Publications by authors named "Edward Kai-Hua Chow"

53 Publications

IDentif.AI: Rapidly optimizing combination therapy design against severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) with digital drug development.

Bioeng Transl Med 2021 Jan 1;6(1):e10196. Epub 2020 Dec 1.

The N.1 Institute for Health (N.1) National University of Singapore Singapore Singapore.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to multiple drug repurposing clinical trials that have yielded largely uncertain outcomes. To overcome this challenge, we used IDentif.AI, a platform that pairs experimental validation with artificial intelligence (AI) and digital drug development to rapidly pinpoint unpredictable drug interactions and optimize infectious disease combination therapy design with clinically relevant dosages. IDentif.AI was paired with a 12-drug candidate therapy set representing over 530,000 drug combinations against the SARS-CoV-2 live virus collected from a patient sample. IDentif.AI pinpointed the optimal combination as remdesivir, ritonavir, and lopinavir, which was experimentally validated to mediate a 6.5-fold enhanced efficacy over remdesivir alone. Additionally, it showed hydroxychloroquine and azithromycin to be relatively ineffective. The study was completed within 2 weeks, with a three-order of magnitude reduction in the number of tests needed. IDentif.AI independently mirrored clinical trial outcomes to date without any data from these trials. The robustness of this digital drug development approach paired with in vitro experimentation and AI-driven optimization suggests that IDentif.AI may be clinically actionable toward current and future outbreaks.
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http://dx.doi.org/10.1002/btm2.10196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823122PMC
January 2021

The 2020 Top Ten: Translating Life Sciences Innovation.

SLAS Technol 2021 Feb;26(1):37-41

National University of Singapore, Singapore.

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http://dx.doi.org/10.1177/2472630320982580DOI Listing
February 2021

Capitalizing on Synthetic Lethality of MYC to Treat Cancer in the Digital Age.

Trends Pharmacol Sci 2021 03 6;42(3):166-182. Epub 2021 Jan 6.

Cancer Science Institute of Singapore, National University of Singapore, Singapore; The N.1 Institute for Health, National University of Singapore, Singapore; The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Biomedical Engineering, National University of Singapore, Singapore. Electronic address:

Deregulation of MYC is among the most frequent oncogenic drivers of cancer. Developing targeted therapies against MYC is, therefore, one of the most critical unmet needs of cancer therapy. Unfortunately, MYC has been labelled as undruggable due to the lack of success in developing clinically relevant MYC-targeted therapies. Synthetic lethality is a promising approach that targets MYC-dependent vulnerabilities in cancer. However, translating the synthetic lethality targets to the clinics is still challenging due to the complex nature of cancers. This review highlights the most promising mechanisms of MYC synthetic lethality and how these discoveries are currently translated into the clinic. Finally, we discuss how in silico computational platforms can improve clinical success of synthetic lethality-based therapy.
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http://dx.doi.org/10.1016/j.tips.2020.11.014DOI Listing
March 2021

Advances in Technology to Address COVID-19.

SLAS Technol 2020 12;25(6):511-512

Shanghai Jiao Tong University, School of Biomedical Engineering, Shanghai, China.

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http://dx.doi.org/10.1177/2472630320969634DOI Listing
December 2020

Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression.

Hepatol Commun 2020 Sep 27;4(9):1362-1381. Epub 2020 Jul 27.

Singapore Bioimaging Consortium, Agency for Science, Technology, and Research Singapore Singapore.

