Overcoming Cancer Drug Resistance

 
(left to right) Asst Prof Charles Chuah, Assoc Prof Ong Sin Tiong and Dr Darren Lim identified the reason why some patients fail to respond to some of the most successful cancer drugs.

Meanwhile, another collaborative team in cancer research also made headlines. Helmed by Assoc Prof Ong Sin Tiong, also in the Cancer and Stem Cell Biology Signature Research Program at Duke-NUS, the team identified the reason why some patients fail to respond to some of the most successful cancer drugs.

For some cancers, such as chronic myelogenous leukaemia (CML) and nonsmall cell lung cancer (NSCLC), tyrosine kinase inhibitor drugs (TKI) are typically prescribed to prevent cancer cells from flourishing.

However, TKIs have been found to not work as well in some East Asian patients. Through genome sequencing, the team discovered that about 15% of the East Asian population inherit a variation in the ‘BIM’ gene which cause this. They were able to determine that a new class of drugs, the so-called ‘BH3 mimetics’, could overcome it.

Published in Nature Medicine in March this year, this research outcome is an important discovery, as the general assumption is that drug resistance in cancer arise during treatment, not inherited from one’s parents.

This paradigm shift will likely play a part in shaping the future of cancer research and influence the way cancer treatments are developed and personalised. For example, we can test patients for the gene variant, predict their chances of becoming resistant to TKI and determine if additional therapy is required.

The team’s discovery is very unusual because it has the potential to change the practice of medicine within a very short timeframe.

Complementary Expertise and a Common Interest

Assoc Prof Ong was quick to credit his team of collaborators for the research.One of his earliest collaborations was with Asst Prof Charles Chuah, a Senior Consultant in SGH’s Department of Haematology, whom he met some 10 years ago at an American Society of Hematology meeting in the US. Fuelled by their common interest in CML, the two continued their interactions when they returned to Singapore, leading to the start of the study in 2008.

Dr Darren Lim, Senior Consultant at NCCS, was intrigued and readily joined the team, sharing his expertise and data on NSCLC. “You can say it was a constellation of factor; the stars aligned,” Dr Lim said with a laugh. “We had the right combination of expertise, interest and information, at the right time.”

A team at the Genome Institute of Singapore (GIS) made the initial discovery of the BIM gene variation in SGH patient samples using advanced sequencing technology. Combined with Asst Prof Chuah’s deep knowledge in CML and his clinical database, they revealed a strong correlation between TKI resistance and the gene variant. The Duke-NUS team then worked to prove that the variant indeed causes TKI resistance and discover that BH3 mimetic drugs could overcome it.

Made out of complex genomic data, the study implies that it is extremely difficult for a single investigator to generate highly impactful results. A team effort is practically a must.

What then, is the secret to a successful collaboration?

“Friendships help but common interest is the most essential,” said Assoc Prof Ong. “We also need to remember that our utmost priority is to help patients.”

Mutual trust is therefore pivotal. In fact, the trust between the two doctors is so strong that there is a completely free exchange of unpublished data, reagents, and expertise between their two research groups.

“We’ve shown that such collaborations can result in a win-win situation for all parties and only good news for the patients” explained Asst Prof Chuah, “I hope this can serve as an example to foster more trust and collaborations between clinicians and scientists.”

Such an exemplary model of the collaborative spirit can only fortify the Academic Medicine culture at SingHealth. Certainly, it augurs well for patients and the future of Medicine.

Duke-NUS’ five Signature Research Programs (SRP) work closely with SingHealth’s Academic Clinical Programs (ACP), along with the Academic Medicine Research Institute and Education Institute.

Prof Teh Bin Tean, Assoc Prof Ong Sin Tiong, Assoc Prof Patrick Tan and Asst Prof Charles Chuah are SingHealth clinicians who are members of the Duke-NUS Cancer and Stem Cell Biology SRP.

Duke-NUS Signature Research Programs:
1. Cancer & Stem Cell Biology Director: Prof David Virshup
2. Cardiovascular & Metabolic Disorders Director: Prof Thomas Coffman
3. Emerging Infectious Diseases: Director Prof Wang Linfa
4. Health Services & Systems Research Director: Prof David Matchar
5. Neuroscience & Behavioral Disorders Director: Prof Dale Purves

Extracted from Tomorrow's Medicine (Issue 03-2012), a SingHealth Publication