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肿瘤生物学与转化医学 Cancer Biology & Translation Medicine

肿瘤生物学与转化医学 Cancer Biology & Translation Medicine. 陈志南 Zhi-Nan Chen. 第四军医大学 znchen@fmmu.edu.cn. Global Action Against Cancer. 1 Lung. Global (Year). 7 Esopha- geal. 2 Breast. 7.6 million Deaths. 10.9 million New Cases. Cancer. 3 Colon. 6 Cervical. 5 Liver. 4 Gastric.

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肿瘤生物学与转化医学 Cancer Biology & Translation Medicine

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  1. 肿瘤生物学与转化医学 Cancer Biology & Translation Medicine 陈志南 Zhi-Nan Chen 第四军医大学znchen@fmmu.edu.cn

  2. Global Action Against Cancer 1 Lung Global (Year) 7 Esopha- geal 2 Breast 7.6 million Deaths 10.9 million New Cases Cancer 3 Colon 6 Cervical 5 Liver 4 Gastric Update Edition 2005

  3. Cancer Against Cancer in China Incidence 2,000,000 Mortality 1,500,000 1 Lung 8 Nasopharyn- geal 2 Liver Liver Cancer Mortality/100,000 Countryside 26.93(1st) 7 Breast 3 Gastric City 24.41 (2nd) Cancer 6 Cervical 4 Esopha- geal 5 Colon Disease Control Division, Ministry of Health of PRC, 2008

  4. The third time investigation of death causes: cancer ranks second with a mortality rate of 22.32%. ——Ministry of Health, April 2008

  5. Cancer Cell: Contributing Factors 增生 • Inherited susceptibility • Chemical carcinogens • Radiation • Infectious agents • DNA repair system • General health (diet, stress, etc) • Immune system 异常 Cancer Etiology Cancer: Three Characteristics Multiple Carcinogen

  6. Cell Dysplasia genomic DNA transcription Carcinoma in situ post-transcription translation Primary cancer post translation Metastasis (2nd Cancer) Tumor Initiation Development Invasion Metastasis Multiple Stages

  7. Loss of genomic integrity and imbalance of molecules are mechanism for the cancer incidence Multiple Gene Mutation EMBO reports 1, 2, 115-119, 2000

  8. Cancer Initiation & Invasion Four Mechanisms

  9. Breast cancer 11 Samples Colon cancer 11 Samples removing errors, normal variants Sequencing: 13,023 genes Cancer Genome Atlas Mining the cancer genome Cancer Molecular Balance & Mutation 1149 mutation genes (Individual tumors: average 90) (Significant frequency: 189 genes) (Significant frequency:average 11 per tumor) Tobias Sjoblom, et al. Science 314: 268-274, 2006

  10. Cancer Genome Atlas Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution Sohrab P. Shah, Ryan D. Morin, Jaswinder Khattra, Leah Prentice, Trevor Pugh, Angela Burleigh, Allen Delaney, Karen Gelmon, Ryan Guliany, Janine Senz, Christian Steidl, Robert A. Holt, Steven Jones, Mark Sun, Gillian Leung, Richard Moore, Tesa Severson, Greg A. Taylor, Andrew E. Teschendorff, Kane Tse, Gulisa Turashvili, Richard Varhol, René L. Warren, Peter Watson, Yongjun Zhao, Carlos Caldas, David Huntsman, Martin Hirst, Marco A. Marra & Samuel Aparicio Recent advances in next generation sequencing 1, 2, 3, 4 have made it possible to precisely characterize all somatic coding mutations that occur during the development and progression of individual cancers. We found 32 somatic non-synonymous coding mutations present in the metastasis. Five of the 32 mutations (in ABCB11, HAUS3, SLC24A4, SNX4 and PALB2) were prevalent in the DNA of the primary tumour removed at diagnosis 9 years earlier, six (in KIF1C, USP28, MYH8, MORC1, KIAA1468 and RNASEH2A) were present at lower frequencies (1–13%), 19 were not detected in the primary tumour, and two were undetermined. Sohrab P. Shah, et al. Nature 461: 809-813, 2009

