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AHCC Current Studies

AHCC07	Precision Medicine in Liver Cancer across an Asia-Pacific Network (The PLANet Study) (Clinicaltrials.gov identifier: NCT03267641)
Funding	NMRC TCR Tier 1
Period	16 May 2016 to 15 May 2022
Status	Completed recruitment of 120 patients in January 2021 (planned recruitment is 100)
Abstract	Hepatocellular carcinoma (HCC) is the 6th most common cancer in the world but the 2nd most important cause of cancer death. Due to its highly heterogeneous nature, the current approach to identifying druggable targets have not delivered efficacious therapies in HCC and is a main reason for the high case fatality. Even when surgical resection is potentially curative in early disease, tumor recurrence remains high and long term survival poor because of the absence of useful adjuvant therapy. It is shown that through multi-region sampling of freshly resected HCC and phylogenetic analysis, that significant intra-tumoral heterogeneity exists and have identified the specific positions of known clonal drivers. Simultaneously we have analyzed the immune landscape of the tumor microenvironment with deep immune-phenotyping and found unique inter-patient immune landscapes predictive of clinical trajectory. Clinical trajectories are tracked and genomic and immunological studies are repeated when tumors recur, to confirm clonally dominant driver mutations and immunological processes that are targetable. Concurrently, representative pre-clinical models will be developed from the tissues sampled. The study aims to combine these approaches to overcome the challenges posed by genomic and immunomics heterogeneity and to guide the development of therapeutics and precision medicine in HCC.
Outcome	Publication: 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. 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. 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 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 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. Lim CJ, Chew V. (May 2020) Impact of Viral Etiologies on the Development of Novel Immunotherapy for Hepatocellular Carcinoma. Seminars in Liver Disease. 10.1055/s-0039-3399534 Samuel Chuah, Valerie Chew. (Feb 2020) High-dimensional immune-profiling in cancer: implications for immunotherapy. Journal for ImmunoTherapy of Cancer. 10.1136/jitc-2019-000363 Jin, Y., Wong, Y.S., Goh, B.K.P., Chan, C.Y., Cheow, P.C., Chow, P.K.H., Lim, T.K.H., Goh, G.B.B., Krishnamoorthy, T.L., Kumar, R., Ng, T.P., Chong, S.S., Tan, H.H., Chung, A.Y.F, Ooi, L.L., Chang, J.P.E., Tan, C.K., and Lee, C.G.L. (2019) Circulating microRNAs as potential diagnostic and prognostic biomarkers in hepatocellular carcinoma. Sci. Rep., 9(10464). https://doi.org/10.1038/s41598-019-46872-8 Jin, Y., Lee, W.Y., Toh, S.T., Tennakoon, C., Toh, H.C., Chow, P.K., Chung, A.Y., Chong, S.S, Ooi, L.L., Sung, W.K., and Lee., C.G. (2019) Comprehensive analysis of transcriptome profiles in hepatocellular carcinoma. J. Transl. Med. https://doi.org/10.1186/s12967-019-2025-x Justin L Tan, Feng Li, Joanna Z Yeo, Kol Jia Yong, Mahmoud A Bassal, Guo Hao Ng, May Yin Lee, Chung Yan Leong, Hong Kee Tan, Chan-Shuo Wu, Bee Hui Liu, Tim H Chan, Zi Hui Tan, Yun Shen Chan, Siyu Wang, Zhi Han Lim, Tan Boon Toh, Lissa Hooi, Kia Ngee Low, Siming Ma, Nikki R Kong, Alicia J Stein, Yue Wu, Matan T Thangavelu, Atsushi Suzuki, Giridharan Periyasamy, John M Asara, Yock Young Dan, Glenn K Bonney, Edward K Chow, Guo-Dong Lu, Huck Hui Ng, Yoganathan Kanagasundaram, Siew Bee Ng, Wai Leong Tam, Daniel G Tenen, Li Chai. (Aug 2019) New High-Throughput Screening Identifies Compounds That Reduce Viability Specifically in Liver Cancer Cells. Gastroenterology. 