Hepatocellular carcinoma (HCC) continues to pose a significant unmet clinical need that can only be addressed by rigorous and sustained translational and clinical research. Despite being the sixth-most common cancer worldwide, it is the second-most common cause of cancer-related deaths globally. Unfortunately, almost 80% of all HCC cases are found in the Asia-Pacific region, because of the high incidence of viral hepatitis and the increasing rates of steato-hepatitis. Although early-stage HCC can be treated with potentially curative ablative therapies, such as surgical resection, most patients present at intermediate or advanced stages of the cancer.
Central to the challenge of HCC is the absence of efficacious systemic therapy, which can augment ablative or loco-regional therapies. The highly heterogeneous intra- and inter-patient genomic, immunomic, and metabolic profiles of HCC remain incompletely understood, and there is currently no validated therapeutic biomarker for the cancer. Liver cancer research at the NCCS spans the entire spectrum of Discovery, Translation and Application to address this urgent unmet clinical need. Fundamental research on molecular carcinogenesis and genomics anchors the programme at one end, with translational research on immunomics, targeted therapies, and in vivo models linking these facets to clinical research.
The clinical end of the research spectrum is linked to the NCCS led 40-member, multi-centre Asia-Pacific Hepatocellular Carcinoma Trials Group, which has conducted six prospective multi-centre trials.
Translational research at the NCCS leverages on three nationally funded programmes, namely the NMRC Translation-Clinical Research Flagship Programme in Liver Cancer, the NMRC Large-Collaborative Grant Virus-Induced Cancer: Translational Oncology Research & immunology programme and the BMRC IAF-PP funded Patient-specific diagnostic and predictive platform for Precision Medicine in HCC.
The Laboratory of Molecular Carcinogenesis (Prof. Kanaga Sabapathy) focuses on the mechanistic basis of cancer development and resistance to therapeutic drugs, and translates the findings to generate effective therapies for cancer. Multiple, nationally funded projects are undertaken by the team. “Generation and Characterisation of Mouse Models for Cancers” focuses on: 1) Understanding the development of liver cancers, especially thosethat arise in conjunction with hepatitis B virus, to identify biomarkers for early detection and altered molecular pathways for therapeutic targeting; 2) Generating mouse models to recapitulate the development of liposarcomasfor testing novel treatment modalities; and 3) Understanding the cellular basis of breast cancer development, with a particular focus on the role of the stromal microenvironment in contributing to breast neoplasms. The use of the mouse as a model organism has provided us with significant advantages in our understanding of multiple cancer types.
“Targeting p53 Family Members” characterises the various p53 mutants identified in humans, which has led to the concept of the “rainbow of p53 mutants”, all of which display varying degrees of oncogenic potential. Based on this concept, we have developed novel, first-in-class, mutation-specific antibodies that are useful in the clinical diagnosis of mutants. We are working toward using these antibodies, as well as mutation-specific siRNAs, to target mutant p53 to improve treatment. Similar work is also underway to understand the functions of p73—a homologue of p53—to target its oncogenic functions in tumours.
The Bek Chai Heah Laboratory of Cancer Genomics (Prof. Kam Man Hui) employs unbiased genome-wide strategies to survey relevant human HCC tissues to identify key genes/ regulatory pathways that are altered in HCC. The laboratory seeks to understand how these changes affect the carcinogenesis of HCC with the aim of modulating these regulatory pathways to combat HCC. Molecular evidence is systematically gathered and clinically corroborated to discover molecular biomarkers that, independently from clinical risk factors, can provide clinicallymeaningful avenues for designing strategies to decipher the underlying molecular networks leading to HCC recurrence. This in turn is used to identify reliable diagnostic and prognostic molecular biomarkers and to develop novel therapeutics for HCC. The group has recently identified microtubule-associated Protein Regulator of Cytokinesis 1 (PRC1) as a new factor that is overexpressed in HCC and that promotes recurrence. Deciphering the role PRC1 plays in cell proliferation and migration helped to explain how PRC1 activates the Wnt/β- catenin pathway and how its expression is controlled by Wnt signalling (Chen et al., Gut, 2016). To address metastatic HCCdisease, the group collaborates with the Institute of Molecular and Cell Biology, Singapore. In a recent paper, the group show that, compared with its Golgi-localised counterpart, ER-G1 glycosylates the matrix metalloproteinase MMP14, a process required for tumour expansion (Nguyen et al., Cancer Cell, 2017). The group has also explored novel therapeutics: the group recently synthesised a Pt nanocluster assembly (Pt-NA) composed of assembled platinum nanoclusters that incorporate a pH-sensitive polymer and HCC-targeting peptide to target chemo-resistant HCC (Xia et al., ACS Central Sci, 2016). Future research will focus on the identification and characterisation of molecular biomarkers to detect early HCC disease and to dissect the heterogeneity and drug resistance associated with HCC using CRISPR–Cas9-based strategies.
The Hepatobiliary Cancer Programme (Prof. Bin Tean Teh) focuses on genomic and epigenomic profiling of both HCC and cholangiocarcinoma (CCA). In collaboration with Prof. Steve Rozen of Duke-NUS and other international collaborators, the group recently found high frequencies of a mutational signature in HCC related to a known herbal carcinogen, aristolochic acid (AA), in certain Asian countries (Ng et al., 2017 STM). This significant implication raises awareness of the risks of AA exposure and has led regulatory agencies to formulate strict policies on the use of AA-containing herbal supplements.