Tumor-specific metabolic rewiring, acquired to confer a proliferative and survival advantage over nontransformed cells, represents a renewed focus in cancer therapy development. Hepatocellular carcinoma (HCC), a malignancy that has hitherto been resistant to compounds targeting oncogenic signaling pathways, represents a candidate cancer to investigate the efficacy of selectively antagonizing such adaptive metabolic reprogramming. To this end, we sought to characterize metabolic changes in HCC necessary for tumorigenesis. We analyzed gene expression profiles in three independent large-scale patient cohorts who had HCC. We identified a commonly deregulated purine metabolic signature in tumors with the extent of purine biosynthetic enzyme up-regulation correlated with tumor grade and a predictor of clinical outcome. The functional significance of enhanced purine metabolism as a hallmark in human HCC was then validated using a combination of HCC cell lines, patient-derived xenograft (PDX) organoids, and mouse models. Targeted ablation of purine biosynthesis by knockdown of the rate-limiting enzyme inosine-5'-monophosphate dehydrogenase () or using the drug mycophenolate mofetil (MMF) reduced HCC proliferation and decreased the tumor burden . In comparing the sensitivities of PDX tumor organoids to MMF therapy, we found that HCC tumors defined by high levels of IMPDH and guanosine nucleosides were most susceptible to treatment. Mechanistically, a phosphoinositide 3-kinase (PI3K)-E2F transcription factor 1 (E2F1) axis coordinated purine biosynthetic enzyme expression, deregulation of which altered the activity of mitogen-activated protein kinase/RAS signaling. Simultaneously abolishing PI3K signaling and IMPDH activity with clinically approved inhibitors resulted in greatest efficacy in reducing tumor growth in a PDX mouse model. Enhanced purine metabolic activity regulated by PI3K pathway-dependent activation of E2F1 promotes HCC carcinogenesis, suggesting the potential for targeting purine metabolic reprogramming as a precision therapeutic strategy for patients with HCC.
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http://dx.doi.org/10.1002/hep4.1559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471427PMC
September 2020

A Flexi-PEGDA Upconversion Implant for Wireless Brain Photodynamic Therapy.

Adv Mater 2020 Jul 2;32(29):e2001459. Epub 2020 Jun 2.

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore.

Near-infrared (NIR) activatable upconversion nanoparticles (UCNPs) enable wireless-based phototherapies by converting deep-tissue-penetrating NIR to visible light. UCNPs are therefore ideal as wireless transducers for photodynamic therapy (PDT) of deep-sited tumors. However, the retention of unsequestered UCNPs in tissue with minimal options for removal limits their clinical translation. To address this shortcoming, biocompatible UCNPs implants are developed to deliver upconversion photonic properties in a flexible, optical guide design. To enhance its translatability, the UCNPs implant is constructed with an FDA-approved poly(ethylene glycol) diacrylate (PEGDA) core clad with fluorinated ethylene propylene (FEP). The emission spectrum of the UCNPs implant can be tuned to overlap with the absorption spectra of the clinically relevant photosensitizer, 5-aminolevulinic acid (5-ALA). The UCNPs implant can wirelessly transmit upconverted visible light till 8 cm in length and in a bendable manner even when implanted underneath the skin or scalp. With this system, it is demonstrated that NIR-based chronic PDT is achievable in an untethered and noninvasive manner in a mouse xenograft glioblastoma multiforme (GBM) model. It is postulated that such encapsulated UCNPs implants represent a translational shift for wireless deep-tissue phototherapy by enabling sequestration of UCNPs without compromising wireless deep-tissue light delivery.
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http://dx.doi.org/10.1002/adma.202001459DOI Listing
July 2020

Frequent upregulation of G9a promotes RelB-dependent proliferation and survival in multiple myeloma.

Exp Hematol Oncol 2020 22;9. Epub 2020 May 22.

1Cancer Science Institute of Singapore, Centre for Translational Medicine, National University of Singapore, (MD6) #13-01G, 14 Medical Drive, Singapore, 117599 Singapore.

Background: Multiple myeloma is an incurable hematological malignancy characterized by a heterogeneous genetic and epigenetic landscape. Although a number of genetic aberrations associated with myeloma pathogenesis, progression and prognosis have been well characterized, the role of many epigenetic aberrations in multiple myeloma remain elusive. G9a, a histone methyltransferase, has been found to promote disease progression, proliferation and metastasis via diverse mechanisms in several cancers. A role for G9a in multiple myeloma, however, has not been previously explored.

Methods: Expression levels of G9a/EHMT2 of multiple myeloma cell lines and control cells Peripheral Blood Mononuclear Cells (PBMCs) were analyzed. Correlation of G9a expression and overall survival of multiple myeloma patients were analyzed using patient sample database. To further study the function of G9a in multiple myeloma, G9a depleted multiple myeloma cells were built by lentiviral transduction, of which proliferation, colony formation assays as well as tumorigenesis were measured. RNA-seq of G9a depleted multiple myeloma with controls were performed to explore the downstream mechanism of G9a regulation in multiple myeloma.

