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透視未來醫療-精準醫學及高精確醫學

2017-10-21

精準醫療
精準醫療
精準醫療
精準醫療
主辦單位:中國醫藥大學附設醫院
❈ 本場活動全程以英文進行
 

   立即報名

 

主持人: 

蔡進發 博士

♢ President of Asia University, Taiwan

♢ Chair Professor of Bioinformatics and Medical Engineering, Asia University, Taiwan

張建國 博士

♢ Deputy Superintendent, China Medical University Hospital

♢ Director, Department of Laboratory Medicine, China Medical University Hospital

♢ Professor, School of Medicine, China Medical University

♢ Director, Epigenome Research Center, China Medical University Hospital

♢ Director, Center for Precision Medicine, China Medical University Hospital


13:10 – 14:00 
Marker-guided targeted therapy, PARP inhibitors, and novel post-translational modification of PD-L1

 

 Elizabeth Shpall, MD

Mien-Chie Hung, PhD

♢ Vice President, Basic Research

♢ Professor and Chair, the Department of Molecular and Cellular Oncology

♢ The University of Texas MD Anderson Cancer Center

 

Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. Three PARP inhibitors have been approved by the FDA to treat ovarian cancer with (olaparib and rucaparib)or without BRCA mutations (niraparib). BRCA1 and BRCA2 play essential roles in repairing DNA double strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. My group recently demonstrated that receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907. Phosphorylation of PARP1 Tyr907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. Combining c-Met and PARP1 inhibitors synergized to suppress growth of breast cancer cells in vitro and xenograft tumor models. Similar synergistic effects were observed in a lung cancer xenograft tumor model. These results suggest that PARP1 pTyr907 abundance may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients bearing tumors with high c-Met expression who do not respond to PARP inhibition alone (Nature Medicine 22:194-201, 2016). Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumor-associated immune escape. Here, we show that the immunosuppression activity of PD-L1 is stringently modulated by ubiquitination and N-glycosylation. We identified glycogen synthase kinase 3b (GSK3b) as a novel protein that interacts with PD-L1 and can induce phosphorylation-dependent proteasome degradation by b-TrCP. We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3b inactivation in basal-like breast cancer (BLBC). Inhibition of EGF signaling by gefitinib destabilizes PD-L1, enhances antitumor T cell immunity and therapeutic efficacy of PD-1 blockade in syngeneic mice models. Together, we demonstrated a novel interchange between glycosylation and phosphorylation regulating ubiquitination and degradation of PD-L1. This regulatory event is critical for BLBC cells that escape immune surveillance via PD-L1/PD-1 interaction. Importantly, inhibition of EGF-mediated PD-L1 stabilization enhances a therapeutic efficacy of PD-1 blockade to promote tumor-infiltrating cytotoxic T cell immune response. Thus, targeting PD-L1 stabilization provides a novel strategy to combat BLBC-mediated immunosuppression and may potentially apply to other cancer types (Nature Communications 7:12632, 2016). In a most recent study, we identified TNFα as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1) (Cancer Cell, 30:925, 2016). To this end, in collaboration with StCube Pharmaceuticals Inc., we have developed monoclonal antibodies against glycosylation-specific PD-L1. Impressive therapeutic effect was observed through ab-drug-conjugate approach and a manuscript is currently under view in Cancer Cell.

  


14:00 – 14:50 
The limits of immunotherapy: Next generation anti-CTLA4 antibodies

 

 Katy Rezvani, MD, PhD

Alan J. Korman, PhD

♢ Vice President, Immuno-Oncology Discovery, Bristol-Myers Squibb

 

The activity of ipilimumab (anti-CTLA-4) as a single agent alone and in combination with nivolumab (anti-PD-1) in melanoma as well as the use of ipilimumab/nivolumab combinations in other malignancies has confirmed the importance of CTLA-4 blockade in immunotherapy.  The anti-tumor effect of this treatment also results in significant immune-related adverse events that limit dosing and result in patient discontinuation.  The mechanism of action of anti-PD-1 and anti-CTLA-4 antibodies in murine models has been studied.  In addition, we have taken two approaches to alter the activity of ipilimumab so as to improve its potency and its safety profile.  One approach is to enhance the antibody dependent cellular cytotoxicity (ADCC) activity of ipilimumab in order to increase the potential for Treg depletion at the tumor site; this would be expected to increase the activity of the antibody.  The second approach is to produce a pro-drug form of ipilimumab that will have reduced activity systemically, but will become proteolytically cleaved at the tumor site to produce the fully functional antibody; this approach would be expected to reduce the adverse event profile while retaining the anti-tumor activity of ipilimumab.

