Cancer - Singapore General Hospital

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Envisioned Future

Our vision is to build and sustain a dynamic ecosystem of high impact research in blood, breast, colorectal and prostate cancer, with novel methods for early detection, unravelling of the tumour microenvironment and its inflammatory milieu, translating to targeted therapeutics for quality survival, supported by robust registries and tissue repositories, to be achieved in the next 5 years.

Research Strategy

Transforming Early Detection And Screening
Translational Pathology – Focus On The Tumour Immune Microenvironment
Targeted Therapy - Reduce Morbidity and Maintain QOL
Registries and Tissue Repositories

1. Transforming Early Detection And Screening

Key outcome: Early screening service in SGH where biomarker based assays in leukaemia, breast, colon and prostate cancer allow earlier and more accurate detection of cancer than current approaches.

Aim 1: Common cancers of the blood, breast, colon and prostate frequently "shed" DNA in the blood and urine where it can be detected using NGS.
Aim 2: Micro-environmental changes are part of carcinogenesis and may be used to predict presence or susceptibility to disease.
Aim 3: Multi-parametric approach in detection with a refocus to detect clinically significant/actionable early lesions.

Colon: predicting cancer	Identify early genetic changes that predict subsequent occurrence of colorectal cancer in archival samples in correlation with blood biomarkers.
Prostate: improving diagnostic precision	Detect clinically significant cancers using multiparametric MRI and MRI-US fusion biopsies. Develop novel tissue and blood biomarkers to detect clinically significant cancer rather than indolent, clinically insignificant ones
Breast: better than mammogram	Mammography has its disadvantages, with a 10% false negative rate, reduced sensitivity for younger women with dense breasts, and discomfort during the mammography process. Aim to discover biomarkers in blood that may serve as a sensitive predictor for breast cancer, as an alternative or adjunct to mammography.
Blood: preleukaemia	Investigate bone marrow microenvironmental changes that affect pre-leukaemia development and combine information with current investigations on blood cells.

2. Translational Pathology – Focus On The Tumour Immune Microenvironment

Key outcomes:

Interpreting changes in the tumour microenvironment during routine diagnostic pathology in the era of cancer immunotherapy.

Integrate parameters of tumour and immune microenvironment (TIME) into prognostic and therapeutic models.

Aim 1: Examine how the molecular and cellular nature of the tumour immune microenvironment (TIME) influence cancer development and therapy (eg. dysfunctional signaling, chronic inflammation, etc).

Aim 2: Investigating the biological nature of T-cells (innate or adoptively infused) within the TIME and their ability to successfully reject tumours as a prognostic capability.

Breast cancer

Triple negative: Investigate signaling transduction pathways in immune checkpoint proteins (involved in immune checkpoint protein (PD-1/PD-L1, CTLA-4/CD80, etc) which impact immunotherapy strategies.
DCIS: A better understanding of cellular and molecular changes occurring during the transition from DCIS to invasive form could improve immunotherapies for both early and advanced breast cancer.

Blood cancer

Bone marrow microenvironmental changes that occur in support of leukaemogenesis are however not captured in current assessments.
Chronic inflammation, various changes in functional properties of supportive cells are all indicators of disease initiation and progression. We will be studying how to target these changes more efficiently.

3. Targeted Therapy - Reduce Morbidity and Maintain QOL

Key outcomes:

Development of robust platforms at SGH for supporting the delivery of targeted therapies that are oncologically efficacious, have minimal side effects, and allow patients to maintain their quality of life.

Such platforms include: Imaging and molecular guidance systems and preclinical animal models.

Aim 1: Identify targets for therapy.

Aim 2: Develop therapeutic approaches to attack these targets.

Aim 3: Develop predictive biomarkers in order to select suitable patients for targeted therapy.

Blood Cancer	Establish PDX models In vivo and ex vivo preclinical therapeutic screening Profile human tissue and PDX models Identify novel targets and biomarkers Determine mechanisms of resistance Early phase biomarker driven clinical trials
Prostate Cancer	Multi-parametric MRI for improved staging Multi-parametric MRI-TRUS fusion for targeted prostate biopsy Tesla MR-guided focused ultrasound for focal therapy
Colorectal Cancer	Ex vivo model that mimics human in vivo milieu and minimal culture adaptation Complemented with genomics, proteomics and metabolomics Targeting KRAS
Exercise in Cancer	Determine if cardiorespiratory fitness (CRF) is predictive of risk of cancer incidence and relapse Determine if exercise programs are able to increase CRF and reduce incidence of cancer and cancer-related mortality Determine if correlative or associative studies are able to prove the above

4. Registries and Tissue Repositories

Key outcomes:

Harnessing artificial intelligence and deep learning via the registry to monitor and improve patient outcomes.
Consent and biobanking should be part of routine care (standard in other leading AMC).

Registries:

Aim is to capture demographics, clinical features at presentation, management and outcomes of patients.
Important disease and patient characteristics which may affect treatment decisions and disease outcomes will be captured for future longitudinal studies.
Availability of this data is vital for any large AMC.

Tissue Repositories

Heterogeneity within our patient population and differences between our patients and typical subjects of large published trials.
To address these differences and achieve our goals for precision medicine, we should endeavor to store serial specimens from as many of our patients as possible.

Blood Cancer	More than 3000 samples Multiple collaborations leading to high impact factor publications Discovery of genetic polymorphism which mediates resistance and inferior responses to TKI in East Asian CML and NSCLC National clinical registry AML database
Prostate Cancer	Registry has data on 5590 patients Multiple publications Used jointly with Cambridge Urology research group to validate the Cambridge Prognostic Groups for improved prediction of mortality in primary non-metastatic prostate cancer
Colorectal Cancer	More than 7000 tissue and blood specimens Discovery of CNV region (CNVR) via GWAS involving 2000 Chinese cases and controls Singapore Polyposis Registry housed with Dept of Colorectal Surgery
Breast Cancer	Largest series of DCIS in Singapore Largest series of TNBC in Singapore Largest single institutional series of phyllodes tumours in the world Multiple publications and collaborations