Precision Medicine in Liver Cancer across an Asia-Pacific Network (The PLANet Study) (Clinicaltrials.gov identifier:
Hepatocellular carcinoma (HCC) is the 6th most common cancer in the world but the 2nd most important cause of cancer death. Due to its highly heterogeneous nature, the current approach to identifying druggable targets have not delivered efficacious therapies in HCC and is a main reason for the high case fatality. Even when surgical resection is potentially curative in early disease, tumor recurrence remains high and long term survival poor because of the absence of useful adjuvant therapy.
It is shown that through multi-region sampling of freshly resected HCC and phylogenetic analysis, that significant intra-tumoral heterogeneity exists and have identified the specific positions of known clonal drivers. Simultaneously we have analyzed the immune landscape of the tumor microenvironment with deep immune-phenotyping and found unique inter-patient immune landscapes predictive of clinical trajectory. Clinical trajectories are tracked and genomic and immunological studies are repeated when tumors recur, to confirm clonally dominant driver mutations and immunological processes that are targetable. Concurrently, representative pre-clinical models will be developed from the tissues sampled.
The study aims to combine these approaches to overcome the challenges posed by genomic and immunomics heterogeneity and to guide the development of therapeutics and precision medicine in HCC.
Yoong Boon Koon (University Malaya Medical Center)
Maria Vanessa H. de Villa (The Medical City)
Pierce Chow (National Cancer Centre), Glenn Bonney (National University Hospital), Brian Goh (Singapore General Hospital)
Rawisak Chanwat (National Cancer Institute)
United States of America
Sabino Zani Jr (Duke University School of Medicine)
Theme 1: Genomic evolution in HCC and the discovery of novel drug targets
Theme PI: Zhai Weiwei (Senior Research Scientist, Genome Institute of Singapore)
Theme 2: Translational Immunomics: Immune-phenotyping, monitoring and discovery of novel immunotherapies
Theme PI: Salvatore Albani (Director, SingHealth Translational Immunology and Inflammation Centre)
Theme 3: Clinical Trajectory and Translational Therapeutics
Theme PI: Pierce Chow (Senior Consultant, National Cancer Centre)
Early Detection of Hepatocellular Carcinoma: miRNA, microbiome and imaging biomarkers in the evolution of chronic liver disease in a high-risk prospective cohort (ELEGANCE)
In Singapore, hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer death in male and 4th in female. A major reason for its lethality is the absence of diagnostic modalities with high accuracy for the detection of early stage HCC. Currently only 20% of HCC are diagnosed in the early stage when curative treatment can be carried out. The inability to diagnose HCC at an early stage for the majority of patients is thus an urgent unmet public health need.
Current guidelines for the surveillance of patients at risk of developing HCC involves a combination of serum alpha-fetoprotein (AFP) and abdominal ultrasound (US) every 6 months. AFP and US have accuracies of 76.6% and 84% respectively for the detection of HCC but for early HCC, sensitivity with US drops to only 47% and adding AFP to US increases sensitivity in this group to only 63%. There is thus an imperative to develop novel diagnostic modalities that can more accurately detect early HCC. Plasma microRNAs (miRNAs) have shown promise in preliminary studies and in this collaboration with MIRXES, we aim to develop the 1st miRNA in-vitro diagnostic (IVD) kit for HCC that has higher accuracy and better ease of use compared with the extant combination of AFP and US.
Patients with chronic liver diseases have increased risk of developing HCC. There is currently no accurate method to identify individuals at higher risk of developing HCC in a sufficiently granular manner such that we can devote more resources for targeted surveillance. We continue our earlier collaboration with Perspectum to develop the 1st AI algorithm with MRI to predict individual risks of developing HCC within a specific timeline.
There is a worldwide increase in the prevalence of metabolic liver disease. The biology and clinical trajectories of metabolic liver diseases and cancer remain unclear but emerging data have shown association with changes in the microbiome and metabolome. There is therefore urgency to study the association between gut microbiome, metabolome and the liver in order to stratify individual patient risks and prevent disease progression and the development of HCC. We collaborate with AMILI to build on their existing microbiome library from healthy donors and to expand our collaboration with the Singapore Phenome Centre (SPC) to examine changes in the microbiome and metabolome in the build-up to the development of HCC. The aim is to identify potential therapeutic targets in the microbiome and metabolome where intervention can prevent the development of HCC and slow the progression of chronic liver diseases.
In this study, we collaborate with MIRXES, Perspectum and AMILI on research that will be carried out on a prospective cohort study of 2,000 patients at risk of developing HCC (AHCC10, main study) and a parallel cohort of 100 patients already diagnosed with HCC (AHCC11, parallel study).
Eugene Wong (Changi General Hospital), Toh Han Chong (National Cancer Centre), Lee Guan Huei (National University Hospital), Jason Chang (Singapore General Hospital), Chong Oi Fong (SingHealth Polyclinics – Bedok), Sabrina Wee (SingHealth Polyclinics – Bukit Merah), Tan Kee Tung (SingHealth Polyclinics – Marine Parade), Ong Kok Kiong (SingHealth Polyclinics – Outram), Tan Ngiap Chuan (SingHealth Polyclinics – Pasir Ris), Yeap Xin Yi (SingHealth Polyclinics – Punggol), Choo Han Jun (SingHealth Polyclinics – Sengkang), Sulaiha Binte Ithnin (SingHealth Polyclinics – Tampines), Marianne De Roza (Sengkang General Hospital), Yang Wei Lyn (Tan Tock Seng Hospital)
In this proposed study, we continue our collaboration with MIRXES and AMILI on a cohort of 100 patients already diagnosed with HCC. This study will also act as a positive control to the AHCC10 ELEGANCE Study.
We will use the miRNA profiles of 100 patients with diagnosis of HCC confirmed by histology at surgical resection to confirm the hypothesis that the miRNA biomarkers that are predictive of occurrence in HCC will revert back to profiles similar to non-HCC cohort. In addition, we aim to determine if progressive changes in miRNA signatures are predictive of recurrence and to discover new signatures for recurrence prediction.
Adrian Chiow (Changi General Hospital), Pierce Chow (National Cancer Centre), Glenn Bonney (National University Hospital), Brian Goh (Singapore General Hospital), Kam Juinn Huar (Sengkang General Hospital), Vishalkumar G. Shelat (Tan Tock Seng Hospital)
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