Results: G9a is upregulated in a range of multiple myeloma cell lines. G9a expression portends poorer survival outcomes in a cohort of multiple myeloma patients. Depletion of G9a inhibited proliferation and tumorigenesis in multiple myeloma. RelB was significantly downregulated by G9a depletion or small molecule inhibition of G9a/GLP inhibitor UNC0642, inducing transcription of proapoptotic genes and . Rescuing RelB eliminated the inhibition in proliferation and tumorigenesis by G9a depletion.

Conclusions: In this study, we demonstrated that G9a is upregulated in most multiple myeloma cell lines. Furthermore, G9a loss-of-function analysis provided evidence that G9a contributes to multiple myeloma cell survival and proliferation. This study found that G9a interacts with NF-κB pathway as a key regulator of RelB in multiple myeloma and regulates RelB-dependent multiple myeloma survival. G9a therefore is a promising therapeutic target for multiple myeloma.
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http://dx.doi.org/10.1186/s40164-020-00164-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243326PMC
May 2020

The 2020 Ten: Translating Life Sciences Innovation.

SLAS Technol 2020 02;25(1):1-5

Cancer Science Institute of Singapore, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

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http://dx.doi.org/10.1177/2472630319896750DOI Listing
February 2020

Nanodiamond-Mediated Delivery of a G9a Inhibitor for Hepatocellular Carcinoma Therapy.

ACS Appl Mater Interfaces 2019 Dec 26;11(49):45427-45441. Epub 2019 Nov 26.

Department of Pharmacology, Yong Loo Lin School of Medicine , National University of Singapore , 117600 , Singapore.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with high mortality but limited therapeutic options. Epigenetic regulations including DNA methylation and histone modification control gene expressions and play a crucial role during tumorigenesis. G9a, also known as EHMT2 (euchromatic histone-lysine -methyltransferase 2), is a histone methyltransferase predominantly responsible for dimethylation of histone H3 lysine 9 (H3K9). G9a has been shown to play a key role in promoting tumor progression. Recent studies have identified that G9a is a critical mediator of HCC pathogenesis. UNC0646 is a G9a inhibitor that has shown potent in vitro efficacy. However, due to its water insolubility, the in vivo efficacy of UNC0646 is not satisfactory. In this study, nanodiamonds (NDs) were utilized as a drug delivery platform to improve in vivo delivery of this small-molecule inhibitor. Our results showed that ND-UNC0646 complexes could be rapidly synthesized by physical adsorption, meanwhile possessing favorable drug delivery properties and was able to improve the dispersibility of UNC0646 in water, therefore making it amenable for intravenous administration. The release profile of UNC0646 from ND-UNC0646 was demonstrated to be pH-responsive. Moreover, ND-UNC0646 maintained the biological functionality of UNC0646, with higher efficacy in reducing H3K9 methylation as well as enhanced invasion suppressive effects. Most importantly, increased in vivo efficacy was demonstrated using an orthotopic HCC mouse model, which paves the way of translating this small-molecule inhibitor toward HCC treatment. Our work demonstrates the potential of NDs in the clinical application for HCC treatment.
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http://dx.doi.org/10.1021/acsami.9b16323DOI Listing
December 2019

Targeting Jak/Stat pathway as a therapeutic strategy against SP/CD44+ tumorigenic cells in Akt/β-catenin-driven hepatocellular carcinoma.

J Hepatol 2020 01 18;72(1):104-118. Epub 2019 Sep 18.

Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Background & Aims: Hepatic resection and liver transplantation with adjuvant chemo- and radiotherapy are the mainstay of hepatocellular carcinoma (HCC) treatment, but the 5-year survival rate remains poor because of frequent recurrence and intrahepatic metastasis. Only sorafenib and lenvatinib are currently approved for the first-line treatment of advanced, unresected HCC, but they yield modest survival benefits. Thus, there is a need to identify new therapeutic targets to improve current HCC treatment modalities.

