Programme in Translational and Clinical Liver Research

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Primary liver cancer or hepatocellular carcinoma (HCC) imposes significant challenges to healthcare with huge unmet clinical needs. HCC is the second leading cause of cancer-related mortality worldwide in males and 80% of HCC are found in the Asia-Pacific. While early-stage HCC is potentially curable by surgical resection, liver transplantation or radiofrequency ablation, recurrences remain common and limits overall survival. Survival in intermediate stage HCC may be prolonged by loco-regional therapy in advanced HCC by systemic therapies. Overall, clinical outcomes in HCC remain poorer than that of other common cancers due to the lack of efficacious systemic therapies. The biology of HCC is intrinsically challenging as HCC is the common end-point of a number of etiologies with different molecular pathways. In addition, significant heterogeneity also exists within the same tumor.

Concerted research leveraging on an inter-disciplinary approach is therefore required to address these challenges. The Program in Translational and Clinical Liver Cancer Research, led by Prof Pierce Chow, is a multi-institutional and multi-national enterprise with NCCS leading translational research platforms and prospective clinical studies in HCC. Nested within the program is the Secretariat of the Asia-Pacific Hepatocellular Carcinoma (AHCC) Trials Group (17 countries, >50 sites) which is currently coordinating an investigator-initiated multi-national randomized phase II trial involving up to 13 sites in the Asia-Pacific. Other active studies under the AHCC Trials Group include a clinical-translational prospective cohort of patients receiving current best-in-class adjuvant therapeutics (AHCC12), surveillance program of 2,000 patients at risk for HCC (AHCC10) and a parallel cohort of 100 HCC patients (AHCC11). Our current portfolio of clinical studies and translational research platforms include:

• Precision Medicine in Liver Cancer across an Asia-Pacific Network 2.0 (PLANet 2.0, comprises of AHCC12 – EMPHASIS and AHCC13). Two prospective, investigator-initiated, multi-national and multi-center study in collaboration with both local clinical sites (CGH, NCCS, NUH, SGH, SKH, TTSH) and across Asia-Pacific. Academic collaborators include GIS, IMCB, NTU, NCCS, NUS-CSI, Duke-NUS, and supported by NMRC Open Fund-Large Collaborative Grant. 
  
  
• Prospective Cohort Study of Changes in Circulatory micro-RNA after Surgical Resection of Hepatocellular Carcinoma (AHCC11) – PROSECT. Investigator-initiated multi-center study in collaboration with clinical sites (CGH, NCCS, NUH, SGH, SKH, TTSH,), academic institutes (NTU, Duke-NUS) and industrial partners (MiRXES Pte Ltd and Asian Microbiome Library Pte Ltd) supported by A*Star Industry Alignment Fund – Industry Collaboration Project (IAF-ICP) Grant.
  

• Early detection of hepatocellular carcinoma (HCC): miRNA, microbiome and imaging biomarkers in the evolution of chronic liver disease in a high-risk prospective cohort (AHCC10) - ELEGANCE. Investigator-initiated multi-center study in collaboration with clinical sites (CGH, NCCS, NUH, SGH, SKH, TTSH, SingHealth Polyclinics), academic institutes (NTU, Duke-NUS) and industrial partners (MiRXES Pte Ltd, Perspectum Asia Pte Ltd and Asian Microbiome Library Pte Ltd) supported by A*Star Industry Alignment Fund – Industry Collaboration Project (IAF-ICP) Grant. 
  
  
• Multi-national, double-blind, randomized phase II trial to compare the safety and efficacy of SIRT-Y90 followed by atezolizumab plus bevacizumab versus SIRT-Y90 followed by placebo in patients with locally advanced hepatocellular carcinoma (AHCC09) – STRATUM. Investigator-initiated multi-national study with clinical sites across Asia Pacific in collaboration with Roche and Sirtex Medical. 
  
  
• Precision Medicine in Liver Cancer across an Asia-Pacific Network (AHCC07) – the PLANET study. Investigator-initiated multi-omics multi-national prospective cohort study in collaboration with clinical sites (NCCS, SGH, NUH, University Malaya Medical Centre - Malaysia, The Medical City – Philippines, National Cancer Institute – Thailand, Duke University Hospital – USA) and academic institutes (GIS, IMCB, TII, NTU, NUS) supported by NMRC Translational and Clinical Research Grant. Renewed in 2022 with NMRC Open Fund-Large Collaborative Grant. 
  
  
• Development of a companion diagnostic test kit for selective internal radiation therapy and immunotherapy for hepatocellular carcinoma (HCC): A prospective clinical translational study. Translational research study in collaboration with Stratificare Pte Ltd and supported by A*Star Industry Alignment Fund – Industry Collaboration Project (IAF-ICP) Grant. 
  
  
• Comprehensive interrogation of the epigenetics promoter and enhancer landscape in HCC to identify aberrant regulatory mechanisms associated with HCC. Translational Research study in collaboration with A*STAR GIS supported by NMRC Clinician-Scientist Individual Research Grant (CS-IRG) Grant. 
  
