Prostate Cancer 

Precision Oncology Prostate Cancer

Prostate cancer has emerged as the 3rd commonest cancer among men in Singapore. At NCCS, our research is focused along the following themes – 1) to characterize the germline and somatic genomic landscape of Singaporean men with prostate cancer; 2) to investigate the molecular drivers of therapeutic resistance in high-risk and advanced prostate cancers; and 3) to conduct novel treatment-intensification trials with new generation anti-androgens.

For theme 1, we are interested if germline genetics for prostate cancer susceptibility differs between different racial demographics in Singapore (Chinese vs Malays vs Indians), and also between Asians and Caucasians. To this end, we have a prospective cohort of >1,000 men on follow-up, for which we are running WES and SNP genotyping; paired clinical data is available for all patients. This research is performed in collaboration with the Ontario Institute of Cancer Research (OICR), Toronto. We are also a member of the PRACTICAL (www.practical.icr.ac.uk) consortium, which seek to investigate the risk genes for prostate cancer in 200,000 men globally. 

Additionally, we are investigating for the prevalence of specific germline mutations in DNA repair genes and HSD3B1, which may have a clinical relevance in predicting therapeutic sensitivity to chemotherapeutic agents and hormonal therapy (HT), respectively. Separately, on the somatic genomic landscape, we have collaborated with OICR to publish one of the largest comprehensive molecular dataset on 500 localized prostate tumors. Similar to the findings by TCGA, we again observed that prostate cancer is a C-class tumor, but more importantly, we found that epigenomic dysregulation of TCERG1L gene carries a greater impact on prognosis than recurrent copy number aberrations like CMYC and TP53 (Fraser et al., Nature, 2017). We further performed subclonal reconstruction in these tumor's, and found that polyclonal tumours have a higher risk of relapse post-treatment than monoclonal tumors (Espiritu et al., Cell, 2018). Finally, we made an interesting discovery of recurrent mitochondrial mutations that appear to be linked to recurrent nuclear mutations in prostate cancer, and these compound mutational events may affect prognosis in patients (Hopkins et al., Nat Comms, 2017).

For theme 2, we adopt the same NGS approaches to determine the mutational events that are enriched in recurrent and high-risk prostate cancers that are resistant to radiotherapy and surgery, using a matched case-control design. We observed that clonal selection of resistant tumor clones predominate in prostate cancer at the time of recurrence (Chua et al., ASTRO, 2017). To perform functional characterization, we have established radioresistant prostate cancer cell lines (RR-22RV1 and RR-DU145). Next, we are investigating for differential molecular genetics in high Gleason’s grade (GS9-10) prostate cancers between tumors that recur within 18 months, post-therapy against those that are controlled with single modality surgery or combination hormonal-radiotherapy. This will allow us to hopefully identify molecular drivers that are associated with highly aggressive prostate cancers. Lastly, we are conducting a prospective study to validate the role of circulating ARV7 in predicting resistance to second-generation anti-androgen therapy of enzalutamide and abiraterone in Asian men with metastatic castrate resistant prostate cancer; NCCS is the lead institution in this international multicenter study, involving five other institutions from Asia.