Methods: The HCC tumor model was generated by hydrodynamic transfection of AKT1 and β-catenin (CTNNB1) oncogenes. Cancer cells with stemness properties were characterized following isolation using side population (SP) and CD44 surface markers by flow cytometry. The effect of Jak/Stat inhibitors was analyzed in vitro by using tumorsphere culture and in vivo using an allograft mouse model.

Results: Co-activation of both Wnt/β-catenin and Akt/mTOR pathways was found in 14.4% of our HCC patient cohort. More importantly, these patients showed poorer survival than those with either Wnt/β-catenin or Akt/mTOR pathway activation alone, demonstrating the clinical relevance of our study. In addition, we observed that Akt/β-catenin tumors contained a subpopulation of cells with stem/progenitor-like characteristics identified through SP analysis and expression of the cancer stem cell-like marker CD44, which may contribute to tumor self-renewal and drug resistance. Consequently, we identified small molecule inhibitors of the Jak/Stat pathway that demonstrated efficacy in mitigating tumor proliferation and formation in Akt/β-catenin-driven HCC.

Conclusions: In conclusion, we have shown that Akt/β-catenin tumors contain a subpopulation of tumor-initiating cells with stem/progenitor-like characteristics which can be effectively targeted with inhibitors of the Jak/Stat pathway, demonstrating that inhibition of the Jak/Stat pathway could be an alternative method to overcome drug resistance and effectively treat Akt/β-catenin-driven HCC tumors.

Lay Summary: The prognosis for patients with hepatocellular carcinoma is poor, partly because of the lack of effective treatment options for those with more advanced disease. In this study, we identified a subpopulation of cancer cells with stem cell-like properties that were critical for tumor maintenance and growth in a mouse model of hepatocellular carcinoma. Through further experiments, we demonstrated that the Jak/Stat pathway is a promising therapeutic target in hepatocellular carcinoma.
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http://dx.doi.org/10.1016/j.jhep.2019.08.035DOI Listing
January 2020

Epigenetics of hepatocellular carcinoma.

Clin Transl Med 2019 May 6;8(1):13. Epub 2019 May 6.

Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, MD6 #12-01, Singapore, 117599, Singapore.

In recent years, large scale genomics and genome-wide studies using comprehensive genomic tools have reshaped our understanding of cancer evolution and heterogeneity. Hepatocellular carcinoma, being one of the most deadly cancers in the world has been well established as a disease of the genome that harbours a multitude of genetic and epigenetic aberrations during the process of liver carcinogenesis. As such, in depth understanding of the cancer epigenetics in cancer specimens and biopsy can be useful in clinical settings for molecular subclassification, prognosis, and prediction of therapeutic responses. In this review, we present a concise discussion on recent progress in the field of liver cancer epigenetics and some of the current works that contribute to the progress of liver cancer therapeutics.
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http://dx.doi.org/10.1186/s40169-019-0230-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500786PMC
May 2019

Dual-Targeting Dual-Action Platinum(IV) Platform for Enhanced Anticancer Activity and Reduced Nephrotoxicity.

Angew Chem Int Ed Engl 2019 06 23;58(24):8109-8114. Epub 2019 Apr 23.

Department of Pharmacy, National University of Singapore, 3 Science Drive 2, 117543, Singapore, Singapore.

A novel and highly efficient dual-targeting platform was designed to ensure targeted in vivo delivery of dual-action Pt prodrugs. The dual targeting was established by liposomal encapsulation of Pt complexes, thereby utilizing the enhanced permeability and retention (EPR) effect as the first stage of targeting to attain a high accumulation of the drug-loaded liposomes in the tumor. After the release of the Pt prodrug inside cancer cells, a second stage of targeting directed a portion of the Pt prodrugs to the mitochondria. Upon intracellular reduction, these Pt prodrugs released two bioactive molecules, acting both on the mitochondrial and on the nuclear DNA. Our Pt system showed excellent activity in vitro and in vivo, characterized by a cytotoxicity in a low micromolar range and complete tumor remission, respectively. Notably, marked in vivo activity was accompanied by reduced kidney toxicity, highlighting the unique therapeutic potential of our novel dual-targeting dual-action platform.
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http://dx.doi.org/10.1002/anie.201903112DOI Listing
June 2019

The 2019 SLAS Technology Ten: Translating Life Sciences Innovation.