The group also investigates liver fluke (collective name for parasitic worms)-related CCA, which is endemic in the northeast part of Thailand and neighbouring countries, including Cambodia and Laos, and in other parts of the world, including Singapore. This has led to the development of a CCA-specific programme at the International Cancer Genomic Consortium. The group published the first genomic landscape of fluke and non-fluke related CCA, identifying numerous novel CCArelated genes and showing a difference in the spectrum andfrequency of gene alterations between the two groups (Ong et al., Nature Genet, 2012; Chan-on et al., Nature Genet, 2013). The group’s latest integrated analysis of fluke and non-flukeassociated CAA (Jusakul et al., Cancer Discov, 2017) revealed four molecular subtypes, laying the foundation for future umbrella clinical trials based on genomic and epigenomic profiles of the tumours. Importantly, the latter can be further manipulated anddeveloped into biomarkers for early detection and screening, as well as for monitoring the disease.
The Liver Cancer Functional Genomics Laboratory (Assoc. Prof. Caroline Lee) has three major focuses. The first is to understand the role of chronic inflammation in tumorigenesis to facilitate the development of strategies to intervene with this process. FAT10 has been identified as a molecule that plays an important role in liver cancers associated with chronic inflammation. Currently, the group aims to determine how polymorphisms in the molecule modulate cancer risk, and are exploring strategies to target this molecule. The second focus is to elucidate the role of hepatitis B virus (HBV) in cancer development. Comprehensive characterisation of the integration of HBV into the host genome in patients with HCC at both the genomic and transcriptomic levels have been carried out, and chimeric HBV-human transcripts with variable potential for tumorigenesis have been observed. The third focusof the laboratory is to elucidate the role of various non-coding RNAs (including circular RNA, microRNAs and long noncoding RNAs) in HCC. The group has employed an integrative, big-data approach to identify clinically relevant networks of non-coding RNAs in the cancer pathway. Non-coding RNA networks are being characterised for their tumorigenic potential to identify novel molecular biomarkers that can be used to more accurately detect liver cancer at an early stage and/or predict responses to treatments and that can be used as targets for therapy.
The Laboratory of Molecular Endocrinology (Prof. The Hung Huynh) focuses on targeted therapies for solid tumours and the development of patient-derived xenograft (PDX) models. More than 250 xenograft tumour models, including models for HCC, gastric cancer, gastrointestinal stromal tumours, and lung and ovarian cancers, have been developed and utilised for discovery-driven translational research in HCC and gastric cancer. These xenografts are the basis of an important drug testing platform, especially for targeted and combined therapies. The group has profiled the protein expression, gene expression, and mutational analysis of these xenografts. ThisPDX platform is a recognised industry and academic leader in the areas of HCC and gastric cancer drug development, and represents a powerful in vivo model that can be used to investigate ways to repurpose drugs for new indications. The group is developing a humanised HCC mouse (HHM) model by the concurrent transplantation of human haematopoietic stem cells and MHC-mismatched HCC cells into the livers of NOD-scid IL2Rγnull mice; this will provide a cutting-edge technology for drug screening, especially for immunotherapy, target discovery, and validation.
The Programme in Translational and Clinical Liver Research (Prof. Pierce Chow) houses the NMRC Translational-Clinical Research Flagship Programme in Liver Cancer (A Multi-national Cohort Study on the impact of intra-tumoural genomic heterogeneity and the immune micro-environment on the Clinical Trajectory of Resected Hepatocellular Carcinoma – the PLANet study) and the BMRC IAF-PP-funded Patient-specific diagnostic and predictive platform for Precision Medicine in HCC – the PuRPOSE Platform. The NCCS leads these multiinstitutional programmes in collaboration with the Translational Immunology Institute (TII), Singapore; the Genome Institute of Singapore; the Institute of Molecular and Cell Biology (IMCB), Singapore; the Cancer Science Institute, Singapore; the National University Hospital, Singapore; Singapore General Hospital; and the Samsung Medical Center, South Korea. The PLANet study is a discovery programme that investigates the heterogeneity of the multiple “-omics” layers of HCC through multi-region sampling of HCC in a prospective surgical cohort from four countries (Zhai et al., Nat Comm, 2017). Recurrent cancer is sampled and interrogated to elucidate targetable driver mutations, immunomic profiles, and metabolomic moieties. Patient-derived progenitors and xenografts, verified by Sanger sequencing, have been created from the same samples, and a humanised mouse model has been successfully created through collaboration with IMCB (Chen et al., Gut, 2018).
The PuRPOSE Platform is a high-throughput, patient-specific diagnostic and predictive platform that integrates genomics, immunomics, and clinical data, and delivers drug response screening results in clinically relevant timelines (~a few weeks) which is invaluable for patient selection in clinical trials and for therapeutic decision making. The programme collaborates with the Samsung Medical Center to re-purpose their proprietary AVATAR platform to HCC and subsequently to other cancers. Proof-of-principle data of the veracity of this platform in HCChas been obtained.
The secretariat of the Asia-Pacific Hepatocellular Carcinoma (AHCC) Trials Group is also housed in this programme. The AHCC trials group completed their sixth multi-centre HCC trial in 2017 (the SIRveNIB Study across 27 centres in 11 countries; see Chow et al., J Clin Oncol, 2018) and is currently conducting a nine-country, 2,500-patient HCC registry in the Asia-Pacific region.
The Laboratory of Cancer Immunotherapy (Assoc. Prof. Han Chong Toh) houses the NMRC Large-Collaborative Grant funded Virus-Induced Cancer: Translational Oncology Research & immunology programme (the VICTORY Programme). The group carries out multiple investigator-initiated and collaborative industry studies.
Early-phase clinical trials in HCC are carried out at the Experimental Cancer Therapeutics Unit.
The multi-disciplinary Comprehensive Liver Cancer Clinic is the clinical research interface in HCC and conducts multiple investigator-initiated and industry-sponsored studies. Seminal translational research demonstrating significant immune modulation of HCC with radio-embolisation has been recently completed in collaboration with TII (Chew et al., Gut, 2018).
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