Lung cancer is one of the most common cancers in Singapore and also a high cancer death ratio. Although the unique local patient demographics of lung cancer led many initial research efforts to be centred on a type of mutation known as Epidermal Growth Factor Receptors (EFGR), the disease has now become the “poster child” for precision oncology. The term “Precision Oncology” is used to describe molecular profiling of a tumour and using diverse strategies in cancer medicine to treating cancer. The Lung Cancer Research Programme has been in place since 2007, initially set up as a platform to foster large clinical and molecular database across different disciplines. The Lung Cancer Consortium Singapore has also further expanded to include other public restructured hospitals and private clinics, and collaborates with other research institutes to perform cutting-edge translational research. More recently, a research and trials office was established within NCCS to coordinate multinational studies in the Asian region (ATORG).
Figure 1: Current Interactions of the Lung Cancer Consortium, Singapore
At present, we have clinical data for approximately 6,000 patients with non-small cell lung cancer (NSCLC), of which about half have provided information about lifestyle and family through detailed, structured questionnaires. We have also amassed about 1,000 tumours, with accompanying blood and saliva samples, which be subject to genetic testing. In collaboration with the Genome Institute of Singapore, we have embarked on genome-wide association studies to delineate risk alleles to better understand the unusually high prevalence of EGFR mutations in the Asian population. Through partnership with the POLARIS programme, we have established next-generation sequencing in our pathology laboratories, where fit-for-purposesequencing for stratification into clinical trials are ongoing. ATORG will further establish a molecular screening protocol (ATORG001) for up to 500 patients in Asia.
We have also been successful in obtaining consecutive flagship grants—Lung TCR (2013–2018), recent LCG renewal 2018–2022—maintaining a core group of thoracicresearchers covering genomics, computational biology, translational immunology and disease biology with a focus on tumour metabolism, transcription regulators and evolutionary modelling of novel therapies and immunology. Through this group, we have undertaken multi-regional exome/RNA sequencing of EGFR-mutant NSCLC and have sequenced more than 250 Asian lung tumours to better understand the genomic/ transcriptomic landscape of NSCLC. We have also identified novel metabolic targets such glycine decarboxylase. This work has given us deeper insight into drug resistance as well as the evolutionary trajectories of smoking- and non-smoking-related, oncogene-driven NSCLC (Figure 2).
We have further developed novel computational algorithms to de-convolute stromal vs. tumour- specific gene expression, as well as gene expression-based extracellular matrix scores for prognostication. Finally, our translational immunology group recently identified a cell-surface marker, CD39, which may identify a tumour antigen that recognises exhausted T cells specific to tumour antigens; this may potentially represent a highprecision patient selection biomarker for checkpoint inhibition. Leadership in the field of lung cancer is further demonstrated by our involvement in the development of global guidelines for the International Association for Study of Lung Cancer.
In addition to ongoing involvement in pivotal clinical trials, we work closely with the phase I unit that has expanded in tandem with the Thoracic Programme, as many novel agents in lung cancer have demonstrated successes and even attained regulatory approval in early-phase trials. With many more oncogenic drivers amenable to targeted therapies (e.g., ALK, ROS1, BRAF, NTRK, RET), the Experimental Cancer Therapeutics Unit has been at the forefront of the development of targeted compounds and immunotherapy. For instance, our group played a key role in the Phase I – III development of ceritinib, one of the early second-generation ALK inhibitors. Broadening the biomarker repertoire to interrogate various druggable traits and develop rational combination therapies is a key research priority. By integrating the latest tools in genetic, experimental, and computational analyses, together with the use of the latest anti-cancer drugs, our goal is to innovate on current drug development approaches, accelerate timelines for drug approvals, and improve our understanding of lung cancer drivers and tumour heterogeneity.
Figure 2: Smoking and non-smoking evolutionary trajectories.
PLANS FOR THE NEXT 2 TO 3 YEARS
1) Although low-dose CT (LDCT) screening to detect early-stage disease has conferred benefit amongst smokers, identifying the never-smokers who are at risk of lung cancer remains a challenge. We plan to adopt a blood-based biomarker detection strategy with LDCT screening to better select persons at risk or those who have developed early-stage cancer; this is expected to increase the chances of long-term survival. We believe this will enable risk-stratified lung cancer screening approaches for our unique patient population.
2) Through the National Lung Molecular Profiling Programme, we plan to implement panel-based sequencing for all lung cancer patients in Singapore. This will allow us to better understand the natural history of each molecular subtype and facilitate subsequent enrolment to molecularly selected clinical trials. Patients without known driver alterations may be subject to deeper profiling with exome/RNA-seq, and we anticipate that novel targets may be discovered (e.g. GLDC) and either developed at A*STAR (Experimental Therapeutics Centre); or other industry partners.
3) We will continue to broaden our translational therapeutics programme, both in terms of identifying new compounds that address first-in-class targets and characterising the causes of drug resistance to targeted and immuno-therapy. Current plans also include exploring novel trial designs that consider the evolutionary potential of individual tumours, as well as basket umbrella concepts that are built around novel biomarkers.
HUMAN CAPITALThe lung programme has provided a platform for training students, post-doctoral fellows (10) and clinician-scientists (4). At present, Dr. Amit Jain is an Associate Consultant furthering his interest in cell therapy and undertaking a PhD under the supervision of Prof. Dario Campana. We have also trained fellows and early career faculty members who continue to pursue translational research in thoracic oncology and have won international awards for their research (Dr. Wan Ling Tan,Dr. Gillianne Lai and Dr. Aaron Tan). The ongoing programme will provide ample training opportunities for biologists, computational scientists, coordinators and clinicians.
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