SLAS Technol 2019 Feb;24(1):66-69

1 Cancer Science Institute of Singapore, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

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http://dx.doi.org/10.1177/2472630318812656DOI Listing
February 2019

Artificial Intelligence-Driven Designer Drug Combinations: From Drug Development to Personalized Medicine.

SLAS Technol 2019 Feb 24;24(1):124-125. Epub 2018 Sep 24.

1 Cancer Science Institute of Singapore, National University of Singapore, Singapore.

Artificial intelligence holds great promise in transforming how drugs are designed and patients are treated. In a study recently published in Science Translational Medicine, a unique artificial intelligence platform makes efficient use of small experimental datasets to design new drug combinations as well as identify the best drug combinations for specific patient samples. This quadratic phenotypic optimization platform (QPOP) does not rely on previous assumptions of molecular mechanisms of disease, but rather uses system-specific experimental data to determine the best drug combinations for a specific disease model or a patient sample. In this commentary, we explore how QPOP was applied toward multiple myeloma in the study. We also discuss how this study demonstrates the potential for applications of QPOP toward improving therapeutic regimen design and personalized medicine.
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http://dx.doi.org/10.1177/2472630318800774DOI Listing
February 2019

Clinical Applications of Carbon Nanomaterials in Diagnostics and Therapy.

Adv Mater 2018 Nov 21;30(47):e1802368. Epub 2018 Aug 21.

Cancer Science Institute of Singapore, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.

Nanomaterials have the potential to improve how patients are clinically treated and diagnosed. While there are a number of nanomaterials that can be used toward improved drug delivery and imaging, how these nanomaterials confer an advantage over other nanomaterials, as well as current clinical approaches is often application or disease specific. How the unique properties of carbon nanomaterials, such as nanodiamonds, carbon nanotubes, carbon nanofibers, graphene, and graphene oxides, make them promising nanomaterials for a wide range of clinical applications are discussed herein, including treating chemoresistant cancer, enhancing magnetic resonance imaging, and improving tissue regeneration and stem cell banking, among others. Additionally, the strategies for further improving drug delivery and imaging by carbon nanomaterials are reviewed, such as inducing endothelial leakiness as well as applying artificial intelligence toward designing optimal nanoparticle-based drug combination delivery. While the clinical application of carbon nanomaterials is still an emerging field of research, there is substantial preclinical evidence of the translational potential of carbon nanomaterials. Early clinically trial studies are highlighted, further supporting the use of carbon nanomaterials in clinical applications for both drug delivery and imaging.
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http://dx.doi.org/10.1002/adma.201802368DOI Listing
November 2018

Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP).

Sci Transl Med 2018 08;10(453)

Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.

Multiple myeloma is an incurable hematological malignancy that relies on drug combinations for first and secondary lines of treatment. The inclusion of proteasome inhibitors, such as bortezomib, into these combination regimens has improved median survival. Resistance to bortezomib, however, is a common occurrence that ultimately contributes to treatment failure, and there remains a need to identify improved drug combinations. We developed the quadratic phenotypic optimization platform (QPOP) to optimize treatment combinations selected from a candidate pool of 114 approved drugs. QPOP uses quadratic surfaces to model the biological effects of drug combinations to identify effective drug combinations without reference to molecular mechanisms or predetermined drug synergy data. Applying QPOP to bortezomib-resistant multiple myeloma cell lines determined the drug combinations that collectively optimized treatment efficacy. We found that these combinations acted by reversing the DNA methylation and tumor suppressor silencing that often occur after acquired bortezomib resistance in multiple myeloma. Successive application of QPOP on a xenograft mouse model further optimized the dosages of each drug within a given combination while minimizing overall toxicity in vivo, and application of QPOP to ex vivo multiple myeloma patient samples optimized drug combinations in patient-specific contexts.
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http://dx.doi.org/10.1126/scitranslmed.aan0941DOI Listing
August 2018

Datasets describing the growth and molecular features of hepatocellular carcinoma patient-derived xenograft cells grown in a three-dimensional macroporous hydrogel.

Data Brief 2018 Jun 17;18:594-606. Epub 2018 Mar 17.

Institute of Bioengineering and Nanotechnology, Agency for Science, Technology and Research (ASTAR) Singapore.

