Publications by authors named "Kah Weng Lau"

8 Publications

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Intra-tumoral CD39CD8 T cells predict response to PD-1/PD-L1 blockade in patients with NSCLC.

J Thorac Oncol 2021 May 8. Epub 2021 May 8.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore. Electronic address:

Background: Programmed cell death-1 (PD-1)/ programmed death-ligand 1 (PD-L1) blockade is currently widely used in the treatment of metastatic non-small cell lung cancer (NSCLC). Despite available biomarker stratification, clinical responses vary. Thus, the search for novel biomarkers with improved response prediction is ongoing. Previously, using mass cytometry deep immune-profiling (CyTOF), our group provided evidence that CD39CD8 T cells represent tumor antigen-specific, cytotoxic T cells in treatment-naïve NSCLC. We hypothesized that accurate quantitation of this T cell subset would predict immunotherapy outcome.

Methods: In order to translate this to a clinical setting, the present study compared CyTOF data to results obtained via a range of clinically relevant methods; including conventional immunohistochemistry (IHC), multiplex immunohistochemistry/immunofluorescence (mIHC/IF), and gene expression assay by NanoString.

Results: Quantification using mIHC/IF but not conventional IHC or NanoString correlated with the CyTOF results. The specificity and sensitivity of mIHC/IF was then assessed in a separate retrospective NSCLC cohort. CD39CD8 T cell proportion, as determined by mIHC/IF, successfully stratified responders and non-responders to PD-1/PD-L1 inhibitors (Objective Response Rate 63.6%, compared to 0% for the negative group). This predictive capability was independent from other confounding factors, such as total CD8 T cell proportion, CD39 lymphocyte proportion, PD-L1 positivity, epidermal growth factor receptor mutation status, and other clinicopathological parameters.

Conclusion: Our results suggest that the mIHC/IF platform is a clinically relevant method to assess CD39CD8 T cell proportion and this marker can serve as a potential biomarker that predicts response to PD-1/PD-L1 blockade in NSCLC patients. Further validation in additional NSCLC cohorts is warranted.
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http://dx.doi.org/10.1016/j.jtho.2021.04.016DOI Listing
May 2021

Expanded molecular interrogation for potential actionable targets in non-squamous non-small cell lung cancer.

Ann Transl Med 2017 Sep;5(18):372

Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

The advent of targeted therapies has established new standards of care for defined molecular subsets of non-small cell lung cancer (NSCLC). Not only has this led to significant changes in the routine clinical management of lung cancer e.g., multiplexed genomic testing, but it has provided important principles and benchmarks for determining "actionability". At present, the clinical paradigms are most evolved for EGFR mutations and ALK rearrangements, where multiple randomized phase III trials have determined optimal treatment strategies in both treatment naïve and resistant settings. However, this may not always be feasible with low prevalence alterations e.g., ROS1 and BRAF mutations. Another emerging observation is that not all targets are equally "actionable", necessitating a rigorous preclinical, clinical and translational framework to prosecute new targets and drug candidates. In this review, we will cover the role of targeted therapies for NSCLC harbouring BRAF, MET, HER2 and RET alterations, all of which have shown promise in non-squamous non-small cell lung cancer (ns-NSCLC). We further review some early epigenetic targets in NSCLC, an area of emerging interest. With increased molecular segmentation of lung cancer, we discuss the upcoming challenges in drug development and implementation of precision oncology approaches, especially in light of the complex and rapidly evolving therapeutic landscape.
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http://dx.doi.org/10.21037/atm.2017.08.42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635263PMC
September 2017

Incidental Multiple Pulmonary Nodules in a Middle-Aged Woman.

Ann Acad Med Singap 2017 Feb;46(2):79-80

Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore.

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February 2017

The curious incident of 3 melanomas and their possible origins-A case report and review of literature.

Int J Surg Case Rep 2016 13;23:77-81. Epub 2016 Apr 13.

Division of Surgical Oncology, National Cancer Centre Singapore, Singapore.

Background: We describe an unusual case of 2 intra-parenchymal breast melanomas with a concomitant subcutaneous melanoma in the ipsilateral upper limb and no definite primary lesion.

Case Report: Our patient is a 40-year-old Chinese female who presented with a breast lump in her left breast for which excision biopsy showed melanoma. A PET-CT revealed a second lesion in her breast. A left upper arm nodule with no overlying skin changes was also noted. She underwent a mastectomy and excision biopsy of the upper arm nodule. Histology showed that the second breast lesion was also a melanoma, while the arm nodule contained melanoma cells within a fibrous capsule.

Conclusion: The presence of a melanoma in the breast should prompt a close and meticulous search for a primary lesion and potential signs of metastasis. Encapsulated subcutaneous nodules can be attributed to replaced lymph nodes or subcutaneous melanoma which can be either primary dermal melanoma or metastasis from an unknown primary.
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http://dx.doi.org/10.1016/j.ijscr.2016.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855744PMC
June 2016

Ciliated muconodular papillary tumor: a solitary peripheral lung nodule in a teenage girl.

Hum Pathol 2016 Mar 28;49:22-6. Epub 2015 Oct 28.