  11. Primary tumor (Cell escape) Invasion Travel Intravasation Transport Extravasation Migration Growth (2nd tumor) Invasion & Metastasis — Main Death Causes

  12. Adhesion Movement A little long cell Need protease Mesenchymal cell-like movement Form of pseudopodium Rho/ROCKsignal A little circle cell A little rely on protease Amoeba-like movement Myosin strong Contraction Rac/WAVE2 signal Cell. 2008 Oct 31; 135 (3): 510-523

  13. R Control of cell cycle G1: DNA pre-synthesis S: DNAsynthesis G2: DNApost- synthesis M: Cell division GO: Oncogenes STOP: Tumor superessor G1→S→G2→M

  14. Matrix Degradation —— MMPs Matrix degradation: Structural base of tumor invasion & metastasis Epithelial lining cells Transformed epithelial cells Tumor fb MMP-1, 2, 3, 11, 14 Tissue Martrix Tumor fb Transformed epithelial cells MMP-7, 13(9) Epithelial cells of tumor angiogenesis MMP-1, 2, 14

  15. Angiogenesis • Tumor>2-3mm: Need vessels • Key Molecular: MMPs, VEGF, bFGF, PDGF • Tumor vessels density is a marker for early diagnosis and prognosis Nature Rev Cancer, 4,2004

  16. Cancer: Wounds that fail to heal The Chain of Inflammation & Cancer Tumor Development Nature, 420, 2002

  17. Bacterial H pylori 幽门螺杆菌 Virus EB, HCV Parasite flukes, schistosomes 吸虫，血吸虫 Chronic inflammation Cancer Chemial irritis PMA 佛波酯 Nondigestible Particles asbestos, silica 石棉纤维，矽 Strong association: inflammation and cancer

  18. DNA repair DNA repair P53、Rb Oxidative Stress氧化应激 Chronic inflammation ROS 活性氧 RNS 活性氮 Oxidized DNA nucleosides 氧化脱氧核苷酸 Peroxynitrite 过氧亚硝基 Aldehydes醛 DNA damage DNA mutation

  19. Inflammatory cytokines & Oncogenes Tumor inflammation environment Cancer Letters, 267, 2008

  20. Signal Transduction Blood vessel Cytokines Chemokines Macrophage CypA CD147 Hypoxia ROS CypA PI3K Erk1/2 P38 HIF Proliferation Anti-apoptosis Angiogenesis Reported Cancer cell Our study Not confirmed

  21. The Seven Hallmarks of Cancer and Their Links to Tumor Metabolism 增生 环路 凋亡 血管 生成 免疫 逃避 侵袭转移 抵抗 抑瘤 无限 增殖 Tumor Metabolism Cancer Cell. 13: 472-482, 2008

  22. Intratumoral hypoxia and metabolic symbiosis Anaerobic glycolysis or Aerobic stromal cell J Clin Invest. 118 (12): 3835-3837, 2008

  23. Molecular Mechanisms of Cancer-Specific Metabolic Reprogramming 葡萄糖转运 糖原分解 乳酸产生 氧化磷酸化降低 脂类合成 氧化抑制

  24. Cancer Biomarker -- A Systems Approach • 高危评估 Risk assessment • 早期诊断 Noninvasive screening for early-stage disease • 检测定位 Detection and localization • 预后判断 Disease stratification and prognosis • 治疗反应 Response to therapy • 复发监测 Screening for disease recurrence Leland H. Hartwell, et al. Nat Biotech, 24 (8), 2006

  25. Seperation and identification of mixture sample Ab array, Cell array, Tissue array, Co-IP (pull-down), Biosence, etc. Comparative proteomics 2DE, 2DELC-MS Validation peptides sequence of protein MALDI-MS, SELDI-MS, LC-MSMS, ESI-MS (m/z) Analysis of the databases How Identified Cancer Biomarker? • Biomarker Discovery: • Expression Mapping (Modification mapping) • Functional proteomics: interaction of the proteins • Epitope mapping (active core)