This data article presents datasets associated with the research article entitled "Generation of matched patient-derived xenograft models using 3D macroporous hydrogels for the study of liver cancer" (Fong et al., 2018) [1]. A three-dimensional macroporous sponge system was used to generate counterparts to various hepatocellular carcinoma patient-derived xenograft (HCC-PDX) lines. This article describes the viability, proliferative capacity and molecular features (genomic and transcriptomic profiles) of the cultured HCC-PDX cells. The sequencing datasets are made publicly available to enable critical or further analyzes.
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http://dx.doi.org/10.1016/j.dib.2018.03.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996264PMC
June 2018

Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy.

Gut 2018 10 30;67(10):1845-1854. Epub 2018 Mar 30.

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.

Objective: As the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing.

Design: Patient-derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD- (NSG) mice. The longitudinal changes of the tumour and immune responses as well as the efficacy of immune checkpoint inhibitors are investigated.

Results: Similar to the clinical outcomes, the human immune system in our model is educated by the tumour and exhibits exhaustion phenotypes such as a significant declination of leucocyte numbers, upregulation of exhaustion markers and decreased the production of human proinflammatory cytokines. Notably, cytotoxic immune cells decreased more rapidly compared with other cell types. Tumour infiltrated T cells have much higher expression of exhaustion markers and lower cytokine production compared with peripheral T cells. In addition, tumour-associated macrophages and myeloid-derived suppressor cells are found to be highly enriched in the tumour microenvironment. Interestingly, the tumour also changes gene expression profiles in response to immune responses by upregulating immune checkpoint ligands. Most importantly, in contrast to the NSG model, our model demonstrates both therapeutic and side effects of immune checkpoint inhibitors pembrolizumab and ipilimumab.

Conclusions: Our work provides a model for immune-oncology study and a useful parallel-to-human platform for anti-HCC drug testing, especially immunotherapy.
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http://dx.doi.org/10.1136/gutjnl-2017-315201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145285PMC
October 2018

The 2018 SLAS Technology Ten: Translating Life Sciences Innovation.

SLAS Technol 2018 02;23(1):1-4

1 National University of Singapore, Singapore.

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http://dx.doi.org/10.1177/2472630317744283DOI Listing
February 2018

Generation of matched patient-derived xenograft in vitro-in vivo models using 3D macroporous hydrogels for the study of liver cancer.

Biomaterials 2018 03 4;159:229-240. Epub 2018 Jan 4.

Institute of Bioengineering and Nanotechnology, Agency for Science, Technology and Research (A*STAR), Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Mechanobiology Institute, National University of Singapore, Singapore; BioSyM, Singapore-MIT Alliance for Research and Technology, Singapore; Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China; NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, often manifesting at the advanced stage when cure is no longer possible. The discrepancy between preclinical findings and clinical outcome in HCC is well-recognized. So far, sorafenib is the only targeted therapy approved as first-line therapy for patients with advanced HCC. There is an urgent need for improved preclinical models for the development of HCC-targeted therapies. Patient-derived xenograft (PDX) tumor models have been shown to closely recapitulate human tumor biology and predict patient drug response. However, the use of PDX models is currently limited by high costs and low throughput. In this study, we engineered in vitro conditions conducive for the culture of HCC-PDX organoids derived from a panel of 14 different HCC-PDX lines through the use of a three-dimensional macroporous cellulosic sponge system. To validate the in vitro HCC-PDX models, both in vivo and in vitro HCC-PDX models were subjected to whole exome sequencing and RNA-sequencing. Correlative studies indicate strong concordance in genomic and transcriptomic profiles as well as intra-tumoral heterogeneity between each matched in vitro-in vivo HCC-PDX pairs. Furthermore, we demonstrate the feasibility of using these in vitro HCC-PDX models for drug testing, paving the way for more efficient preclinical studies in HCC drug development.
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http://dx.doi.org/10.1016/j.biomaterials.2017.12.026DOI Listing
March 2018

Applications of stimuli-responsive nanoscale drug delivery systems in translational research.