10.1053/j.gastro.2019.08.022. Tai D, Choo SP, Chew V. (Dec 2019) Rationale of Immunotherapy in Hepatocellular Carcinoma and Its Potential Biomarkers. Cancers. 10.3390/cancers11121926. 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. Lim, C.J., Lee, Y.H., Pan, L., Lai, L., Chua, C., Wasser, M., Lim, T.K.H., Yeong, J., Toh, H.C., Lee, S.Y., Chan, C.Y., Goh, B.K., Chung, A., Heikenwalder, M., Ng, I.O., Chow, P., Albani, S., and Chew, V. (2018). Multidimensional Analyses Reveal Distinct Immune Microenvironment in Hepatitis B Virus-Related Hepatocellular Carcinoma. Gut. https://doi.org/10.1136/gutjnl-2018-316510. 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. Fong ELS, Toh TB, Lin QXX, Liu Z, Hooi L, Mohd Abdul Rashid MB, Benoukraf T, Chow EK, Huynh TH, Yu H. (2018) Generation of Matched Patient-Derived Xenograft in Vitro-in Vivo Models Using 3d Macroporous Hydrogels for the Study of Liver Cancer. Biomaterials. 10.1016/j.biomaterials.2017.12.026 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 Chew V, Lai L, Pan L, Lim CJ, Li J, Ong R, Chua C, Leong JY, Lim KH, Toh HC, Lee SY, Chan CY, Goh BKP, Chung A, Chow PKH, Albani S. (2017). Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses. Proc. Natl. Acad. Sci., 114(29):5900-09. https://doi.org/10.1073/pnas.1706559114. Patents: A system and method for classifying cancer patients into appropriate cancer treatment groups and compounds for treating the patient (Valerie Chew, Pierce Chow, Albani Salvatore) (Application number: 10201709924T; Filing Date: 30/11/2017) Cell-based biomarkers of immunotherapy in hepatocellular carcinoma (Ankur Sharma, Florent Ginhoux, Ramanuj Dasgupta, Pierce Chow) (Singapore Provisional Application number.: 10202007868Q; Filing Date: 17/08/2020)
Contributing Principal Investigators and Centres	Malaysia Yoong Boon Koon (University Malaya Medical Center) Philippines Maria Vanessa H. de Villa (The Medical City) Singapore Pierce Chow (National Cancer Centre), Glenn Bonney (National University Hospital), Brian Goh (Singapore General Hospital) Thailand Rawisak Chanwat (National Cancer Institute) United States of America Sabino Zani Jr (Duke University School of Medicine)
Thematic Principal Investigators	Theme 1: Genomic evolution in HCC and the discovery of novel drug targets Theme PI: Zhai Weiwei (Senior Research Scientist, Genome Institute of Singapore) Theme 2: Translational Immunomics: Immune-phenotyping, monitoring and discovery of novel immunotherapies Theme PI: Salvatore Albani (Director, SingHealth Translational Immunology and Inflammation Centre) Theme 3: Clinical Trajectory and Translational Therapeutics Theme PI: Pierce Chow (Senior Consultant, National Cancer Centre)
Protocol Chair	Pierce Chow pierce.chow.k.h@singhealth.com.sg

AHCC10	Early Detection of Hepatocellular Carcinoma: miRNA, microbiome and imaging biomarkers in the evolution of chronic liver disease in a high-risk prospective cohort (ELEGANCE) (Clinicaltrials.gov identifier: NCT04965259)
Funding	A*Star IAF ICP and Industry (MiRXES, Perspectum and AMILI)
Period	22 Feb 2021 to 21 Feb 2025
Status	Recruiting. Planned recruitment of 2,000 patients.