  26. System Biology Approaches “-omic” Technologies (Preclinical or Clinical Utilization) MALDI-MS/MS 2D Gels- MS NMR GC-MS LC-MS FT-IR Microarray SAGE Amplichip Cyp 450 Test Global SNP Arrays Trends Biotechnol. 23 (11), 544-546, 2005

  27. What is an Ideal Cancer Biomarker? • Screening a healthy population or a high risk population for the presence of cancer • Making a diagnosis of cancer or of a specific type of cancer • Determining the prognosis in a patient • Monitoring the course in a patient in remission or while receiving surgery, radiation, chemotherapy, or biotherapy • Screening a healthy population or a high risk population for the presence of cancer • Making a diagnosis of cancer or of a specific type of cancer • Determining the prognosis in a patient • Monitoring the course in a patient in remission or while receiving surgery, radiation, chemotherapy, or biotherapy

  28. Application of Cancer Biomarker • Identification and diagnosis • Individuals affected with disease • People who may be at risk but do not yet exhibit symptoms • Monitor progress of disease • Monitor effects of treatment • Remission • Follow-up • Cancers found in early stage: low morbidity and recurrence rates • Cancers identified in late stage: high recurrence and mortality rates

  29. AFP = alpha fetoprotein CEA = carcinogenic embryonic antigen CA 15-3 = carbohydrate antigen 15-3 CA 19-9 = carbohydrate antigen 19-9 CA 125 = carbohydrate antigen 125 PSA = free prostate specific antigen + prostate specific antigen - alpha(1)antichymotrypsin complex PSAF = free prostate specific antigen PSAC = prostate specific antigen - alpha(1)antichymotrypsin complex PAP = prostatic acid phosphatase hTG = human thyroglobulin hCGb = human chorionic gonadotropin beta Ferr = Ferritin NSE = neuron specific enolase IL-2 = interleukin 2 IL-6 = interleukin 6 A2M = alpha 2 macroglobulin B2M = beta 2 microglobulin Cancer Biomarker and Types of Cancer: statistically significant association between a particular cancer and the associated cancer marker (s)

  30. Problems of Cancer Biomarker • No cancer biomarker is absolutely specific • No cancer biomarker test is free of false negatives • No cancer biomarker test is free of false positives • No cancer biomarker is absolutely specific • No cancer biomarker test is free of false negatives • No cancer biomarker test is free of false positives

  31. Antibody Based Cancer Biomarkers

  32. This has empowered more direct means of target identification, e.g. by expanding protein databases and enabling the mapping of novel cancer-associated genes (Venter et al. 2001). Antibody Based Cancer Biomarkers • Human genome is 2.91-billion base pairs in length (1990) • There are about 25,000 genes exist in the human genome (42% have an unknown function) • Approximately 12,000 genes that appear to have the capacity to make secreted proteins, all the genes have been determined the entire nucleotide sequences (3141 genes locus on the first chromosome) • At May 2006, the first chromosome sequences were completed, at least 1,000 new genes were found. This is the end of 16 year’s Human Genomic Plan.

  33. Antibody Based Cancer Biomarkers • Complete genome sequences have provided a plethora of potential drug targets. But the hard task of finding their weak spots is just beginning (about 5000 genes can be used as drug target) • A challenging new development in the field of drug-target discovery is systems biology, or the recognition that genes, or better the gene products, are part of, and function, in large complex networks. Nature, 428, 225-231, 2004.

