Prof Soon Thye LIMDr Dachuan HUANGDr Jing TANDr Jing Quan LIMDr Nicholas GRIGOROPOULOSDr Shin Yeu OngDr Miriam TAODr Tiffany TANGDr Jason CHANDr Nagavalli d/o SOMASUNDARAMDr Mohamed Farid BIN HARUNAL RASHIDDr Nagarajan CHANDRAMOULIDr Chee Leong CHENGJeslin HAEsther WONGDaryl CHEAHKelila CHAIKerry LimAlisa SAIRIHaniffa HASANLay Poh KHOOFathimah RAFI’EELIM Xiang Yun
The Lymphoma Genomic Translational Research Laboratory, led by Principal Investigator Dr Choon Kiat ONG, is dedicated to gaining a better understanding of the pathogenesis and aetiology of lymphoma, and subsequently translating significant findings into novel treatment approaches for patients through clinical trials. Lymphoma is a very complex disease with many different subtypes. Our research focuses mainly on non-Hodgkin’s lymphoma, especially T and NK cell lymphomas which are more prevalent in Asia. Besides understanding the disease through the use of various types of sequencing methodologies, we have also developed patient-derived xenograft (PDX), humanized and transgenic mouse models which are highly relevant to clinical drug testing and development. This capability allows us to further verify our discoveries at the genomic level, generating preclinical data and bringing the studies towards clinical trials. We are also in a good position to partner with pharmaceutical and diagnostic companies to develop drugs and biomarkers, respectively.
Our contribution to the understanding of the disease is summarized in Figure 1. Using genomic approaches, we have discovered novel therapeutic targets in Natural Killer/T-cell lymphoma (NKTCL)1,2, which allow us to develop therapeutic strategies against the disease3,4. To understand the pathogenic contribution of Epstein-Barr virus (EBV), we have also sequenced the virus genome from these tumors. We observed transcriptional defects at the BARTs miRNA and the disruption of host NHEJ1 by EBV integration, implying novel pathogenesis mechanisms of EBV5. Recently, we have demonstrated that a sub-group of relapsed/refractory NKTCL patients responded very well to immune checkpoint (ICP) inhibitors6,7. Through analysis of genomic, histological and clinical data, we have discovered novel biomarkers of response in NKTCL which will allow us to better select patients for ICP blockade therapy8. In partnership with Lucence Diagnostics, we have successfully developed a clinical grade assay for the detection of these biomarkers in our patients, moving our discovery from “Bench to Bedside”8,9. Using a germline approach, we have successfully gained further insights into the pathobiology of these aggressive diseases10-13.
Using similar research strategies, we have deciphered the genomic landscape of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)14,15, which allow us to design rational therapeutic strategies with the help of quadratic phenotypic optimization platform (QPOP)15. The use of QPOP also enable us to identified effective combinatorial drug treatment for a hepatosplenic T-cell lymphoma (HSTL) patient16. Our team has improved the accuracy of prognosis and diagnosis of T and NK-cell lymphoma with the eventual aim of improving treatment17-20. We will continue to study and understand this group of diseases, devising novel therapeutic strategies to improve their clinical outcome.
Over the years, our laboratory has secured research grants from various funding agencies, namely the National Medical Research Council (NMRC), the National Health Innovation Centre (NHIC), and the NCC Research Fund (NCCRF). In 2019, our team was awarded with the Large Collaborative Grant (LCG) by NMRC, for a cross-institutional project entitled “SYMPHONY”. “SYMPHONY” is an extension of the existing Translational and Clinical Research (TCR) programme (2014 – 2019), and it builds upon the findings and collaborations over the last 5 years to further the understanding of and develop novel strategies to combat this debilitating disease. We have also received industrial support for several projects from pharmaceutical companies, including Bayer Pharmaceuticals, ASLAN, Principia Biopharma, and SYNthesis Pte Ltd, and we are actively seeking out more potential partners for collaborations.
Dr ONG, along with other collaborating scientists in the field of cancer research, was awarded the “AACR Team Science Award 2018” by the American Association for Cancer Research (AACR), recognising the outstanding interdisciplinary team’s work in furthering the knowledge of Asian prevalent cancers and contributing to the progress of cancer detection, treatment and prevention. Dr Ong is currently leading the whole-genome sequencing of T and natural killer-cell lymphoma at the International Cancer Genomic Consortium (ICGC). This initiative has proudly placed Singapore on the world map in the field of cancer genomic research.
