Upper Aerodigestive Tract Cancer Study Program

In response to the health policy of Ministry of Health and Welfare (MOHW), an integrated, disease-oriented translational oral cancer study program has been initiated in 2008 and expended to the upper aerodigestive tract cancer one. The study program focuses on head and neck cancer (including nasopharyngeal carcinoma), esophageal cancer and lung cancer.

Head and neck cancer study program

This group has established 3 fundamental infrastructures to support its studies.

  1. A case-control study entitled of “Environmental and Genetic Epidemiology and Prognostic Study of Head and Neck Cancer” aims to identify environmental and genetic risk factors for the development and the prognosis of HNSCC.
  2. In collaboration with NCKUH physicians, the group collected 40 pairs of OSCC tumor tissue and their normal counter parts from male patients with betel-nut chewing habits for human OSCC genome-wide association study. The samples assayed for 4 different microarray included gene expression array, DNA methylation array, microRNA array and SNP array.
  3. The group has established a chemical carcinogen-induced oral cancer mouse model.

 

Nasopharyngeal carcinoma

This program, led by Distinguished Investigator JY Chen, emphasizes on exploration a novel concept regarding the importance of Epstein-Barr virus (EBV) reactivation in the pathogenesis and progression of nasopharyngeal carcinoma (NPC). It aims to identify new targets for therapy as well as evolve new strategies for disease prevention and treatment, and to translate these into the clinic. The major findings of the program in the past few years are summarized in the following figures.

Dr. Chen subsequently proposed that adjuvant therapy aiming to prevent EBV reactivation could be a potential strategy to reduce NPC recurrence in patients after curative-intent radiotherapy. The clinical trial “Study of Epstein-Barr virus reactivation and the effect of dietary supplement epigallocatechin gallate (EGCG) on virus reactivation in remission patients with nasopharyngeal carcinoma – a randomized trial” has been funded by the NRPB/NSC from August, 2012 to July, 2015, under the supervision of Deputy Director and the Chief of TCOG, Dr. TW Liu. This study has completed patient enrollment in mid-2017. The final results, the effects of EGCG on reducing EBV reactivation and perhaps tumor recurrence, are expected to available in late 2019.

Lung cancer

Patients of non-small cell lung cancer (NSCLC) with mutated EGFR are relatively sensitive to EGFR-TKI treatment and have longer progression-free survival (PFS) when treated with EGFR-TKI, compared with platinum-based chemotherapy. Dr. IS Chang & SS Jiang collaborated with the director of Institute of Population Health Science (IPHS), Dr. CA Hsiung, conducted a genome-wide association (GWAS) study on PFS in never-smoking women with lung ADC receiving first-line EGFR-TKIs. They identified the association between SNPs at 4q12 and PFS, with an estimated hazard ratio greater than 4. The finding was also replicated in an independent NSCLC cohort. Follow-up functional analyses showed that these SNPs are associated with the expression of EGFR and a nearby gene NMU, which encodes a GPCR ligand known to be involved in the progression of NSCLC. The findings indicate genetic variants in 4q12 might be potential pharmacogenomic predictors for TKI therapy in lung ADC. [Am J Resp Critical Care Med 2017]

In addition, Dr. SE Chuang identified a post-transcriptional negative feedback loop regulation of AXL, a well-known receptor tyrosine kinase, by miR-34a and miR-449a/c via the JNK/ELK1 pathway. The kinase domain and the Y779 tyrosine phosphorylation site of AXL were found to be crucial for this auto-regulation. R428, a selective small molecule inhibitor of AXL kinase, and AXL-Fc, a soluble form of AXL containing only the extracellular domain of the AXL protein, both could block this feedback effect. The data suggests that this is a built-in mechanism biologically devised to subtly control the activity and functions of AXL at the mRNA level. [RNA, 2016]

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