Drug Discov Today 2018 05 16;23(5):1043-1052. Epub 2017 Nov 16.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore; Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, 117599, Singapore. Electronic address:

Nanoscale drug delivery systems or nanocarriers have shown tremendous promise in the target-specific delivery of therapeutics as well as diagnostic agents. Additional properties can be introduced into nanocarriers to enhance the bioavailability and targeting efficiency of the transported drugs at diseased sites. Such nanocarriers are usually incorporated with stimuli-responsive components that can be triggered by specific stimuli (e.g., temperature, pH, or enzymes) and further induced by certain biological responses, such as enzyme hydrolysis and molecular conformational changes, leading to the controlled release of the transported molecules at targeted sites. In this review, we discuss various stimuli-responsive nanoscale delivery systems and summarize the current perspectives as well as challenges facing the successful translation of these innovative stimuli-responsive nanocarriers from the bench to the bedside.
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http://dx.doi.org/10.1016/j.drudis.2017.11.009DOI Listing
May 2018

Inhibition of the H3K9 methyltransferase G9A attenuates oncogenicity and activates the hypoxia signaling pathway.

PLoS One 2017 16;12(11):e0188051. Epub 2017 Nov 16.

Cancer Stem Cells and Biology Program, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.

Epigenetic mechanisms play important roles in the regulation of tumorigenesis, and hypoxia-induced epigenetic changes may be critical for the adaptation of cancer cells to the hypoxic microenvironment of solid tumors. Previously, we showed that loss-of-function of the hypoxia-regulated H3K9 methyltransferase G9A attenuates tumor growth. However, the mechanisms by which blockade of G9A leads to a tumor suppressive effect remain poorly understood. We show that G9A is highly expressed in breast cancer and is associated with poor patient prognosis, where it may function as a potent oncogenic driver. In agreement with this, G9A inhibition by the small molecule inhibitor, BIX-01294, leads to increased cell death and impaired cell migration, cell cycle and anchorage-independent growth. Interestingly, whole transcriptome analysis revealed that genes involved in diverse cancer cell functions become hypoxia-responsive upon G9A inhibition. This was accompanied by the upregulation of the hypoxia inducible factors HIF1α and HIF2α during BIX-01294 treatment even in normoxia that may facilitate the tumor suppressive effects of BIX-01294. HIF inhibition was able to reverse some of the transcriptional changes induced by BIX-01294 in hypoxia, indicating that the HIFs may be important drivers of these derepressed target genes. Therefore, we show that G9A is a key mediator of oncogenic processes in breast cancer cells and G9A inhibition by BIX-01294 can successfully attenuate oncogenicity even in hypoxia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188051PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690420PMC
December 2017

Clinical validation of a nanodiamond-embedded thermoplastic biomaterial.

Proc Natl Acad Sci U S A 2017 11 23;114(45):E9445-E9454. Epub 2017 Oct 23.

Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, CA 90095;

Detonation nanodiamonds (NDs) are promising drug delivery and imaging agents due to their uniquely faceted surfaces with diverse chemical groups, electrostatic properties, and biocompatibility. Based on the potential to harness ND properties to clinically address a broad range of disease indications, this work reports the in-human administration of NDs through the development of ND-embedded gutta percha (NDGP), a thermoplastic biomaterial that addresses reinfection and bone loss following root canal therapy (RCT). RCT served as the first clinical indication for NDs since the procedure sites involved nearby circulation, localized administration, and image-guided treatment progress monitoring, which are analogous to many clinical indications. This randomized, single-blind interventional treatment study evaluated NDGP equivalence with unmodified GP. This progress report assessed one control-arm and three treatment-arm patients. At 3-mo and 6-mo follow-up appointments, no adverse events were observed, and lesion healing was confirmed in the NDGP-treated patients. Therefore, this study is a foundation for the continued clinical translation of NDs and other nanomaterials for a broad spectrum of applications.
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http://dx.doi.org/10.1073/pnas.1711924114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5692571PMC
November 2017

Stimuli-Responsive Nanodiamond-Based Biosensor for Enhanced Metastatic Tumor Site Detection.

SLAS Technol 2018 02 11;23(1):44-56. Epub 2017 Oct 11.

