Publications by authors named "Phuong Luong"

5 Publications

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Dismantling the bacterial glycocalyx: Chemical tools to probe, perturb, and image bacterial glycans.

Bioorg Med Chem 2021 Jul 7;42:116268. Epub 2021 Jun 7.

Department of Chemistry & Biochemistry, Bowdoin College, 6600 College Station, Brunswick, ME 04011, USA. Electronic address:

The bacterial glycocalyx is a quintessential drug target comprised of structurally distinct glycans. Bacterial glycans bear unusual monosaccharide building blocks whose proper construction is critical for bacterial fitness, survival, and colonization in the human host. Despite their appeal as therapeutic targets, bacterial glycans are difficult to study due to the presence of rare bacterial monosaccharides that are linked and modified in atypical manners. Their structural complexity ultimately hampers their analytical characterization. This review highlights recent advances in bacterial chemical glycobiology and focuses on the development of chemical tools to probe, perturb, and image bacterial glycans and their biosynthesis. Current technologies have enabled the study of bacterial glycosylation machinery even in the absence of detailed structural information.
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http://dx.doi.org/10.1016/j.bmc.2021.116268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276522PMC
July 2021

Structure-based analysis of Bacilli and plasmid dihydrofolate reductase evolution.

J Mol Graph Model 2017 01 22;71:135-153. Epub 2016 Nov 22.

Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-1030, USA; Department of Chemistry, Southwestern College, 900 Otay Lakes Rd., Chula Vista, CA 91910, USA. Electronic address:

Dihydrofolate reductase (DHFR), a key enzyme in tetrahydrofolate-mediated biosynthetic pathways, has a structural motif known to be highly conserved over a wide range of organisms. Given its critical role in purine and amino acid synthesis, DHFR is a well established therapeutic target for treating a wide range of prokaryotic and eukaryotic infections as well as certain types of cancer. Here we present a structural-based computer analysis of bacterial (Bacilli) and plasmid DHFR evolution. We generated a structure-based sequence alignment using 7 wild-type DHFR x-ray crystal structures obtained from the RCSB Protein Data Bank and 350 chromosomal and plasmid homology models we generated from sequences obtained from the NCBI Protein Database. We used these alignments to compare active site and non-active site conservation in terms of amino acid residues, secondary structure and amino acid residue class. With respect to amino acid sequences and residue classes, active-site positions in both plasmid and chromosomal DHFR are significantly more conserved than non-active site positions. Secondary structure conservation was similar for active site and non-active site positions. Plasmid-encoded DHFR proteins have greater degree of sequence and residue class conservation, particularly in sequence positions associated with a network of concerted protein motions, than chromosomal-encoded DHFR proteins. These structure-based were used to build DHFR specific phylogenetic trees from which evidence for horizontal gene transfer was identified.
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http://dx.doi.org/10.1016/j.jmgm.2016.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203806PMC
January 2017

Arginine Deprivation With Pegylated Arginine Deiminase in Patients With Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial.

JAMA Oncol 2017 Jan;3(1):58-66

Barts Health NHS Trust, St Bartholomew's Hospital, London, England.

Importance: Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer.

Objective: To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma.

Design, Setting, And Participants: A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma.

Interventions: Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m2, weekly intramuscular) plus best supportive care (BSC) or BSC alone.

Main Outcomes And Measures: The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti-ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18F-fluorodeoxyglucose positron-emission tomography.

Results: Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, -1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS.

Conclusions And Relevance: In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers.

Trial Registration: clinicaltrials.gov Identifier: NCT01279967.
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http://dx.doi.org/10.1001/jamaoncol.2016.3049DOI Listing
January 2017

Prognostic and therapeutic impact of argininosuccinate synthetase 1 control in bladder cancer as monitored longitudinally by PET imaging.

Cancer Res 2014 Feb 27;74(3):896-907. Epub 2013 Nov 27.

Authors' Affiliations: Barts Cancer Institute-a Cancer Research UK Center of Excellence, John Vane Science Center, Queen Mary University of London; Department of Medicine, Imperial College, Charing Cross Campus; St Bartholomew's Hospital, Barts Health NHS Trust, West Smithfield, London; Wellcome Trust Center for Human Genetics, Oxford; Cancer Research UK Cambridge Research Institute, Li Ka Shing Center; Hutchison/MRC Research Center, University of Cambridge, Medical Research Council Cancer Unit; Pharmacometrics Ltd., Cambridge; Dundee Cancer Center, University of Dundee, Ninewells Hospital, Dundee, United Kingdom; Laboratory of Cancer Genetics and Translational Oncology, S Croce General Hospital, Cuneo, Italy; Department of Structural Biology, Medical University of Lodz, Lodz, Poland; Polaris Group, San Diego, California; Department of Pathology, Chi-Mei Medical Center; Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan; and National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.

Targeted therapies have yet to have significant impact on the survival of patients with bladder cancer. In this study, we focused on the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) as a therapeutic target in bladder cancer, based on our discovery of the prognostic and functional import of ASS1 in this setting. ASS1 expression status in bladder tumors from 183 Caucasian and 295 Asian patients was analyzed, along with its hypothesized prognostic impact and association with clinicopathologic features, including tumor size and invasion. Furthermore, the genetics, biology, and therapeutic implications of ASS1 loss were investigated in urothelial cancer cells. We detected ASS1 negativity in 40% of bladder cancers, in which multivariate analysis indicated worse disease-specific and metastasis-free survival. ASS1 loss secondary to epigenetic silencing was accompanied by increased tumor cell proliferation and invasion, consistent with a tumor-suppressor role for ASS1. In developing a treatment approach, we identified a novel targeted antimetabolite strategy to exploit arginine deprivation with pegylated arginine deiminase (ADI-PEG20) as a therapeutic. ADI-PEG20 was synthetically lethal in ASS1-methylated bladder cells and its exposure was associated with a marked reduction in intracellular levels of thymidine, due to suppression of both uptake and de novo synthesis. We found that thymidine uptake correlated with thymidine kinase-1 protein levels and that thymidine levels were imageable with [(18)F]-fluoro-L-thymidine (FLT)-positron emission tomography (PET). In contrast, inhibition of de novo synthesis was linked to decreased expression of thymidylate synthase and dihydrofolate reductase. Notably, inhibition of de novo synthesis was associated with potentiation of ADI-PEG20 activity by the antifolate drug pemetrexed. Taken together, our findings argue that arginine deprivation combined with antifolates warrants clinical investigation in ASS1-negative urothelial and related cancers, using FLT-PET as an early surrogate marker of response.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-1702DOI Listing
February 2014

Metabolic response to pegylated arginine deiminase in mesothelioma with promoter methylation of argininosuccinate synthetase.

J Clin Oncol 2013 Mar 14;31(7):e111-3. Epub 2013 Jan 14.

Barts Cancer Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M6BQ, England, UK.

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http://dx.doi.org/10.1200/JCO.2012.42.1784DOI Listing
March 2013
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