Boon Cher Goh
National University of Singapore
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Featured researches published by Boon Cher Goh.
Clinical Pharmacokinectics | 2005
Shu-Feng Zhou; Sui Yung Chan; Boon Cher Goh; Eli Chan; Wei Duan; Min Huang; Howard L. McLeod
Consistent with its highest abundance in humans, cytochrome P450 (CYP) 3A is responsible for the metabolism of about 60% of currently known drugs. However, this unusual low substrate specificity also makes CYP3A4 susceptible to reversible or irreversible inhibition by a variety of drugs. Mechanism-based inhibition of CYP3A4 is characterised by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYP isoenzymes to reactive metabolites capable of irreversibly binding covalently to CYP3A4. Approaches using in vitro, in silico and in vivo models can be used to study CYP3A4 inactivation by drugs. Human liver microsomes are always used to estimate inactivation kinetic parameters including the concentration required for half-maximal inactivation (KI) and the maximal rate of inactivation at saturation (kinact).Clinically important mechanism-based CYP3A4 inhibitors include antibacterials (e.g. clarithromycin, erythromycin and isoniazid), anticancer agents (e.g. tamoxifen and irinotecan), anti-HIV agents (e.g. ritonavir and delavirdine), anti-hypertensives (e.g. dihydralazine, verapamil and diltiazem), sex steroids and their receptor modulators (e.g. gestodene and raloxifene), and several herbal constituents (e.g. bergamottin and glabridin). Drugs inactivating CYP3A4 often possess several common moieties such as a tertiary amine function, furan ring, and acetylene function. It appears that the chemical properties of a drug critical to CYP3A4 inactivation include formation of reactive metabolites by CYP isoenzymes, preponderance of CYP inducers and P-glycoprotein (P-gp) substrate, and occurrence of clinically significant pharmacokinetic interactions with coadministered drugs.Compared with reversible inhibition of CYP3A4, mechanism-based inhibition of CYP3A4 more frequently cause pharmacokinetic-pharmacodynamic drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesised CYP3A4 protein. The resultant drug interactions may lead to adverse drug effects, including some fatal events. For example, when aforementioned CYP3A4 inhibitors are coadministered with terfenadine, cisapride or astemizole (all CYP3A4 substrates), torsades de pointes (a life-threatening ventricular arrhythmia associated with QT prolongation) may occur.However, predicting drug-drug interactions involving CYP3A4 inactivation is difficult, since the clinical outcomes depend on a number of factors that are associated with drugs and patients. The apparent pharmacokinetic effect of a mechanism-based inhibitor of CYP3A4 would be a function of its KI, kinact and partition ratio and the zero-order synthesis rate of new or replacement enzyme. The inactivators for CYP3A4 can be inducers and P-gp substrates/inhibitors, confounding in vitro-in vivo extrapolation. The clinical significance of CYP3A inhibition for drug safety and efficacy warrants closer understanding of the mechanisms for each inhibitor. Furthermore, such inactivation may be exploited for therapeutic gain in certain circumstances.
Lancet Oncology | 2010
Keith C. Bible; Vera J. Suman; Julian R. Molina; Robert C. Smallridge; William J. Maples; Michael E. Menefee; Joseph Rubin; Kostandinos Sideras; John C. Morris; Bryan McIver; Kevin P Webster; Carolyn Bieber; Anne M. Traynor; Patrick J. Flynn; Boon Cher Goh; Hui Tang; Susan Percy Ivy; Charles Erlichman
BACKGROUND Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. METHODS This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. FINDINGS 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35-68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=-0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. INTERPRETATION Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patients response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. FUNDING National Cancer Institute, supported in part by NCI CA15083 and CM62205.
