A/Prof Christopher Beng Ti Ang
MBBS, FRCSEd(SN), FAMSSenior Consultant, Department of Neurosurgery Principal Investigator, Neuro-Oncology Research Laboratory
A/Prof Carol TangVisiting Academic, Research, Neuro-Oncology Research Laboratory
Contact Information
Neuro-Oncology Research LaboratoryNational Neuroscience Institute11 Jalan Tan Tock Seng, Singapore 308433Tel: (65) 6357 7549 (Lab) Email: ang.beng.ti@singhealth.com.sg
The Team
Overview
The Neuro-Oncology Research Laboratory at National Neuroscience Institute is dedicated to elucidating the molecular underpinnings of glioblastoma (GBM) and delineating the complex cellular mechanisms dictating microenvironmental influences on GBM disease states, invasiveness and treatment resistance, consequently enabling the development of truly effective therapeutic strategies and improving clinical outcomes. Under the scientific leadership of both A/Profs Christopher Ang Beng Ti and Carol Tang, the laboratory has established significant milestones in setting up the NNI brain tumor resource (Glioportal) comprising patient-derived cells, orthotopic xenograft mouse models and clinical material fully annotated with deep content molecular data (Figure 1). This aids in facilitating the transition of cutting-edge therapeutic methods from research to clinical application, bridging the gap from bench to bedside.
Figure 1. Glioportal brain tumor resource, a subset of the NNI Tissue Bank. Bank set-up; Top panel describes the organizational workflow. A trusted third party (TTP) maintains the link between the clinical and research teams; latter which works with de-identified material and information. Middle panel details the materials collected. Bottom panel elaborates on the type of research empowered by Glioportal.
FFPE, formalin-fixed paraffin-embedded; CSF, cerebrospinal fluid; IRB, Institutional Review Board.
Our laboratory first started in June 2005 with a focus on the establishment of patient-derived glioma-propagating cells (GPCs) (Chong et al., 2009; Foong et al., 2011). Furthermore, we showed that GPCs established from patient tumors with similar histology are transcriptomically distinct, highlighting the limitation of histology to diagnose and subsequently treat patients. Indeed, several works from our laboratory further supported the advancement of genomic technologies in assessing brain tumors and validate future studies utilizing patient-derived GPCs as a clinically relevant cellular platform (Chong et al., 2016; Choudhury et al., 2012; Foong et al., 2012; Koh et al., 2013; Ng et al., 2012; Xu et al., 2018; Yeo et al., 2012). Importantly, these foundational studies suggest that inter-tumor molecular heterogeneity dictates responsiveness to targeted therapeutic strategies. In our recent study published in Nature Communications (Tan et al., 2019), we investigated mechanisms that potentiate the tissue heterogeneity and aggressiveness of GBMs and found proneural-mesenchymal transition (PMT), a molecular subtype “switch”, is a key event upon recurrence. Importantly, we provided proof-of-concept that our STAT3 functionally-tuned gene signature identified potential responders of STAT3 inhibition therapy (STAT3-high) and enriched for the more aggressive mesenchymal class (Figure 2). We show that the STAT3 response predicted in patient tumors illustrates a key aspect of precision medicine. Significantly, we demonstrated using patient-derived cells and animal models that STAT3-high clinical material showed favorable response to AZD1480, a potent STAT3 inhibitor in clinical trials.
Figure 2. STAT3 functionally-tuned gene signature stratifies patient survival independent of current clinical indicators. Left panel Identification of STAT3 as a key regulator for proneural-mesenchymal transition (PMT). STAT3-high GBM patient cohort was enriched in mesenchymal and classical molecular subtypes. STAT3-low tumors, in contrast, comprised mostly the proneural molecular subtype. Right panel STAT3-high clinical material showed favorable response to STAT3 inhibitor AZD1480.
Since then, this forward-looking bank has empowered capabilities in the team’s preclinical investigations. Both A/Profs Christopher Ang Beng Ti and Carol Tang were awarded the Neuro-Oncology Translational and Clinical Research (TCR) Flagship Program Grant and the Open Fund Large Collaborative Grant (OF-LCG) in 2016 and 2021 respectively. Currently, a key limitation in clinical practice is the inability to accurately and rapidly monitor disease progression where repeat surgery is not always possible, due to the invasiveness of tumor cells (Chong et al., 2016; Choudhury et al., 2012; Ma et al., 2016; Monzo et al., 2021), as well as location of tumor tissue in eloquent areas of the brain. It is thus imperative that any solution must account for such tumor molecular heterogeneity and translate current molecular stratification towards a functional/therapeutic and curative outcome. Working with long-term key collaborators, Prof Patrick Tan and Dr Huilin Shao, Glioportal has facilitated the elucidation of actionable therapeutic vulnerabilities mediating tumor recurrence (Cheng et al., 2021; Cheng et al., 2024), as well as the establishment of novel diagnostic technologies (Bae et al., 2021; Bae et al., 2018; Wang et al., 2020; Zhang et al., 2023) utilizing predictive biomarker profiles. Together with our collaborator A/Prof Huilin Shao, we have created a minimally invasive nanosensor diagnostic platform capable of detecting composite biomarker signatures represented in nucleic acid, glycan and protein profiles (Wang et al., 2020; Zhang et al., 2023). We have shown proof-of-concept data that we are now able to assess transcriptomic signatures with high accuracy and sensitivity using patient serum (exosomal RNA markers) (Zhang et al., 2023), thus allowing for longitudinal monitoring of disease progression and bringing forth new clinical opportunities for the implementation of targeted therapies in stratified patient cohorts. These findings underscore a paradigm shift in GBM diagnosis where molecular stratification of patients with associated clinical information, rather than sole reliance on morphological features of tumor tissue, guides treatment decision. Our lab’s goal is thus to capitalize on Glioportal resources in order to improve the outcome of patients with malignant GBM through continued multidisciplinary, integrated, flexible and highly translational research approaches by identifying novel targeted therapies for a curative outcome.
Selected Publications
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