- Cholangiocarcinoma (CCA) or cancer of the bile duct is a heterogenous disease that is prevalent in Southeast Asia with no effective treatments and a dismal prognosis
- A new study has effectively targeted three groups in CCA with drug inhibitors
- These findings provide potential new tailored treatment strategies for CCA
Singapore, 22 January 2024 – An international study led by the National Cancer Centre Singapore (NCCS) and Duke-NUS Medical School has effectively targeted three distinct groups in cholangiocarcinoma (CCA)—or cancer of the bile duct—with drug inhibitors. These findings, recently published in the high impact journal Gut, deepen our understanding of the mechanisms that cause CCA to develop and propose new therapeutic targets for this lethal disease. This research is of particular relevance to the Southeast Asian region, where bile duct cancer is endemic.
CCA is widespread in the Northeast of Thailand, and neighbouring Laos and Cambodia. In that region, it is typically caused by exposure to a liver fluke parasite, which is transmitted by eating raw or undercooked fish. Alarmingly, CCA incidence is also on the rise in Taiwan, Korea and China, where bile duct inflammation, hepatitis, liver stones or exposure to the herbal carcinogen aristolochic acid are among the potential causes of the disease. As incidence rises worldwide, so too does the need to detect the disease early and improve treatments. Currently, chemotherapy is the first-line treatment for CCA, and targeted therapy and immunotherapy are second line treatments. Unfortunately, all are largely ineffective, and most patients have a poor prognosis with five-year survival rates of only five per cent.
Noting the urgent clinical need for new and effective therapies for CCA, a team of scientists who are leaders in the field from NCCS, Duke-NUS, A*STAR’s Genome Institute of Singapore (GIS), Sun Yat-sen University (Guangzhou, China) and Khon Kaen University (Thailand) sought to understand how they could target the dysregulation and genomic abnormalities that causes CCA formation. In 2017, the same team identified different subtypes of CCA, with different causes, mutations and DNA activity, as part of a major international effort to improve understanding of CCA led by the International Cancer Genome Consortium (ICGC).
In their latest study, the team built on their previous study and looked at enhancer activities, which control regulatory DNA sequences responsible for switching genes on or off, in the different CCA subtypes. They found that the enhancer activities rely on different pathways that could potentially be targeted with drugs.
The first group, linked to the liver fluke parasite, had increased activity in oestrogen signalling. The second group of CCAs, not caused by the liver fluke parasite, showed higher activity in a pathway related to metabolism. The third group is related to immune activities and may be linked to the consumption of herbal plants containing aristolochic acid. The researchers discovered that specific treatments targeting these different pathways slowed the growth of these cancers in experimental models. Drugs that block MTOR were effective against the first group, while inhibitors of oxidative phosphorylation worked better against the second group.
“There are currently no effective targeted treatments for CCA patients, resulting in dismal prognoses. Our latest research presents novel therapeutic approaches in the personalised treatment of CCA, showing that it’s possible to use multiomic profiling to segment patients into groups and tailor treatment accordingly using targeted therapies that are effective for the type of CCA identified,” said Professor Teh Bin Tean, Deputy Chief Executive Officer (Research) at NCCS and a co-senior author of the study. He is also a Professor in the Cancer and Stem Cell Biology Signature Research Programme at Duke-NUS.
"By bringing together the best experts in the field, integrating cutting-edge multiomics technologies and interrogating CCA through fresh approaches, our research has yielded insights that may pave the way for more targeted, personalised treatments that can prolong and improve patients’ lives,” said Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS and a co-author of the study. “As clinicians and scientists, it is incredibly rewarding to see our research translate from lab to bedside. We hope our findings will open new therapeutic avenues and spur progress against this difficult-to-treat cancer that impacts many in Singapore and beyond.”
The scientists hope the results will accelerate the clinical development of personalised therapies for CCA patients. The use of multiple latest and cutting-edge technologies, including VISIUM, VECTRA and tissue ChiP-Sequencing in this study, enabled better understanding of this challenging disease to accelerate the discovery of new therapeutic strategies.
The team plans to advance personalised drug development for CCA patients and bring novel drugs targeting different groups of CCA patients to clinical trials in the near future.
This research is supported by Singapore Ministry of Health’s National Medical Research Council (NMRC) under its Singapore Translational Research Investigator Award (MOH-STAR18NOV-0001; COVID19TUG21-0144) and under its Open Fund-Individual Research Grant (OFIRG18may-0120; COVID19TUG21-0146).
Study: Hong JH, Yong CH, Heng HL, et al. Integrative multiomics enhancer activity profiling identifies therapeutic vulnerabilities in cholangiocarcinoma of different etiologies. Gut. Published Online First: 24 November 2023. doi: 10.1136/gutjnl-2023-330483
For media enquiries, please contact:
National Cancer Centre Singapore
Duke-NUS Medical School
Communications & Strategic Relations
Tel: 6601 3272
About the National Cancer Centre Singapore
The National Cancer Centre Singapore (NCCS) is a leading national and regional tertiary cancer centre with specialists who are experts in treating cancer. In addition to offering holistic and multidisciplinary oncology care, our clinicians and scientists collaborate with local and international partners to conduct robust, cutting-edge clinical and translational research. To achieve its vision of being a global leading cancer centre, NCCS offers world-class care and shares its depth of experience and expertise by training local and overseas medical professionals.
To meet growing healthcare needs, the new NCCS building opened in 2023 with increased capacity and expanded facilities dedicated to cancer care, rehabilitation, research and education. To give patients the best treatment outcomes, advanced and innovative treatment such as proton therapy is offered at the new Goh Cheng Liang Proton Therapy Centre at NCCS.
In 2024, NCCS celebrates its silver anniversary, celebrating 25 years of advancing cancer care from breakthroughs to healing.
For more information, please visit: www.nccs.com.sg
About Duke-NUS Medical School
Duke-NUS is Singapore’s flagship graduate entry medical school, established in 2005 with a strategic, government-led partnership between two world-class institutions: Duke University School of Medicine and the National University of Singapore (NUS). Through an innovative curriculum, students at Duke-NUS are nurtured to become multi-faceted ‘Clinicians Plus’ poised to steer the healthcare and biomedical ecosystem in Singapore and beyond. A leader in ground-breaking research and translational innovation, Duke-NUS has gained international renown through its five signature research programmes and 10 centres. The enduring impact of its discoveries is amplified by its successful Academic Medicine partnership with Singapore Health Services (SingHealth), Singapore’s largest healthcare group. This strategic alliance has spawned 15 Academic Clinical Programmes, which harness multi-disciplinary research and education to transform medicine and improve lives.
For more information, please visit www.duke-nus.edu.sg