Embo Molecular Medicine | 2013
Tuan Zea Tan; Qing Hao Miow; Ruby Yun-Ju Huang; Meng Kang Wong; Jieru Ye; Jieying Amelia Lau; Meng Chu Wu; Luqman Hakim Abdul Hadi; Richie Soong; Mahesh Choolani; Ben Davidson; Jahn M. Nesland; Lingzhi Wang; Noriomi Matsumura; Masaki Mandai; Ikuo Konishi; Boon Cher Goh; Jeffrey T. Chang; Jean Paul Thiery; Seiichi Mori
Epithelial ovarian cancer (EOC) is hallmarked by a high degree of heterogeneity. To address this heterogeneity, a classification scheme was developed based on gene expression patterns of 1538 tumours. Five, biologically distinct subgroups — Epi‐A, Epi‐B, Mes, Stem‐A and Stem‐B — exhibited significantly distinct clinicopathological characteristics, deregulated pathways and patient prognoses, and were validated using independent datasets. To identify subtype‐specific molecular targets, ovarian cancer cell lines representing these molecular subtypes were screened against a genome‐wide shRNA library. Focusing on the poor‐prognosis Stem‐A subtype, we found that two genes involved in tubulin processing, TUBGCP4 and NAT10, were essential for cell growth, an observation supported by a pathway analysis that also predicted involvement of microtubule‐related processes. Furthermore, we observed that Stem‐A cell lines were indeed more sensitive to inhibitors of tubulin polymerization, vincristine and vinorelbine, than the other subtypes. This subtyping offers new insights into the development of novel diagnostic and personalized treatment for EOC patients.
Clinical Pharmacology & Therapeutics | 2006
Lai-San Tham; Boon Cher Goh; Anne Nafziger; Jia-Yi Guo; Lingzhi Wang; Richie Soong; Soo-Chin Lee
Because of the unique lack of genetic diversity despite the multiethnicity in the Asian population, we hypothesize that single‐nucleotide polymorphisms in cytochrome P450 (CYP) 2C9 (CYP2C9*3) and vitamin K epoxide reductase complex subunit 1 (VKORC1) at position 381, used to infer VKORC1haplotype in combination with demographic factors, can accurately predict warfarin doses. The aims of this study were to derive a pharmacogenetics‐based dosing algorithm by use of retrospective information and to validate it through a data‐splitting method in a separate cohort of equal size.
Clinical Pharmacology & Therapeutics | 2006
Soo-Chin Lee; S.S. Ng; Johannes Oldenburg; Pei‐Yi Chong; Simone Rost; Jia-Yi Guo; Hui-Ling Yap; Sheila Clare Rankin; Hui‐Boon Khor; Tiong‐Cheng Yeo; Kheng‐Siang Ng; Richie Soong; Boon Cher Goh
Chinese and Malay subjects have been reported to require less maintenance warfarin than Indians that could not be accounted for by cytochrome P450 (CYP) 2C9 variants. Vitamin K epoxide reductase complex 1 (VKORC1) is the target enzyme of warfarin, and VKORC1 intronic variants and haplotypes have recently been shown to influence VKORC1 activity and warfarin requirements.
Nature Genetics | 2014
De-Chen Lin; Xuan Meng; Masaharu Hazawa; Yasunobu Nagata; Ana Maria Varela; Liang Xu; Yusuke Sato; Li-Zhen Liu; Ling-Wen Ding; Arjun Sharma; Boon Cher Goh; Soo-Chin Lee; Bengt Fredrik Petersson; Feng Gang Yu; Paul A. MacAry; Min Zin Oo; Chan Soh Ha; Henry Yang; Seishi Ogawa; Kwok Seng Loh; H. Phillip Koeffler
Nasopharyngeal carcinoma (NPC) has extremely skewed ethnic and geographic distributions, is poorly understood at the genetic level and is in need of effective therapeutic approaches. Here we determined the mutational landscape of 128 cases with NPC using whole-exome and targeted deep sequencing, as well as SNP array analysis. These approaches revealed a distinct mutational signature and nine significantly mutated genes, many of which have not been implicated previously in NPC. Notably, integrated analysis showed enrichment of genetic lesions affecting several important cellular processes and pathways, including chromatin modification, ERBB-PI3K signaling and autophagy machinery. Further functional studies suggested the biological relevance of these lesions to the NPC malignant phenotype. In addition, we uncovered a number of new druggable candidates because of their genomic alterations. Together our study provides a molecular basis for a comprehensive understanding of, and exploring new therapies for, NPC.
