Medical oncology, hematology, anti-cancer drug development, clinical trial design, translation research
- The study investigating DNA damage response and its potential application in cancer cells.
- Diagnosis, treatment and prognosis of colorectal cancer.
- Tumor immunity of solid cancer.
RESEARCH ACTIVITIES & ACCOMPLISHMENT
1. The study investigating DNA damage response and its potential application in cancer cells.
Although targeted drugs and immunotherapies have become popular in cancer treatment, DNA damaging therapies (including radiotherapy) are widely used as standard of care treatment across most tumor types. Inhibiting the repair of DNA damage is also an attractive anticancer strategy and several different DNA repair inhibitors are in clinical development. For example, poly(ADP-ribose) polymerase (PARP) inhibitors which are involved in base excision repair and homologues recombination (HR) pathway are novel DNA damage therapies approved in BRCA-mutated ovarian and breast cancers. RAD51, BRCA1 and BRCA2 are known to be important effectors responsible for the integrity of HR function in repairing DNA double stand breaks (DSBs). In nasopharyngeal carcinoma (NPC) cells, we demonstrated that MGMT is involved in RAD51 expression and BRCA1 phosphorylation. By attenuating HR activity, the MGMT suppression enhanced DSB formation and cell death induced by PARP inhibitor. These results suggest that MGMT is a potential therapeutic and diagnostic target in cancer treatment with PARP inhibitor. Recently, immune checkpoint inhibitors are an emerging type of cancer treatment involved in immune cell activity against tumor growth. Accumulating evidence suggests combining DNA damage therapies and immune checkpoint inhibitor would be a promising strategy in cancer treatment. The potential of this combination therapy in cancer treatment will be examined in our laboratory.
Schematic illustrating the role of MGMT in HR signaling of NPC cells (adapted from J Biomed Sci. 2021 Jan 4;28(1):2. doi: 10.1186/s12929-020-00699-y).
2. Diagnosis, treatment and prognosis of colorectal cancer.
Colorectal cancer (CRC) has long been considered as a Western disease, but its incidence has gradually increased in Taiwan. Therefore, the efforts to improve treatment outcomes of patients with CRC are in unmet need. Genomic medicine has been widely applied in the diagnosis, treatment, and prevention of cancer. The identification of critical genetic mutations is an important diagnostic criterion for certain types of cancer. Advances in next generation sequencing (NGS) have led to the identification of hundreds of mutated genes, including single nucleotide variations (SNVs), copy number variations (CNVs), small insertion/deletions (indels), and fusion genes in a single assay. The studies in understanding the clinical utility of these sequencing tool in patients with CRC are warranted. In patients with stage II-III CRC, we found that age and lymph node ratio, selected by multivariable analysis and the four machine learning (ML) models, were prognostic factors for tumor recurrence. PIK3CA and DNMT3A mutations were more frequently found in older patients compared to their younger counterparts. Studies incorporating molecular and genomic studies in cancer prediction models by ML approaches can be beneficial for Taiwanese patients with stage II–III CRC (Biomedicines. 2022 Feb 1;10(2):340. doi: 10.3390/biomedicines10020340).
An established nomogram for predicting cancer recurrence of patients with stage II-III CRC (adapted from Biomedicines. 2022 Feb 1;10(2):340. doi: 10.3390/biomedicines10020340).
In Taiwanese patients with metastatic CRC (mCRC), we found that the most common mutated gene was TP53 (84.6%), followed by APC (78.0%), KRAS (49.6%), and SMAD4 (22.8%). When mutated genes were allocated into signaling pathways, alterations of cell cycle, Wnt, p53, RTK-RAS, PI3K, TGF-β, Notch, and Myc pathways were identified in 88%, 87%, 85%, 75%, 28%, 26%, 17%, and 10% of mCRC tissues, respectively. The survival analyses revealed that Myc and TGF-β pathway alterations were associated with a shorter overall survival (OS). The negative prognostic impact of altered TGF-β pathway was maintained in patients receiving an anti-EGFR antibody as first-line treatment. The OS of patients with mCRC carrying MYC and BRAF mutation was shorter than those with either MYC or BRAF mutation. These findings may provide new insights of clinical management for Taiwanese patients with mCRC, such as prognosis prediction, treatment guidance, and molecular-targeted therapy development (Diagnostics. 2021 Dec 8;11(12):2308. doi: 10.3390/diagnostics11122308). We will further examine CRC immunity by integrated analyses of single cell sequencing of tumor tissues and functional studies of immune cells from in vitro and in vivo experiments.
Genomic landscape of Taiwanese patients with mCRC (adapted from Diagnostics. 2021 Dec 8;11(12):2308. doi: 10.3390/diagnostics11122308).