Abstract	In Singapore, hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer death in male and 4th in female. A major reason for its lethality is the absence of diagnostic modalities with high accuracy for the detection of early stage HCC. Currently only 20% of HCC are diagnosed in the early stage when curative treatment can be carried out. The inability to diagnose HCC at an early stage for the majority of patients is thus an urgent unmet public health need. Current guidelines for the surveillance of patients at risk of developing HCC involves a combination of serum alpha-fetoprotein (AFP) and abdominal ultrasound (US) every 6 months. AFP and US have accuracies of 76.6% and 84% respectively for the detection of HCC but for early HCC, sensitivity with US drops to only 47% and adding AFP to US increases sensitivity in this group to only 63%. There is thus an imperative to develop novel diagnostic modalities that can more accurately detect early HCC. Plasma microRNAs (miRNAs) have shown promise in preliminary studies and in this collaboration with MIRXES, we aim to develop the 1st miRNA in-vitro diagnostic (IVD) kit for HCC that has higher accuracy and better ease of use compared with the extant combination of AFP and US. Patients with chronic liver diseases have increased risk of developing HCC. There is currently no accurate method to identify individuals at higher risk of developing HCC in a sufficiently granular manner such that we can devote more resources for targeted surveillance. We continue our earlier collaboration with Perspectum to develop the 1st AI algorithm with MRI to predict individual risks of developing HCC within a specific timeline. There is a worldwide increase in the prevalence of metabolic liver disease. The biology and clinical trajectories of metabolic liver diseases and cancer remain unclear but emerging data have shown association with changes in the microbiome and metabolome. There is therefore urgency to study the association between gut microbiome, metabolome and the liver in order to stratify individual patient risks and prevent disease progression and the development of HCC. We collaborate with AMILI to build on their existing microbiome library from healthy donors and to expand our collaboration with the Singapore Phenome Centre (SPC) to examine changes in the microbiome and metabolome in the build-up to the development of HCC. The aim is to identify potential therapeutic targets in the microbiome and metabolome where intervention can prevent the development of HCC and slow the progression of chronic liver diseases. In this study, we collaborate with MIRXES, Perspectum and AMILI on research that will be carried out on a prospective cohort study of 2,000 patients at risk of developing HCC (AHCC10, main study) and a parallel cohort of 100 patients already diagnosed with HCC (AHCC11, parallel study).
Contributing Principal Investigators and Centres	Singapore Eugene Wong (Changi General Hospital), Toh Han Chong (National Cancer Centre), Lee Guan Huei (National University Hospital), Jason Chang (Singapore General Hospital), Chong Oi Fong (SingHealth Polyclinics – Bedok), Sabrina Wee (SingHealth Polyclinics – Bukit Merah), Tan Kee Tung (SingHealth Polyclinics – Marine Parade), Ong Kok Kiong (SingHealth Polyclinics – Outram), Tan Ngiap Chuan (SingHealth Polyclinics – Pasir Ris), Yeap Xin Yi (SingHealth Polyclinics – Punggol), Choo Han Jun (SingHealth Polyclinics – Sengkang), Sulaiha Binte Ithnin (SingHealth Polyclinics – Tampines), Marianne De Roza (Sengkang General Hospital), Yang Wei Lyn (Tan Tock Seng Hospital)
Protocol Chair	Pierce Chow pierce.chow.k.h@singhealth.com.sg

AHCC11	Prospective Cohort Study of Changes in Circulatory micro-RNA after Surgical Resection of Hepatocellular Carcinoma (PROSECT) (Clinicaltrials.gov identifier: pending)
Funding	A*Star IAF ICP and Industry (MiRXES and AMILI)
Period	22 Feb 2021 to 21 Feb 2025
Status	Recruiting. Planned recruitment of 100 patients.
Abstract	In this proposed study, we continue our collaboration with MIRXES and AMILI on a cohort of 100 patients already diagnosed with HCC. This study will also act as a positive control to the AHCC10 ELEGANCE Study. We will use the miRNA profiles of 100 patients with diagnosis of HCC confirmed by histology at surgical resection to confirm the hypothesis that the miRNA biomarkers that are predictive of occurrence in HCC will revert back to profiles similar to non-HCC cohort. In addition, we aim to determine if progressive changes in miRNA signatures are predictive of recurrence and to discover new signatures for recurrence prediction.
Contributing Principal Investigators and Centres	Singapore Adrian Chiow (Changi General Hospital), Pierce Chow (National Cancer Centre), Glenn Bonney (National University Hospital), Brian Goh (Singapore General Hospital), Kam Juinn Huar (Sengkang General Hospital), Vishalkumar G. Shelat (Tan Tock Seng Hospital)
Protocol Chair	Pierce Chow pierce.chow.k.h@singhealth.com.sg