AsianScientist (Jul. 12, 2023)–“I don’t see my goals in research as being fundamentally different from my goals as a physician. For both, it was a desire to help patients with life-threatening diseases,” shared Dr Ong Sin Tiong, Associate Professor at Duke-NUS Medical School, Singapore.
Dr Ong completed his housemanship training at Addenbrooke’s Hospital in Cambridge, United Kingdom, after which he returned home to complete his medical residency at the National University Hospital Singapore. He then left for the United States where he joined the fellowship program in hematology/oncology at the University of Chicago and later became an attending physician at the University of California. Around this time, he began to work on chronic myeloid leukemia (CML), specifically to understand the mechanisms of drug resistance.
Since then, Dr Ong has built a career in basic and translational research, which, over the last two decades, has resulted in three clinical trials arising from discoveries made at the bench. While he still sees patients, he is now more likely to be found in a lab.
“I focus more time on research because I see it as a way of improving the care of many patients around the world, instead of just the one patient sitting in my consultation room,” he explained.
Dr Ong has gained recognition for his seminal research on hematologic cancers, specifically CML. By 2040, CML is projected to be the most prevalent leukemia in the United States with 180,000 cases. Regions with a low socio-demographic index—a measure of socio-economic development—like Southeast Asia have also been reported to experience the highest CML burden.
Many patients with CML remain on costly targeted therapy for life and have to contend with significant issues related to drug side-effects and impaired quality of life. Moreover, for patients who respond poorly to targeted therapy, their CML could transform into an aggressive form of the disease termed blast crisis (BC). At that point, the survival rate is low unless a bone marrow transplant is received.
CML stimulated Dr Ong’s curiosity because although the drug was hitting the target, there was a lack of a complete understanding as to why some patients exhibited resistance to targeted therapy.
In 2012, he and his team discovered an East Asian-specific polymorphism in the BIM gene which influences a patient’s resistance to targeted therapy. They found that patients who inherited a version of the gene—which they termed the BIM deletion variant—had inferior responses to targeted therapy for CML. Importantly, because they uncovered the mechanisms by which the variant caused resistance, they were able to predict that the variant would also cause resistance in lung cancer patients undergoing targeted therapy to the epidermal growth factor receptor (EGFR).
“Mechanisms-based research allows us to extend the findings made in CML, a model malignancy for cancer targeted therapy, to other cancers. It is also an example of how being a scientist increases the reach of your discoveries to patients beyond your clinic,” he elaborated.
This CML research is among the breakthroughs Dr Ong has made with the Cancer and Stem Cell Biology (CSCB) team at Duke-NUS. He started the team in 2007 upon his return to Singapore. He felt confident that the newness of the then two-year-old graduate medical school would foster an open environment conducive for impactful discoveries and translational research.
At Duke-NUS, Dr Ong and the CSCB team were also instrumental in the development of ETC-206, a home-grown blood cancer drug. In collaboration with the then Experimental Therapeutics Centre (ETC; now known as the Experimental Drug Development Centre) of the national Agency for Science, Technology and Research, they identified the MAP kinase-interacting kinases (MNKs) as a drug target in BC CML. ETC-206 started clinical trials in late 2016 and has since been licensed to a biotechnology company.
From this research, the team has started investigating the role of MNKs as a drug target in other cancers, such as glioblastoma and breast cancer. For Dr Ong, as a clinician and as a bench researcher, the whole experience is highly educational, rewarding and valuable. He continues to expand the understanding of targeted therapy resistance in CML alongside the team. In their latest publication, they challenge the long-held assumption that resistance only emerges after the drug therapy is administered.
“The dogma in the field is that resistance to targeted therapies is acquired only after therapy starts and arises from cancer cells that develop mutations which confer drug resistance. In CML, what we’ve discovered is that for primary drug resistance, the die is cast even before you start treatment. The team, in collaboration with Dr Shyam Prabhakar at the Genome Institute of Singapore and Dr Charles Chuah at the Singapore General Hospital, uncovered eight factors that determine how well a particular patient is going to do,” Dr Ong said “These findings will allow us to identify patients destined to develop drug resistance and BC CML when they first present as well as begin forming therapeutic approaches to nip drug resistance in the bud.”
The mission of the CSCB program at Duke-NUS is to advance cancer research and make discoveries that are relevant to Singapore and beyond. The program has since co-developed two cancer drugs with ETC, namely ETC-206 and ETC-159 (which is targeted at a range of cancers).
“I believe we are fulfilling the mission of our school in transforming medicine and improving lives. Collaboration is key to being able to do this. If you look at our papers, you’ll see that we’ve only been able to achieve our goals by harnessing the expertise and effort of many local and international colleagues. We hope to continue serving as a catalyst for these collaborations,” Dr Ong said.
The CSCB program also plays a role in educating the next generation of clinicians, researchers and clinician-scientists. Dr Ong encourages students to pursue their scientific dreams but cautions that because the journey ahead is long and challenging, developing a personal roadmap that is both meaningful and enjoyable is important.
He advised, “Before you embark on this journey, it’s good to try to understand what you want out of your career and life. For me, working as a clinician-scientist is where meaningful work and fun intersect. Some have described science as being a serious form of play, so being able to ‘play’ and, at the same time, make discoveries that can help cancer patients is the perfect calling for me.”
In his own journey, Dr Ong pursued a medical degree because he was interested in helping people in need by leveraging his interest in science and making his own discoveries. His curiosity and optimism about the future of cancer research and a desire to improve the management of life-threatening diseases have sustained his unwavering passion thus far.
Reflecting on his career in Singapore, Dr Ong is heartened to observe the strong footing that local scientists have established in global cancer research. Previously, much of the analyses done on local samples depended on researchers outside the country. Now, researchers turn to Singapore for expertise.
“This change is a testament to the power of collaboration and the international recognition that cancer researchers in Singapore have achieved. That’s something for us to be very proud of, but it is also something that we will have to keep working really hard at to maintain. We are only as good as our last paper,” he said.
With cancer still the top cause of death in Singapore, Dr Ong says there is more work to be done. The advent of increasingly advanced technological tools will enable more insights into understanding the mysteries of cancer. The challenge then lies in how researchers can leverage the tools to translate these discoveries into more effective patient care.
For more information on the research carried out by Dr Ong Sin Tiong and the team through the Cancer and Stem Cell Biology program, visit the program’s website here.
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Source: Duke-NUS Medical School
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