  34. 转化医学与公众健康

  35. 转化医学概念 • EA. Zerhouni，NIH路线图计划（NIH Roadmap），2003 • 将医学生物学基础研究成果迅速有效的转化为可在临床实际应用的理论、技术、方法和药物 • 基础研究→临床应用，实验室成果→产业化 • 在实验室到病房（Bench to Bedside, B2B）之间架起一条快速通道 • 双向、开放： • 基础研究提供新疗法、新药物 • 临床研究者对疾病的进程和特性提供反馈意见 • “驱动临床研究引擎的激发器”

  36. 转化医学发展现状 • 美国已经在38所大学建立了转化医学研究中心，在2012年以前将会达到60个以上，NIH每年资助经费达5亿美元 • 英国已投入4.5亿英镑用于转化医学研究，并启动世界上首个转化医学合作研究中心 • 欧洲共同体为转化医学计划投入60亿欧元 • Science Translational Medicine、Journal of Translational Medicine和Translational Research三本国际性专业杂志

  37. 中国的转化医学 • 转化医学战略研讨会 • 2009，中国工程院 • 2010，中国科学院 • 转化医学中心 • 中南大学 • 上海交通大学 • 同济大学 • 成果转化率：25%，商品化：<15%

  38. 转化医学与4P医学 Predictive Medicine – 预测医学 Preventive Medicine – 预防医学 Personalized Medicine – 个体化医学 Participate Medicine – 参与医学

  39. Prophylactic Surgery Chemoprevention Screening RISK Lifestyle changes Average Moderate High Very High Personalized Prevention & Early Detection

  40. Personalized Medicine – 个体化治疗 • No “one size fits all” drug • Most drugs work for 30% to 70% of patients • Multiple factors determine drug responses • Phamacogenetics is essential for individualized therapy

  41. Personalized Medicine – 个体化治疗 Herceptin, the first marketed personalized medicine, was approved using a coordinated drug/diagnostic approval process that will become more common.

  42. Molecular Docking HAb18G & Its Antibodies Our Study HAb18G/CD147 I Set HAb18G/CD147& HAb18, 6H8, 5A12 Antibodies

  43. Our Study Crystal Structure of HAb18G/CD147 C2 I Xiao-Ling Yu, Zhi-Nan Chen, J Biol Chem, 283 (26), 2008 National patent: 200710018514.X PCT patent: PCT/CN2007/003034 PDB ID: 3B5H

  44. Our Study Tissue Atlas - HAb18G/CD147 HAb18G/CD147

  45. Our Study Tissue Atlas - HAb18G/CD147 HAb18G/CD147

  46. Our Study Tissue Atlas - HAb18G/CD147 Fetal Normal Cancer Liver Lung Shao-Hui Hu, Zhi-Nan Chen, et al. Proteomics, 7 (13), 2007

  47. Our Study Tissue Atlas - HAb18G/CD147 Yu Li, Zhi-Nan Chen, et al. Histopathology, 2009

  48. Iodine (131I) Metuximab Injection (LICARTINTM) Our Study Cancer Biol Ther 5 (7), 2006

  49. Iodine (131I) Metuximab Injection (LICARTINTM) Our Study 82.50% recurrence rate 30.42↓ 61.88% 57.09% survival rate 20.62↑ 26.67% P=0.0174 P=0.0289 87.82% Control group Treatment group AFP 44.08% 60 cases HCC (III, IV stage) P=0.0016 Anti-recurrence Treatment after Liver Transplantation Hepatology, 45 (2): 269-276, 2007

  50. Iodine (131I) Metuximab Injection (LICARTINTM) Our Study • 四期临床（截至21010年4月累计使用1500支） • 北京利卡汀治疗基地，原子能研究院401医院 • 上海利卡汀临床研究中心，东方肝胆医院 • 广州利卡汀治疗基地，广州军区458医院 • 北京佑安医院 解放军总医院 武警总医院 • 北大肿瘤医院 上海中山医院 上海东方肝胆医院 • 中山大学肿瘤医院 浙江大学一院、二院 • 浙江省肿瘤医院 四川大学华西医院 华中附属协和医院 • 湖南省医院 中南大学湘雅医院 福建医大第一医院 • 四军大唐都医院 郑州大学一附院 河南省医院 • 中国医大一附院、二附院 福建医大协和医院

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