Experimental Therapeutics Study Program

The experimental therapeutics program was organized to advance new therapies from the laboratory to the clinical setting, and from engaging in early stage drug discovery and development, to developing innovative research tools for clinical analysis. It is a bridge between basic science and clinical research where therapeutic agents, which battle or ameliorate human disease can be studied on molecular and cellular levels as well as in pre-clinical and clinical models. In the past few years, this program has encouraging results.

Application of ENO1 antibody in autoimmune disease and lung cancer treatment

Using morphologically normal lung tissues as a control lysate vs. those of NSCLC tumor cells from pleural effusion, Dr. NY Shih and Dr. KJ Liu identified a p48 alpha-enolase (ENO1) as tumor-associated antigen. Surface expressed ENO-1 detected by IHC was found to be a poor prognostic factor in NSCLC [Clin Cancer Res, 2003] Their further studies showed α-enolase co-localize with urokinase-type plasminogen activator on the surface of lung cancer cells that located at the site of pericellular degradation of extracellular matrix components in lung cancer tissue. It suggested surface α-enolase promotes extracellular matrix degradation and invasion of cancer cells and can be potential target to suppress tumor metastasis. [PLoS One, 2013] Abundance of surface ENO1 is the key to initiate cell invasive and tissue metastatic events in both NSCLC and PDAC. [Oncotarget, 2015] In addition, differential expression of ENO1 correlates with survival in oral cancer patients regardless cervical lymph node metastasis. Detection of ENO1 in primary tumor may be prognostic marker for oral cancer patients [BMC Cancer, in revision, 2017].

Notably, a single administration of the home-made mAb significantly reduced the nodule number and tumor volume in lung metastatic colony formation assay and pancreas orthotopic tumor models in mice. [Oncotarget, 2015] Therefore, Dr. Shih and Dr. Liu have conjuncture with DCB to file a cancer treatment patent for a specific clone of anti-ENO-1 monoclonal antibody. Later on, they have got 3 US and 2 ROC anti-ENO1-related patents. With all the research effort on the role of ENO1 and ENO1-specific antibody, we have successfully signed a technology transfer contract entitled “Humanized anti-alpha-enolase antibody for the treatment of cancer, multiple sclerosis, rheumatoid arthritis, and sepsis” with the Development Center for Biotechnology on January 2, 2014. This technology transfer was further sub-licensed to HuniLife Biotechnology, Inc on October 27, 2015 for the development of anti-ENO1 monoclonal antibody drug. The total value of the technology transfer for 9 indications is over NTD 3,670M. This is the largest technology transfer deal that NHRI ever has. The planned first IND will be filed before the end of 2018. In addition, Dr. Shih Dr. Liu, and Dr. WC Hung have joined the NHRI SP “Biologics” program and generated an anti-VEGFR2 monoclonal antibody, which targets on the dimerization domain of the VEGFR2. In vitro studies show the antibody can effectively inhibit both angiogenesis and lymphangiogenesis.

c-Myc and mTOR are potential therapeutic targets for pNET

To analyze the genetic aberrations of pancreatic neuroendocrine tumor (pNET) in Taiwan, Dr. HJ Tsai performed gene expression array analysis of frozen tumors and normal tissues and further analyzed by Gene Set Enrichment Analysis (GSEA). Among the up-regulated gene sets, reactome PI3K-AKT activation and KEGG-MTOR-signaling pathway were significantly enriched in tumor tissues. In addition, the up-regulated gene set of Reactime energy-dependent regulation of mTOR-LKB-AMPK as well as reactome_gluconeogenesis and reactome_glucose_metabolism were significantly enriched in tumor tissues. In vitro and in vivo studies suggested that c-Myc up-regulation in pNETs may occur through PTEN/LKB1-dependent and -independent regulation. The results delineated the regulation of PTEN and LKB1 on the AKT/mTOR/c-Myc axis and suggested both c-Myc and mTOR are potential therapeutic targets for pNET. In addition, Dr. Tsai’s group found mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), which is encoded by PCK2, catalyzes the conversion of oxaloacetate to phosphoenolpyruvate could confer mTOR inhibitor resistance in pNET cells [Oncotarget, 2017]. To support her further study, Dr. Tsai is currently running a nation-wide registration trial for all NET in TCOG.

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