1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Metastasis is often critical to cancer progression and linked to poor survival and drug resistance. Early detection of metastasis, as well as identification of metastatic tumor sites, can improve cancer patient survival. Thus, developing technology to improve the detection of cancer metastasis biomarkers can improve both diagnosis and treatment. In this study, we investigated the use of nanodiamonds to develop a stimuli-responsive metastasis detection complex that utilizes matrix metalloproteinase 9 (MMP9) as a metastasis biomarker, as MMP9 increased expression has been shown to be indicative of metastasis. The nanodiamond-MMP9 biosensor complex consists of nanodiamonds functionalized with MMP9-specific fluorescent-labeled substrate peptides. Using this design, protease activity of MMP9 can be accurately measured and correlated to MMP9 expression. The nanodiamond-MMP9 biosensor also demonstrated an enhanced ability to protect the base sensor peptide from nonspecific serum protease cleavage. This enhanced peptide stability, combined with a quantitative stimuli-responsive output function, provides strong evidence for the further development of a nanodiamond-MMP9 biosensor for metastasis site detection. More importantly, this work provides the foundation for use of nanodiamonds as a platform for stimuli-responsive biosensors and theranostic complexes that can be implemented across a wide range of biomedical applications.
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http://dx.doi.org/10.1177/2472630317735497DOI Listing
February 2018

Welcome to the Digital World of Quantitative Biology.

SLAS Technol 2017 08;22(4):367-368

1 Cancer Science Institute of Singapore, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

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http://dx.doi.org/10.1177/2472630317713262DOI Listing
August 2017

Exosomes in Cancer Nanomedicine and Immunotherapy: Prospects and Challenges.

Trends Biotechnol 2017 07 29;35(7):665-676. Epub 2017 Mar 29.

Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Hematology-Oncology, National University Cancer Institute, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore; Developmental Therapeutics Unit, National University Cancer Institute, Singapore.

Exosomes (versatile, cell-derived nanovesicles naturally endowed with exquisite target-homing specificity and the ability to surmount in vivo biological barriers) hold substantial promise for developing exciting approaches in drug delivery and cancer immunotherapy. Specifically, bioengineered exosomes are being successfully deployed to deliver potent tumoricidal drugs (siRNAs and chemotherapeutic compounds) preferentially to cancer cells, while a new generation of exosome-based therapeutic cancer vaccines has produced enticing results in early-phase clinical trials. Here, we review the state-of-the-art technologies and protocols, and discuss the prospects and challenges for the clinical development of this emerging class of therapeutics.
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http://dx.doi.org/10.1016/j.tibtech.2017.03.004DOI Listing
July 2017

3D Culture as a Clinically Relevant Model for Personalized Medicine.

SLAS Technol 2017 06 9;22(3):245-253. Epub 2017 Mar 9.

2 Cancer Science Institute of Singapore, National University of Singapore, Singapore.

Advances in understanding many of the fundamental mechanisms of cancer progression have led to the development of molecular targeted therapies. While molecular targeted therapeutics continue to improve the outcome for cancer patients, tumor heterogeneity among patients, as well as intratumoral heterogeneity, limits the efficacy of these drugs to specific patient subtypes, as well as contributes to relapse. Thus, there is a need for a more personalized approach toward drug development and diagnosis that takes into account the diversity of cancer patients, as well as the complex milieu of tumor cells within a single patient. Three-dimensional (3D) culture systems paired with patient-derived xenografts or patient-derived organoids may provide a more clinically relevant system to address issues presented by personalized or precision medical approaches. In this review, we cover the current methods available for applying 3D culture systems toward personalized cancer research and drug development, as well as key challenges that must be addressed in order to fully realize the potential of 3D patient-derived culture systems for cancer drug development. Greater implementation of 3D patient-derived culture systems in the cancer research field should accelerate the development of truly personalized medical therapies for cancer patients.
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http://dx.doi.org/10.1177/2472630317697251DOI Listing
June 2017

SLAS Technology.

SLAS Technol 2017 02;22(1):1-2

1 Cancer Science Institute of Singapore, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

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http://dx.doi.org/10.1177/2211068216677920DOI Listing
February 2017

The 2017 SLAS Technology Ten.

SLAS Technol 2017 02;22(1):3-6

1 Cancer Science Institute of Singapore, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

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http://dx.doi.org/10.1177/2472630316683633DOI Listing
February 2017