Department of Pathology, Histopathology Section, Singapore General Hospital, Singapore 169856, Singapore. Electronic address:

Papillary tumors of the peripheral lung containing ciliated cells and extracellular mucin include solitary peripheral ciliated glandular papilloma, ciliated muconodular papillary tumor, and well-differentiated papillary adenocarcinoma with cilia formation. We report the case of a 19-year-old woman who was a nonsmoker and presented with an incidental small peripheral lung nodule. The resection specimen showed a soft grayish nodule. Histologic examination further revealed a relatively circumscribed mucinous nodule featuring a tubulopapillary tumor composed of ciliated columnar cells and goblet cells, accompanied with abundant extracellular mucin. No lepidic growth pattern was evident. The tumor cells were immunoreactive for cytokeratin 7, thyroid transcription factor-1, and carcinoembryonic antigen, whereas p63 and cytokeratin 5/6 highlighted the presence of basal cells. Next-generation sequencing did not identify any genetic alterations in targeted regions and mutational hotspots of a panel of 22 genes commonly implicated in lung and colon cancers. Taken together, our case was most likely a ciliated muconodular papillary tumor.
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http://dx.doi.org/10.1016/j.humpath.2015.09.038DOI Listing
March 2016

Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma.

Anticancer Res 2009 Nov;29(11):4337-43

Department of Medical and Molecular Genetics, University of Birmingham, Institute of Biomedical Research, Edgbaston, Birmingham, B15 2TT, UK.

Background: Inactivation of the Von Hippel-Lindau (VHL) tumour suppressor gene leading to overexpression of hypoxia-inducible transcription factors (HIF)-1alpha and -2alpha is a critical event in the pathogenesis of most clear cell renal cell carcinomas (RCC). HIF-1alpha and HIF-2alpha share significant homology and regulate overlapping repertoires of hypoxia-inducible target genes but may have differing effects on RCC cell growth. Loss of HIF-1alpha expression has been described in RCC cell lines and primary tumours. Whether mutations in the alpha-subunits of HIF-1alpha and HIF-2alpha contribute to renal tumourigenesis was investigated here.

Materials And Methods: Mutation analysis of the complete coding sequence of HIF-1alpha and HIF-2alpha was carried out in primary RCC (n=40).

Results: The analysis revealed a somatic HIF1A missense substitution, p.Val116Glu, in a single RCC. Functional studies demonstrated that p.Val116Glu impaired HIF-1alpha transcriptional activity. Genotyping of HIF1A variants p.Pro582Ser and p.Ala588Thr demonstrated no significant differences between RCC patients and controls.

Conclusion: The detection of a loss-of-function HIF1A mutation in a primary RCC is consistent with HIF-1 and HIF-2 having different roles in renal tumourigenesis, However, somatic mutations of HIF1A are not frequently implicated in the pathogenesis of RCC.
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November 2009

Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma.

Mol Cell Biol 2005 Jul;25(13):5675-86

The Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom.

Defective function of the von Hippel-Lindau (VHL) tumor suppressor ablates proteolytic regulation of hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha), leading to constitutive activation of hypoxia pathways in renal cell carcinoma (RCC). Here we report a comparative analysis of the functions of HIF-1alpha and HIF-2alpha in RCC and non-RCC cells. We demonstrate common patterns of HIF-alpha isoform transcriptional selectivity in VHL-defective RCC that show consistent and striking differences from patterns in other cell types. We also show that HIF-alpha isoforms display unexpected suppressive interactions in RCC cells, with enhanced expression of HIF-2alpha suppressing HIF-1alpha and vice-versa. In VHL-defective RCC cells, we demonstrate that the protumorigenic genes encoding cyclin D1, transforming growth factor alpha, and vascular endothelial growth factor respond specifically to HIF-2alpha and that the proapoptotic gene encoding BNip3 responds positively to HIF-1alpha and negatively to HIF-2alpha, indicating that HIF-1alpha and HIF-2alpha have contrasting properties in the biology of RCC. In keeping with this, HIF-alpha isoform-specific transcriptional selectivity was matched by differential effects on the growth of RCC as tumor xenografts, with HIF-1alpha retarding and HIF-2alpha enhancing tumor growth. These findings indicate that therapeutic approaches to targeting of the HIF system, at least in this setting, will need to take account of HIF isoform-specific functions.
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http://dx.doi.org/10.1128/MCB.25.13.5675-5686.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1157001PMC
July 2005

Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans.

PLoS Biol 2004 Oct 7;2(10):e289. Epub 2004 Sep 7.

The Henry Wellcome Building of Genomic Medicine, University of Oxford, Oxford, United Kingdom.

The von Hippel-Lindau (VHL) tumor suppressor functions as a ubiquitin ligase that mediates proteolytic inactivation of hydroxylated alpha subunits of hypoxia-inducible factor (HIF). Although studies of VHL-defective renal carcinoma cells suggest the existence of other VHL tumor suppressor pathways, dysregulation of the HIF transcriptional cascade has extensive effects that make it difficult to distinguish whether, and to what extent, observed abnormalities in these cells represent effects on pathways that are distinct from HIF. Here, we report on a genetic analysis of HIF-dependent and -independent effects of VHL inactivation by studying gene expression patterns in Caenorhabditis elegans. We show tight conservation of the HIF-1/VHL-1/EGL-9 hydroxylase pathway. However, persisting differential gene expression in hif-1 versus hif-1; vhl-1 double mutant worms clearly distinguished HIF-1-independent effects of VHL-1 inactivation. Genomic clustering, predicted functional similarities, and a common pattern of dysregulation in both vhl-1 worms and a set of mutants (dpy-18, let-268, gon-1, mig-17, and unc-6), with different defects in extracellular matrix formation, suggest that dysregulation of these genes reflects a discrete HIF-1-independent function of VHL-1 that is connected with extracellular matrix function.
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http://dx.doi.org/10.1371/journal.pbio.0020289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC515368PMC
October 2004