Cancer Science | 2007
Srinivasa Rao Jada; Robert Lim; Chiung Ing Wong; Xiaochen Shu; Soo-Chin Lee; Qingyu Zhou; Boon Cher Goh; Balram Chowbay
The objectives of the present study were (i) to study the pharmacogenetics of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A in three distinct healthy Asian populations (Chinese, Malays and Indians), and (ii) to investigate the polygenic influence of these polymorphic variants in irinotecan‐induced neutropenia in Asian cancer patients. Pharmacokinetic and pharmacogenetic analyses were done after administration of irinotecan as a 90‐min intravenous infusion of 375 mg/m2 once every 3 weeks (n = 45). Genotypic–phenotypic correlates showed a non‐significant influence of UGT1A1*28 and ABCG2 c.421C>A polymorphisms on the pharmacokinetics of SN‐38 (P > 0.05), as well as severity of neutropenia (P > 0.05). Significantly higher exposure levels to SN‐38 (P = 0.018), lower relative extent of glucuronidation (REG; P = 0.006) and higher biliary index (BI; P = 0.003) were found in cancer patients homozygous for the UGT1A1*6 allele compared with patients harboring the reference genotype. The mean absolute neutrophil count (ANC) was 85% lower and the prevalence of grade 4 neutropenia (ANC ≤ 500/µL) was 27% in patients homozygous for UGT1A1*6 compared with the reference group. Furthermore, the presence of the UGT1A1*6 allele was associated with an approximately 3‐fold increased risk of developing severe grade 4 neutropenia compared with patients harboring the reference genotype. These exploratory findings suggest that homozygosity for UGT1A1*6 allele may be associated with altered SN‐38 disposition and may increase the risk of severe neutropenia in Asian cancer patients, particularly in the Chinese cancer patients who comprised 80% (n = 36) of the patient population in the present study. (Cancer Sci 2007; 98: 1461–1467)
Radiology | 2008
Tong San Koh; Choon Hua Thng; Puor Sherng Lee; Septian Hartono; Helmut Rumpel; Boon Cher Goh; Sotirios Bisdas
This study was institutional review board approved, with waived patient consent for retrospective analysis of the data. The hepatic perfusion at dynamic contrast material-enhanced magnetic resonance (MR) imaging was commonly described and assessed by using a dual-input one-compartment tracer kinetics model. Although the tracer kinetics in normal liver parenchyma can be described by using a single compartment, functional changes in the tumor microenvironment can result in distinctly different tracer behavior that entails a second tissue compartment. A dual-input two-compartment model is proposed to describe the tracer behavior in hepatic metastases. The authors applied this model to the dynamic MR imaging data obtained in three patients. Perfusion parameter maps and region-of-interest analysis revealed that tracer behavior in hepatic metastases-in contrast to that in surrounding normal liver tissue, which effectively involves one compartment-can be described by using two compartments.
Cell | 2012
Qiang Wen; Benjamin Goldenson; Serena J. Silver; Monica Schenone; Vlado Dančík; Zan Huang; Lingzhi Wang; Tim Lewis; W. Frank An; Xiaoyu Li; Mark Anthony Bray; Clarisse Thiollier; Lauren Diebold; Laure Gilles; Martha S. Vokes; Christopher B. Moore; Meghan Bliss-Moreau; Lynn VerPlank; Nicola Tolliday; Rama K. Mishra; Sasidhar Vemula; Jianjian Shi; Lei Wei; Reuben Kapur; Cécile K. Lopez; Bastien Gerby; Paola Ballerini; Françoise Pflumio; D. Gary Gilliland; Liat Goldberg
The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.
Trends in Pharmacological Sciences | 2016
Nicholas L. Syn; Lingzhi Wang; Gautam Sethi; Jean Paul Thiery; Boon Cher Goh
Exosomes are extracellular signalosomes that facilitate eukaryotic intercellular communication under a wide range of normal physiological contexts. In malignancies, this regulatory circuit is co-opted to promote cancer cell survival and outgrowth. Tumour-derived exosomes (TDEs) carry a pro-EMT (epithelial-mesenchymal transition) programme including transforming growth factor beta (TGFβ), caveolin-1, hypoxia-inducible factor 1 alpha (HIF1α), and β-catenin that enhances the invasive and migratory capabilities of recipient cells, and contributes to stromal remodelling and premetastatic niche formation. The integrin expression patterns on TDEs appear to dictate their preferential uptake by organ-specific cells, implying a crucial role of this pathway in organotropic metastasis. Through the expression of immunomodulatory molecules such as CD39 and CD73, TDEs modify the immune contexture of the tumour microenvironment, which could have implications for immunotherapy. Hence, targeting TDE dysregulation pathways, such as the heparanase/syndecan-1 axis, could represent novel therapeutic strategies in the quest to conquer cancer.