Xenograft Platform for Drug Development

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Prof. Huynh is an Adjunct Professor at the National University of Singapore (Singapore) and at McGill University (Canada). He is also Principal Investigator of the Laboratory of Molecular Endocrinology at the NCCS. He has received several awards, including the Dean’s First Honour List for his PhD, The United States Army Medical Research and Material Command Breast Cancer Research Program, Best Researcher Award, and Best Paper Award at the 4th Asian Congress in Urology. Prof. Huynh has published as first or corresponding author in 130 peer-reviewed journals.

The research interest of his laboratory focuses on targeted therapies for solid tumours and the development of patient-derived xenograft (PDX) models. He has developed more than 280 xenograft tumour models, including models for hepatocellular carcinoma (HCC), gastric cancer, gastrointestinal stromal tumours, and lung and ovarian cancers.

Discovery-driven translational research in HCC and gastric cancer is moving steadily from the study of cell-line–derived xenografts to patient-derived tumour xenografts (PDX). These xenografts have proven to be an important platform in drug testing, especially for targeted and combined therapies. Our group has profiled the protein expression, gene expression, and mutational analysis of these xenografts. The PDX platform is fast becoming a recognised industry and academic leader in the areas of HCC and gastric cancer drug development. This platform represents powerful in vivo models that permit us to investigate ways to repurpose drugs for new indications. We are also 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. The results show a solid coexistence and interaction of the cells without evidence of rejection. This HHM model will provide a cutting-edge technology for drug screening, especially for immunotherapy, target discovery, and validation.

PATIENT-DERIVED XENOGRAFT MODELS: TRANSLATIONAL PLATFORMS FOR PRE-CLINICAL STUDY IN

SOLID TUMOURS

Figure 1: Graph shows the number of patient-derived tumour models established from primary tumours for the drug discovery programme. Abbreviations: HCC, hepatocellular carcinoma; GC, gastric cancer; GIST, gastrointestinal stromal, tumour; CRC, colorectal cancer; LC, lung cancer.

Selected publications:

1. Win Lwin Thuya, Li Ren Kong, Nicholas L. Syn, Ling-Wen Ding, Esther Sok Hwee Cheow, Regina Tong Xin Wong, Tingting Wang, Robby Migue Wen-Jing Goh, Hongyan Song, Migara K. Jayasinghe, Minh TN Le, Jian Cheng Hu, Wei-Peng Yong, Soo-Chin Lee, Andrea Li-Ann Wong, Gautam Sethi, Huynh The Hung, Paul Chi-Lui Ho, Jean-Paul Thiery, Siu Kwan Sze, Tiannan Guo, Ross A. Soo, Henry Yang, Yaw Chyn Lim, Lingzhi Wang, Boon-Cher Goh. FAM3C in circulating tumor-derived extracellular vesicles promotes non-small cell lung cancer growth in secondary sites. Theranostics 2023; 13(2): 621-638. [PMID: 36632230]
   