  
• A Prospective Study to develop a Genomics-Immunomics-Phenomics Platform for Precision Medicine in HCC. Translational Research study in collaboration with GIS, TII, and NTU supported by NMRC Clinician Scientist Award Grant. 
  
  
• Predicting survival after surgical resection for entire spectrum of anatomically resectable HCC: a Metro-ticket approach. Investigator-initiated clinical study in collaboration with Duke University Medical Center.
  

Selected publications:

1. Thng DKH, Hooi L, Toh CCM, Lim JJ, Rajagopalan D, Syariff IQC, Tan ZM, Rashid MBMA, Zhou L, Kow AWC, Bonney GK, Goh BKP, Kam JH, Jha S, Dan YY, Chow PKH, Toh TB, Chow EK (2023). Histone-lysine N-methyltransferase EHMT2 (G9a) inhibition mitigates tumorigenicity in Myc-driven liver cancer. Mol Oncol, https://doi.org/10.1002/1878-0261.13417
2. Jeon AJ, Teo YY, Sekar K, Chong SL, Wu L, Chew SC, Chen J, Kendarsari RI, Lai H, Ling WH, Kaya NA, Lim JQ, Ramasamy A, Oguz G, …, Goh BKP, Tucker-Kellogg G, Foo RSY, Chow PKH. (2023) Multi-region sampling with paired sample sequencing analyses reveals sub-groups of patients with novel patient-specific dysregulation in Hepatocellular Carcinoma. BMC Cancer, 23(1):118. https://doi.org/10.1186/s12885-022-10444-3
3. Thng DKH, Toh TB, Pigini P, Hooi L, Dan YY, Chow PK, Bonney GK, Rashid MBMA, Guccione E, Wee DKB, Chow EK. (2022) Splice-switch oligonucleotide-based combinatorial platform prioritizes synthetic lethal targets CHK1 and BRD4 against MYC-driven hepatocellular carcinoma. Bioeng Transl Med, 8(1):e10363. https://doi.org/10.1002/btm2.10363
4. Lee YH, Chuah S, Nguyen PHD, Lim CJ, Lai HLH, Wasser M, …, Chow PKH, Albani S, Liu H, Chew V (2022) IFNγ-IL-17+ CD8 T cells contribute to immunosuppression and tumor progression in human hepatocellular carcinoma, Cancer Lett, 552:215977. https://doi.org/10.1016/j.canlet.2022.215977
5. Chan JJ, Zhang Bin, Chew XH, Salhi A., …., Chow PKH, Yang H, Tay Y. (2022) Pan-cancer pervasive upregulation of 3’ UTR splicing drives tumourigenesis. Nat Cell Biol., https://doi.org/10.1038/s41556-022-00913-z 
6. Nguyen PHD, Wasser M, Tan CT, Lim CJ, Lai HLH, Seow JJW, DasGupta R, Phua CZJ, Ma S, … Zhai WW, Albani S, Chow PKH, Chew V. (2022) Trajectory of immune evasion and cancer progression in hepatocellular carcinoma. Nat Commun., 13(1):1441. https://doi.org/ 0.1038/s41467-022-29122-w 
   
