising clinical activity observed in NSCLC in response to immune checkpoint blockade has spurred great interest in the field of immunooncology, with the scope to develop a diverse repertoire of synergistic and personalised immunotherapeutics. In this Review, we discuss novel therapeutic agents for lung cancer that are in early-stage development, and how prospective clinical trials and drug development may be shaped by a deeper understanding of this heterogeneous disease.

Leong H.S.,Cancer Therapeutics Research Laboratory | Chong F.T.,Cancer Therapeutics Research Laboratory | Sew P.H.,Cancer Therapeutics Research Laboratory | Lau D.P.,Cancer Therapeutics Research Laboratory | And 6 more authors.
Stem Cells Translational Medicine | Year: 2014

Emerging data suggest that cancer stem cells (CSCs) exist in equilibrium with differentiated cells and that stochastic transitions between these states can account for tumor heterogeneity and drug resistance. The aim of this study was to establish an in vitro system that recapitulates stem cell plasticity in head and neck squamous cell cancers (HNSCCs) and identify the factors that play a role in the maintenance and repopulation of CSCs. Tumor spheres were established using patient-derived cell lines via anchorage-independent cell culture techniques. These tumor spheres were found to have higher aldehyde dehydrogenase (ALD) cell fractions and increased expression of Kruppel-like factor 4, SRY (sex determining region Y)-box 2, and Nanog and were resistant to γ-radiation, 5-fluorouracil, cisplatin, and etoposide treatment compared with monolayer culture cells. Monolayer cultures were subject to single cell cloning to generate clones with high and low ALD fractions. ALDHigh clones showed higher expression of stem cell and epithelial-mesenchymal transition markers compared with ALDLow clones. ALD fractions, representing stem cell fractions, fluctuated with serial passaging, equilibrating at a level specific to each cell line, and could be augmented by the addition of epidermal growth factor (EGF) and/or insulin. ALDHigh clones showed increased EGF receptor (EGFR) and insulin-like growth factor-1 receptor (IGF-1R) phosphorylation, with increased activation of downstream pathways compared with ALDLow clones. Importantly, blocking these pathways using specific inhibitors against EGFR and IGF-1R reduced stem cell fractions drastically. Taken together, these results show that HNSCC CSCs exhibit plasticity, with the maintenance of the stem cell fraction dependent on the EGFR and IGF-1R pathways and potentially amenable to targeted therapeutics. © AlphaMed Press 2014.

Iyer N.G.,The Surgical Center | Iyer N.G.,Cancer Therapeutics Research Laboratory | Tan D.S.W.,Cancer Therapeutics Research Laboratory | Tan D.S.W.,National Cancer Center | And 12 more authors.
Cancer | Year: 2015

BACKGROUND The current study was performed to report the long-term results of a trial comparing concurrent chemotherapy and radiotherapy (CCRT) with surgery and adjuvant radiotherapy (RT) in patients with stage III/IV nonmetastatic head and neck squamous cell carcinoma. METHODS Patients with stage III/IV resectable head and neck squamous cell carcinoma were randomized to surgery followed by RT or CCRT. The trial was halted prematurely due to poor accrual. Human papillomavirus status was tested on archival material using polymerase chain reaction sequencing. RESULTS Of the total of 119 patients, 60 patients were randomized to primary surgery (S arm) and 59 patients were randomized to CCRT (C arm). Human papillomavirus status was tested in 75 patients, and only 3 were found to be positive. The median follow-up for surviving patients was 13 years. Analysis of the entire cohort demonstrated no statistically significant difference in overall survival and disease-specific survival (DSS): 5-year rates were 45% versus 35% for overall survival (P = .262) and 56% versus 46% for DSS (P = .637) for the S arm and C arm, respectively. Analysis by subsites indicated that this difference favoring the S arm was mainly driven by survival data among patients with cancers of the oral cavity and maxillary sinus. For patients with oral cavity cancer, survival was significantly better in those who underwent primary surgery compared with CCRT; the 5-year DSS rate was 68% versus 12% for the S arm and C arm, respectively (P = .038). For patients with cancers of the maxillary sinus, the 5-year DSS rate was 71% for patients on the S arm and 0% for patients on the C arm (P = .05). CONCLUSIONS These long-term results demonstrate a significant advantage for primary surgery in patients with cancers of the oral cavity or maxillary sinus, providing strong support for primary surgery as the main modality of treatment for these subsites. In other subsites, CCRT and surgery with adjuvant RT were found to demonstrate similar efficacy for survival in patients with advanced resectable tumors. Cancer 2015;121:1599-1607. © 2015 American Cancer Society.

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