2. David Wai Meng Tai, Thi Bich Uyen Le, Aldo Prawira, Rebecca Zhi Wen Ho, Hung Huynh. Targeted inhibition of FGF19/FGFR cascade improves antitumor immunity and response rate in hepatocellular carcinoma. Hepatology International 2021 Oct; 15(5), 1236-1246 [PMID: 34333737] 
3. Aldo Prawira, Thi Bich Uyen Le, Rebecca Zhi Wen Ho, Hung Huynh. Upregulation of the ErbB family by EZH2 in hepatocellular carcinoma confers resistance to FGFR inhibitor. Journal of Cancer Research and Clinical Oncology 2021 Jun 147(10):2955-2968 [PMID: 34156519] 
4. Aldo Prawira, Thi Bich Uyen Le, Thanh Chung Vu, Hung Huynh. Ribociclib enhances Infigratinib-induced cancer cell differentiation and delays resistance in FGFR-driven hepatocellular carcinoma. Liver International 2021 Mar 41:608-20 [PMID: 33179425] 
5. Tran A, Koh TS, Prawira A, Ho RZW, Le TBU, Vu TC, Hartano S, Teo XQ, Chen WC, Lee P, Thng CH, Huynh H. Dynamic Contrast-Enhanced Magnetic Resonance Imaging as Imaging Biomarker for Vascular Normalization Effect of Infigratinib in High-FGFR-Expressing Hepatocellular Carcinoma Xenografts. Mol Imaging Biol. 2021 Feb 23(1):70-83 [PMID: 32909245] 
6. Hung Huynh, Aldo Prawira, Thi Bich Uyen Le, Thanh Chung Vu, Huai-Xiang Hao, Alan Huang, Youzhen Wang, Diana Graus Porta. FGF401 and vinorelbine synergistically mediates antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma. Experimental and Molecular Medicine. 2020 Nov 52(11): 1857-68   [PMID: 33235319]
7. Thi Bich Uyen Le, Thanh Chung Vu, Rebecca Zhi Wen Ho, Aldo Prawira, Lingzhi Wang, Boon Cher Goh and Hung Huynh.  Bevacizumab Augments the Antitumor Efficacy of Infigratinib in Hepatocellular Carcinoma. International Journal of Molecular Sciences. 2020 Dec 21(24): 9405   [PMID: 33321903]
8. Aldo Prawira, Thi Bich Uyen Le, Thanh Chung Vu, Hung Huynh. Ribociclib enhances Infigratinib-induced cancer cell differentiation and delays resistance in FGFR-driven hepatocellular carcinoma. Liver International 2020 Nov 00:1-13  [PMID: 33179425]
9. Tran A, Koh TS, Prawira A, Ho RZW, Le TBU, Vu TC, Hartano S, Teo XQ, Chen WC, Lee P, Thng CH, Huynh H. Dynamic Contrast-Enhanced Magnetic Resonance Imaging as Imaging Biomarker for Vascular Normalization Effect of Infigratinib in High-FGFR-Expressing Hepatocellular Carcinoma Xenografts. Mol Imaging Biol. 2021 Feb 23(1):70-83 [PMID: 32909245]
10. Kheng Wei Yeoh, Aldo Prawira, Muhammad Zafrie Bin Saad, Kok Ming Lee, Eric Ming Hon Lee, Gee Keng Low, Mohamed Hakim Bin Mohd Nasir, Jun Hao Phua, Wendy Wan Li Chow, Iris Jiu Hia Lim, Yusnita Binte Omar, Rebecca Zhi Wen Ho, Thi Bich Uyen Le, Thanh Chung Vu, Khee Chee Soo and Hung Huynh. Vinorelbine augments radiotherapy in hepatocellular carcinoma. Cancers 2020 Apr 12(4):872 [PMID: 32260169]
11. Li Ren Kong, Nur Afiqah Mohamed Salleh, Richard Weijie Ong, Tuan Zea Tan, Nicholas Syn, Robby Miguel Goh, Chee Wai Fhu, Daniel S.W. Tan, N. Gopalakrishna Iyer, Chandra Verma, Srinivasaraghavan Kannan, Yaw Chyn Lim, Ross Soo, Jingshan Ho, Yiqing Huang, Joline S.J. Lim, Benedict Yan, Min En Nga, Seng Gee Lim, H. Phillip Koeffler, Soo Chin Lee, Dennis Kappei, Huynh Hung, and Boon Cher Goh. A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma. Nature Communication 2020 Mar 11(1): 1556 [PMID: 32214092]
12. Li Ren Kong, Richard Weijie Ong, Tuan Zea Tan, Nur Afiqah Mohamed Salleh, Matan Thangavelu, Jane Vin Chan, Judice Koh, Giridharan Periyasamy, Amelia Lau, Thi Bich Uyen Le, Lingzhi Wang, MiYoung Lee, Srinivasaraghavan Kannan, Chandra Verma, Chwee Ming Lim, CHNG WEE JOO, David Lane, Ashok Venkitaraman, Huynh Hung, Chit Fang Cheok, and Boon Cher Goh. Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation. Nature Communication. 2020 Apr 11(1): 2086  [PMID: 32350249]
13. Henyu Lu, Chen Liu, Hung Huynh, Thi Bich Uyen Le, Matthew J. LaMarche, Morvarid Mohseni, Jeffery A. Engelman, Peter S. Hammerman, Giordano Caponigro and Huai-Xiang Hao. Resistance to allosteric SHP2 inhibition in FGFR-driven cancers through rapid feedback activation of FGFR.  Oncotarget, 2020 Jan 11(3): 265-81. [PMID: 32072487]
14. Hung Huynh, Lee Liek Yeow, Goh KY, Richard Ong, Huai-Xiang Hao, Alan Huang, Youzhen Wang, Diana Graus Porta4, Pierce Chow, Alexander Chung. Infigratinib mediates growth inhibition and vascular normalization, impairs metastasis and improves chemotherapy in hepatocellular carcinoma. Hepatology. 2019 March; 69(3):943-958  [PMID: 30575985]
15. Huynh H, Ong R, Goh KY, Lee LY, Puehler F, Scholz A, Politz O, Mumberg D, Ziegelbauer K. Sorafenib/MEK inhibitor combination inhibits tumor growth and the Wnt/β catenin pathway in xenograft models of hepatocellular carcinoma. Int J Oncol. 2019 Mar;54(3):1123-1133 [PMID: 30747223]