7. Chew SC, Choo SY, Chow PKH. (2021) A new perspective on the immune escape mechanism in HCC: onco-foetal reprogramming. Br. J. Cancer. https://doi.org/10.1038/s41416-021-01286-0. 
8. Nguyen PHD, Ma S, Phua CZJ, Kaya NA, Lai HLH, Lim CJ, Lim JQ, Wasser M, Lai L, Tam WL, Lim TKH, Wan WK, Loh T, Leow WQ, Pang YH, Chan CY, Lee SY, Cheow PC, Toh HC, Ginhoux F, Iyer S, Kow AWC, Young Dan Y, Chung A, Goh BKP, Albani S, Chow PKH, Zhai W, Chew V. (2021) Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma. Nat Commun., 12(1):227. https://doi.org/10.1038/s41467-020-20171-7. PMID: 33431814. 
9. Zhai WW, Lai H, Kaya NA, Chen J, Yang HC, Lu BX, …, Tam WL, Toh HC, Foo RSY, Chow PKH. Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in Hepatocellular Carcinoma: the PLANET study, Nat. Sci. Rev. https://doi.org/10.1093/nsr/nwab192 
10. Gandhi M, Ling WH, Chen CH, Lee JH, Kudo M, Chanwat R, Strasser SI, Xu Z, Lai SH, Chow PKH. (2021) Impact of COVID-19 on Hepatocellular Carcinoma Management: A Multicountry and Region Study. J Hepatocell Carcinoma, 8:1159-67. https://doi.org/10.2147/JHC.S329018 
11. Chew XH, Sultana R, Mathew EN, Ng DCE, Lo RHG, Toh HC, Tai D, Choo SP, Goh BKP, Yan SX, Loke KSH, Thang SP, Gogna A, Venkatanarasimha NK, Tong AKT, Moe FNN, Chua JSS, Ang RWT, Ong AD, Ng AWY, Hoang MTQ, Too CW, Thng CH, Chan WY, Kee W, Chan JHM, Irani F, Leong S, Lim KH, Wang MLC, Chow PKH. (2021) Real-World Data on Clinical Outcomes of Patients with Liver Cancer: A Prospective Validation of the National Cancer Centre Singapore Consensus Guidelines for the Management of Hepatocellular Carcinoma. Liver Cancer. https://doi.org/10.1159/000514400 
12. Sharma A, Seow JJW, Dutertre CA, Pai R, Blériot C, Mishra A, Wong RMM, Singh GSN, Sudhagar S, Khalilnezhad S, Erdal S, Teo HM, Khalilnezhad A, Chakarov S, Lim TKH, Fui ACY, Chieh AKW, Chung CP, Bonney GK, Goh BK, Chan JKY, Chow PKH, Ginhoux F, DasGupta R. (2020) Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma. Cell, 183(2):377-394.e21. https://doi.org/10.1016/j.cell.2020.08.040. PMID: 32976798 
13. Ding, Z., Ericksen, R, Escande-Beillard, N., Lee, Q.Y, Loh A., Denil, S., Steckel, M., Andrea Haegebarth, A., Ho, S.W., Chow, P.K., Toh, H.C., Reversade, B., Gruenewald, S., Han, W. (2020) Metabolic pathway analyses identify proline biosynthesis pathway as a promoter of liver tumorigenesis. J. Hepatol., 72(4):725-35, ISSN 0168-8278, https://doi.org/10.1016/j.jhep.2019.10.026 
14. Hack, S. P., Spahn, J., Chen, M., Cheng, A. L., Kaseb, A., Kudo, M., Lee, H. C., Yopp, A., Chow, P., & Qin, S. (2020). IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. Future Oncol., 16(15):975-89. https://doi.org/10.2217/fon-2020-0162 
15. Chong YC, Toh TB, Chan Z, Lin QXX, Thng DKH, Hooi L, Ding Z, Shuen T, Toh HC, Dan YY, Bonney GK, Zhou L, Chow P, Wang Y, Benoukraf T, Chow EK, Han W. (2020) Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression. Hepatol. Commun., 4(9):1362-81. https://doi.org/10.1002/hep4.1559. 
16. Chew, V., Lee, Y.H., Pan, L., Nasir, N.J.M., Lim, C.J., Chua, C., Lai, L., Hazirah, S.N., Lim, T.K.H., Goh, B.K.P., Chung, A., Lo, R.H.G., Ng, D., Filarca, R.L.F, Albani, S., and Chow, P.K.H. (2018). Immune Activation Underlies a Sustained Clinical Response to Yttrium-90 Radioembolisation in Hepatocellular Carcinoma. Gut. pii: gutjnl-2017-315485. https://doi.org/10.1136/gutjnl-2017-315485. 
    
17. Zhao, Y., Shuen, T.W.H., Toh, T.B., Chan, X.Y., Liu, M., Tan, S.Y., Fan, Y., Yang, H., Lyer, S.G., Bonney, G.K., Loh, E., Chang, K.T.E., Tan, T.C., Zhai, W., Chan, J.K.Y., Chow, E.K., Chee, C.E., Lee, G.H., Dan, Y.Y., Chow, P.K., Toh, H.C., Lim, S.G., and Chen, Q. (2018). Development of a New Patient-Derived Xenograft Humanised Mouse Model to Study Human-Specific Tumour Microenvironment and Immunotherapy. Gut. pii: gutjnl-2017-315201. https://doi.org/10.1136/gutjnl-2017-315201. 
    
18. Pierce K.H. Chow, Mihir Gandhi, Say-Beng Tan, et al. (2018) SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma. J. Clin. Oncol., JCO2017760892. https://doi.org/10.1200/JCO.2017.76.0892. 
19. Zhai W, Lim TK, Zhang T, Phang ST, Tiang Z, Guan P, Ng MH, Lim JQ, Yao F, Li Z, Ng PY, Yan J, Goh BK, Chung AY, Choo SP, Khor CC, Soon WW, Sung KW, Foo RS, Chow PK (2017) The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma. Nat. Commun. 8:4565. https://doi.org/10.1038/ncomms14565 
20. Gebski V, Gibbs E, Gandhi M, Chatellier G, Dinut A, Pereira H, Chow PK, Vilgrain V (2017) VESPRO: An Individual Patient Data Prospective Meta-Analysis of Selective Internal Radiation Therapy Versus Sorafenib for Advanced, Locally Advanced, or Recurrent Hepatocellular Carcinoma of the SARAH and SIRveNIB Trials. JMIR Res. Protoc. 6(2):17. https://doi.org/1010.2196/resprot.7016. 
    
21. Gandhi M, Choo SP, Thng CH, Tan SB, Low AS, Cheow PC, Goh AS, Tay KH, Lo RH, Goh BK, Wong JS, Ng DC, Soo KC, Liew WM, Chow PK (2016) Single administration of Selective Internal Radiation Therapy versus continuous treatment with sorafeNIB in locally advanced hepatocellular carcinoma (SIRveNIB): study protocol for a phase iii randomized controlled trial. BMC Cancer 16(1):856. https://doi.org/10.1186/s12885-016-2868-y