  


14:50 – 15:00 
Coffee Break, 10 minutes
 


15:00 – 15:30 
AI and precision medicine

 

 Xin Lin, PhD

Jeffrey J.P. Tsai, PhD

♢ President of Asia University, Taiwan

♢ Chair Professor of Bioinformatics and Medical Engineering, Asia University, Taiwan

  

Precision medicine includes precision of prediction, prevention, diagnosis and therapy. To reach these goals, we must collect personal genomic data, life style data, environmental data, medical record, and a lot of Omic data, and use these big data to make real-time decision to manage the patient’s problem. In order to handle these big data to achieve precision medicine, we need to use many new methods and tools. Artificial intelligence (AI) has been used to many fields, including analysis of genome structure and function, and shown very promising results. Although AI has been used in the prediction of risk factors of disease, the diagnosis, and treatment of some diseases, but it is rarely used in the integration of precision medicine-related big data. In medicine, AI-related techniques have been used in the image analysis to improve the diagnosis of pathology and radiology and the results are shown much more precise than related specialist. From the performance of AI, we suggest that AI techniques, such as machine learning, deep learning and cognitive computing, may play a critical role in the precision medicine.

  


15:30 – 16:00 
Key ingredients for practicing precision medicine in Taiwan

 

 Pui-Yan Kwok, MD, PhD

Pui-Yan Kwok, MD, PhD

♢ Distinguished Research Fellow and Director, Institute of Biomedical Sciences, Academia Sinica

♢ Henry Bachrach Distinguished Professor, University of California, San Francisco

 

Precision medicine takes into account individual characteristics and disease mechanism to prevent, diagnose, and treat diseases. Key ingredients in the practice of precision medicine include collecting large amounts of individual data (germline genetic information, somatic changes, metabolic profile, environmental exposure, lifestyles, etc.) and disease data (genetic defects, transcriptome profile, metabolic derangement, etc.), and interpreting these data against population norms and other individuals with similar symptoms and genetic background.  As more population data are available and our biological knowledge deepens, our ability to diagnose and treat disease based on disease mechanisms will increase.  Being able to predict disease susceptibility will allow us to implement screening strategies and take active measures to prevent disease.

With a national healthcare system ad a relatively homogeneous population, Taiwan is well positioned to implement the practice of precision medicine. However, its success depends on building a strong infrastructure and the sharing of clinical and genetic data so that data interpretation will be based on solid population characteristics.  With collaboration of all stake holders and acceptance by the population, Taiwan can serve as a model for how to practice precision medicine in a large population.

 


16:00 – 16:30 
Application of genomic technologies in disease diagnosis and drug discovery

 

 Wei-Chiao Chang, PhD

Wei-Chiao Chang, PhD

♢ Professor, Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University

♢ Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, Taipei Medical University, Taiwan

 

Advances in the genomic technologies (GWAS, NGS, single cell RNA sequencing, immune repertoire sequencing) make it possible to rapidly identify the genetic differences ranging from a single base variant to large structural gene events. As the sequencing moves toward the clinic, many biomarkers were observed and detected from patients. These findings have important implications for the disease diagnosis as well as drug discovery. In the first part of my presentation I will use “store-operated calcium channel” as a model to illustrate the clinicopathological significance for store-operated calcium entry and COX-2 in colorectal cancer (CRC) progression. Our studies also indicated a new approach to inhibit STIM1-mediated metastasis with nonsteroidal anti-inflammatory drugs (NSAID). In the second part of my talk I will demonstrate the application of single cell RNA sequencing data to explore the remodeling of the tumor microenvironment that leads to the correlations between calcium signaling, immune infiltrate and the impact on survival in patients. Finally, I will present results from our recent immune repertoire sequencing data and discuss some of the expected challenges ahead.

 


16:30 – 16:50 
Precision medicine in China Medical University Hospital

 

 Shih-Hwa Chiou, MD, PhD

Jan-Gowth Chang, MD

♢ Deputy Superintendent, China Medical University Hospital

♢ Director, Department of Laboratory Medicine, China Medical University Hospital

♢ Professor, School of Medicine, China Medical University

♢ Director, Epigenome Research Center, China Medical University Hospital

♢ Director, Center for Precision Medicine, China Medical University Hospital

 

Precision medicine is the goal of future medicine. The future of precision medicine will enable health care providers to tailor treatment and prevention strategies to people’s unique characteristics, including their genome sequence, microbiome composition, health history, lifestyle, and diet. The core of precision medicine is epigenetic changes in addition to personal genetic differences and microbiome changes. To detect these changes, it is necessary to develop genetic detection technologies and analysis methods, such as whole genome sequencing, exome sequencing, transcriptome sequencing, microbiome sequencing, methylome sequencing, ChIP-seq, and 3C technology. More importantly, we need to analyze these data properly and integrate them to clinical use for precise diagnosis and precise therapy. In the past one year, we have established the platforms for precise detection and diagnosis in the department of laboratory medicine, China Medical University Hospital. We will share these experiences with you in this presentation.

 


16:50 – 17:00 
Closing Remark

 

❈ 主辦單位保留更改活動及報名成功與否的權利