We are interested in circular RNAs expressed in Epstein Barr Virus (EBV)-associated diseases including Nasopharyngeal carcinoma (NPC). Circular RNAs (circRNAs) are a class of non-coding RNAs of various lengths that, unlike linear RNAs, are formed from covalently closed circles where 3’ and 5’ ends are jointed together via backsplicing event. These circRNAs are usually developmental stage and cell type-specific. Essentially, once thought to be by-product of RNA splicing or RNA-sequencing error, circRNAs are found to be biologically important for gene regulation. CircRNAs have been reported to act as miRNA sponges by serving as competitive inhibitors that suppress the ability of miRNA to bind its mRNA targets. CircRNAs are also found to interact with RNA-binding proteins (RBPs) to store, sort, or localize RBPs, and probably regulate the function of RBPs. The full spectrum of circRNA function remains to be discovered but it is a promising therapeutic target or biomarker for diseases including cancer. To date, it remains largely unknown of the pathogen and host cell circRNA gene expression profile in NPC as well as its role in the development and progression of NPC. We aim to investigate the biological role of these circRNAs expressed in NPC and its potential use for NPC diagnosis or treatment.

NPC is closely associated with Epstein-Barr virus (EBV) infection. The overarching aim of our research program is to understand which genetic abnormalities are responsible for causing NPC in order to develop better ways to manage this disease. Our research focuses on (1) Defining the key molecular changes that result in normal cells to transforming into cancerous cells: Using high-throughput genome-wide technologies and functional studies, we have identified a number of signalling pathways that are involved in the pathogenesis of NPC, which represent potential therapeutic targets for this disease; (2) Elucidating the role of EBV infection in the development of NPC: We have determined the contribution of EBV to the gene expression program of NPC and the oncogenic function of EBV-encoded genes in driving the development of NPC is a key direction of investigation. We are also defining the molecular alterations involved in the establishment of stable EBV infection in nasopharyngeal epithelial cells which will provide essential information on the progression of NPC; (3) Understanding the suppressive role of the tumour microenvironment in NPC: We are investigating how EBV infection and stromal cells affect anti-tumour T cell responses with the ultimate aim of refining EBV-based immunotherapy strategies.

Our lab is working on the mechanism of chromosome rearrangement in nasopharyngeal carcinoma (NPC). We hypothesise that the apoptotic nuclease is playing a direct role in chromosome breakages that eventually lead to chromosome rearrangement upon erroneous DNA repair. Our work demonstrated that oxidative stress as well as bile acid induced apoptosis, with the activation of caspases, leading to chromosomes breaks within the AF9 gene. The AF9 gene was of particular interest because it locates at a common deletion site in NPC and it is also a frequent translocation partner for the MLL gene in leukaemia. In addition, we also demonstrated that overexpression of the Epstein-Barr Virus genes such as LMP1 and EBNA1 resulted in similar chromosome breakages. This has prompted us to look into virus reactivation as one of the contributors to NPC carcinogenesis.

My research group focus on studying the roles of ribosomal protein (RP) genes in the context of their association with nasopharyngeal carcinoma (NPC). Over the years, we have identified several NPC-associated RP genes. We are still looking for more candidates. Besides this, we have also identified protein targets / partners of some of these NPC-associated RP genes. This has enabled us to unravel RP-mediated pathways that correlates with NPC tumourigenesis. In addition to these, we have also been studying various purified natural compounds on their anticancer potentials in NPC scenario. The latest addition to our research is the meta-analysis of structural and functional genetic data pertaining to NPC in order construct a comprehensive NPC biomedical profile. With this, we aim to innovate a model for the risk prediction of NPC.

VT3996-301 is a Phase 1b/2, open-label, multicenter study designed to evaluate the safety and preliminary efficacy of oral nanatinostat and valganciclovir alone and in combination with IV pembrolizumab in patients with EBV+RM-NPC. Patients with RM-NPC who have received at least 1 prior line of platinum-based chemotherapy, and no more than 3 prior lines of therapy for RM-NPC will be enrolled. Patients will be randomly assigned 1:1 to receive nanatinostat and valganciclovir with or without pembrolizumab to assess the preliminary anti-tumor activity, safety, tolerability and ORR of each regimen.

KO-TIP-007 is an international, multicenter, open-label single- arm pivotal study. AIM-HN substudy within KO-TIP-007 is an interventional open label, single arm, pivotal study evaluating the efficacy of tipifarnib in HRAS mutant. Patients with HRAS mutations, who have failed at least one prior line of systemic platinum-based therapy, will receive treatment with tipifarnib. The primary objective of AIM-HN is to determine the ORR of tipifarnib in subjects with HNSCC with HRAS mutations and a VAF≥20%, as assessed by IRF.

Selected Publications: Tan, Sing Ean; Satar, Nur Fadhlina Abdul; Majid, Hazreen Abdul (2022). Effects of immunonutrition in head and neck cancer patients undergoing cancer treatment - a systematic review, Frontiers in Nutrition. 9, 821924.

Satar, N. F. A., Von, C. E., Yuin, J. L. P., & Ruey, N. M. (2020). A case of nasopharyngeal carcinoma and precious pregnancy. Medical Journal of Malaysia, 75(6), 738-741.

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Nasopharyngeal carcinoma (NPC) is an aggressive tumour with significant percentage of patients develop distant metastases. NPC and its complex tumour microenvironment (TME) are essential for various aspects of macroscopic tumour growth, maintenance, invasion, metastasis and angiogenesis. Currently conventional two-dimensional (2D) monolayer cell-based assay for metastasis mechanistic study are often carried out in the absence of TME, and also its architecture generally fails to translate accurately the in vivo setting. It had been proven that cancer cells invasion could be enhanced through interactions with stromal cells. Hence, the true biology of metastasis in invasion are poorly representative and understood. With the aim to overcome these limitations, heterotypic multicellular tumour spheroids (MCTS) consisting of 3D co-cultures of cancer and stromal cells (fibroblast and endothelial cells) enable us to create a cell-supportive environment and cell-to-matrix interactions that recapitulates the interactions. Thus, this proposal seeks to develop hetero-type multicellular tumour spheroid of metastatic nasopharyngeal carcinoma with NPC, fibroblast and endothelial cell lines and characterize the early events of metastasis in real-time through real-time cellular analyser. As more than 80% of the NPC patients present with distant metastasis at diagnosis, it is very crucial to be able to predict the metastasis in NPC. Unfortunately, there is currently no reliable model to predict metastasis in NPC. Hence by looking at the early events of metastasis (MCTS will be harvest when the first cell start to invade) and gene profiling of MCTS through RNAseq, comparison data mining from the open source, identification of the biomarker(s) enables us to detect when a tumour initiates the metastasis and detect the possibility of metastasis before it happen. In future, it will throw light and enables to aid cancer metastasis research which best mimic the specificity and eventually provide a platform to more efficiently develop and evaluate anti-metastasis cancer therapies.

Selected Publications: Su, Z.Y., Siak, P.Y., and Cheah, S.C. (2023). The Role of Epstein-Barr virus in Nasopharyngeal Carcinoma. Frontiers in Microbiology. (Accepted)

Su, Z.Y., Siak, P.Y., Leong, C.H., and Cheah, S.C. (2022) Nasopharyngeal Carcinoma and its Microenvironment: Past, Current and future Perspectives. Frontiers in Oncology. 12: 840467.

Siak, P.Y., Khoo, S.B., Leong, C.H., Hoh, B.P. and Cheah, S.C. (2021) Current Status and Future Perspectives About Molecular Biomarkers Of Nasopharyngeal Carcinoma. Cancers, 13(14): 3490.

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