For targeting the “next important” cancers in Taiwan, glandular malignancies including breast, cholangiocarcinoma and prostate cancer have been included since 2010. This program initially supported by funding from the Excellence Center for Cancer Research of MOHW in 2010-2013; while it has been shifted as a Supplementary Project of NHRI since 2014.
Prostate cancer subproject:
Dr. KK Tsai used comparative transcriptome analysis of human prostatic acini generated in a three-dimensional basement membrane that recapitulates the differentiated morphological characteristics and gene expression profile of a human prostate glandular epithelial tissue. He identified an acinar morphogenesis-specific gene profile, with programmed cell death protein 4 (PDCD4) and Kruppel-like factor 6 (KLF6) as surrogate markers, has superior prognostic prediction performance for post-operative relapse compared with clinical criteria and Gleason scores in multivariate analysis. [Am J Pathol, 2013]
Due to the poor clinical outcomes and lack of reimbursed, effective medication, NICR put efforts on both clinical trial and translational researches. Before the reimbursed of gemcitabine, the global standard of care in advanced biliary tract cancer (BTC), in Taiwan, we initiated a KRAS-stratified randomized phase II trail to evaluate the efficacy of add-on cetuximab in patients with advanced BTC receiving gemcitabine plus oxaliplatin (GEMOX), the TCOG T1210 study. Add-on cetuximab, an anti-EGFR mAb, marginally improve tumor response rate (ORR) and progression-free survival (PFS), but not overall survival (OS). KRAS mutations were detected in 36% of tumor samples, but not predictive for therapeutic effect of cetuximab. [Annals of Oncology, 2015] Dr. NJ Chiang then retrospectively explored the predictive value of aberrant expressions of ROS1, ALK and/or c-MET (RAM) by IHC on the T1210 cohort. Of 110 tumors available for all 3 markers, all 18 RAMhigh tumors were intra-hepatic cholangiocarcinomas (IHCC) and had worse OS as compared to that of RAMlow IHCC. Add-on cetuximab significantly improved the disease control rate, PFS, and marginally prolonged median OS, compared to GEMOX treatment alone in RAMlow IHCC sub-cohort. This post-hoc study suggested RAM may be a companion diagnostics marker for advanced biliary tract cancer. [Sci Reports, 2016]
Breast cancer subproject:
NICR focused on two research fields, the interplay between cancer cells and stromal cells, and epigenetic regulation in breast cancer carcinogenesis. Of the first topic, Dr. WC Hung demonstrated COX-2-overexpressing breast cancer cells-secreted PGE2 can act through EP4/STAT3- dependent pathway to upregulate IDO expression in fibroblasts. Conversely, fibroblast-secreted kynurenine promotes the formation of E-cadherin/AhR/Skp2 complex, leading to the degradation of E-cadherin and increase breast cancer invasiveness. It highlights a novel interplay between cancer and stroma via COX-2 and IDO to promote tumor progression and predicts poor patient survival. [Cancer Breast Res, 2014] Whiles, Dr. KK Tsai found high-dose chemotherapy can induce persistent STAT-1 and NF-κB activity in CAF to result in the expression and secretion of ELR motif-positive (ELR+) chemokines, including IL-8, which signal through CXCR-2 on carcinoma cells to trigger cancer cell stemness and invasiveness, leading to paradoxical tumor aggression after chemotherapy. Conversely, such MTD chemotherapy-induced stromal ELR+ chemokine paracrine signaling can be tempered by continuous low-dose exposure, so-called “metronomic”, chemotherapy. [JEM 2016] Regarding the epigenetic regulation in cancer carcinogenesis, Dr. WC Hung also demonstrated that lysine demethylase 2A (KDM2A) functions as an oncogene in breast cancer by promoting stemness and angiogenesis via activation of the Notch signaling. [Oncotarget, 2016] He further demonstrated TET2, a DNA demethylase antagonizing DNMT-mediated DNA methylation, is a direct repression target of KDM2A and reveal a novel mechanism by which KDM2A promotes DNA methylation and breast cancer progression via the inhibition of a DNA demethylase. [Oncogenesis, 2017]