Figure 1. Our contributions to the understanding of NKTCL and PTCL. We discovered frequent mutation of JAK3 in NKTCL and have developed and tested JAK3 specific molecules with Principia Biopharma. We have recently shown that relapsed and refractory NKTCL patients response well to immune checkpoint inhibitor and discovered that PD-L1 structural rearrangement (SR) is highly prevalent in durable responders, but not in the non-responders. Together with Lucence Diagnostic, a clinical grade assay was developed and ready for clinical deployment. Besides upregulating PD-L1 through the PD-L1 SR, we have shown that STAT3 activating mutation, which is highly prevalent in NKTCL, could directly bind to the PD-L1 promoter to upregulate the protein. Besides JAK/STAT pathway, we have observed epigenetic alterations highly prevalent in PTCL. We have discovered the importance of JAK-STAT and MEK-ERK pathways in MEITL, an aggressive and fatal PTCL. We recently demonstrated that combinatorial therapy works very well in this lymphoma and hope to improve the clinical course of this disease. Using genome-wide association study (GWAS) and sequencing, we have identified variants in HLA-DPB1, HLA-DRB1, IL18RAP and FAM160A as susceptible SNPs that predispose individual to NKTCL. Together with NCI, we have also discovered and developed diagnostic biomarker for subtypes of PTCL.
1. Lim JQ, Huang D, Tang T, Tan D, Laurensia Y, Peng RJ, Wong EKY, Cheah DMZ, Chia BKH, Iqbal J, Grigoropoulos NF, Nairismägi ML, Ng CCY, Rajasegaran V, Hong H, Kim SJ, Cho J, Tse E, Mow B, Cai QC, Poon LM, Cai QQ, Tan J, Chan JY, Lim JX, Goh YT, Phipps C, Rötzschke O, Cheng CL, Ha JCH, Khoo LP, Loh YSM, Au-Yeung R, Chan TS, Kwong YL, Hwang W, Kim WS, Bei JX, Lin T, Ong CK, Lim ST. Whole-genome sequencing identifies responders to Pembrolizumab in relapse/refractory natural-killer/T cell lymphoma.. Leukemia. 2020 Aug 5. doi: 10.1038/s41375-020-1000-0. Impact factor: 10.240.
2. Kim SJ, Lim JQ, Laurensia Y, Cho J, Yoon SE, Lee JY, Ryu KJ, Ko YH, Koh Y, Cho D, Lim ST, Beck Enemark M, D'amore F, Bjerre M, Ong CK, Kim WS. Avelumab for the treatment of relapsed or refractory extranodal NK/T-cell lymphoma: an open-label phase 2 study. Blood. 2020 Aug 7:blood.2020007247. doi: 10.1182/blood.2020007247. Impact factor: 16.601.
3. Huang D, Lim JQ, Cheah DMZ, Kahliab KHBM, Laurensia Y, Pang JWL, Wong EKY, Chia BKH, Goh J, Zhang X, Chan JY, Chow EK, Tan SY, Lim ST, Ong CK. Whole-genome sequencing reveals potent therapeutic strategy for monomorphic epitheliotropic intestinal T-cell lymphoma. Blood Adv. 2020 Oct 13;4(19):4769-4774. doi:10.1182/bloodadvances.
4. de Mel S, Rashid MBM, Zhang XY, Goh J, Lee CT, Poon LM, Chan EHL, Liu X, Chng WJ, Chee YL, Lee J, Yuen YC, Lim JQ, Chia BKH, Laurensia Y, Huang D, Pang WL, Cheah DMZ, Wong EKY, Ong CK, Tang T, Lim ST, Ng SB, Tan SY, Loi HY, Tan LK, Chow EK, Jeyasekharan AD. Application of an ex-vivo drug sensitivity platform towards achieving complete remission in a refractory T-cell lymphoma. Blood Cancer J. 2020 Jan 27;10(1):9. Impact Factor 7.895.
5. Lin GW, Xu C, Chen K, Huang HQ, Chen J, Song B, Chan JKC, Li W, Liu W, Shih LY, Chuang WY, Kim WS, Tan W, Peng RJ, Laurensia Y, Cheah DMZ, Huang D, Cheng CL, Su YJ, Tan SY, Ng SB, Tang TPL, Han K, Wang VY, Jia WH, Pei Z, Li YJ, Gao S, Shi Y, Hu Z, Zhang F, Zhang B, Zeng YX, Shen H, He L, Ong CK, Lim ST, Chanock S, Kwong YL, Lin D, Rothman N, Khor CC, Lan Q, Bei JX; International NKTCL Working Group. Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations. Lancet Oncology. 2020 Feb;21(2):306-316. Impact factor: 35.386.
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