肿瘤生物学与转化医学.doc

肿瘤生物学与转化医学 Then the anti-metastasis and recurrence effect of LICARTIN was determined in the post-orthotopic liver transplantation OLT HCC patients Our initial results showed that LICARTIN significantly decreased recurrence rate and increased survival rate of HCC patients compared with untreated control group So LICARTIN is a promising new anti-metastasis and recurrence agent for treating HCC 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 Antibody Based Cancer Biomarkers Cancer Marker Antibody Cancer CA125 OC 125 ovarian cancer CA 15-3 DF3 115D8 breast cancer ovarian cancer CA 549 BC4E549 BC4N154 breast cancer ovarian cancer CA 27-29 B2729 breast cancer MCA b-12 breast cancer ovarian cancer DU-PAN-2 Du-PAN-2 pancreatic cancer ovarian cancer gastrointestinal cancers lung cancer CA 19-9 19-9 pancreatic cancer liver cancer gastrointestinal cancers CA 19-5 19-5 pancreatic cancer ovarian cancer gastrointestinal cancers CA 50 C50 pancreatic cancer rectal cancer gastrointestinal cancers CA 72-4 B273 cc49 gastric carcinoma pancreatic cancer ovarian cancer CA 242 C242 gastrointestinal cancers pancreatic cancer Her-2neu Herceptin breast cancer HAb18GCD147 HAb18 hepatocellular carcinoma ect Antibody Based Cancer Biomarkers Human genome is 291-billion base pairs in length 1990 There are about 25000 genes exist in the human genome 42 have an unknown function Approximately 12000 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 1000 new genes were found This is the end of 16 years Human Genomic Plan This has empowered more direct means of target identification eg by expanding protein databases and enabling the mapping of novel cancer-associated genes Venter et al 2001 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 转化医学与公众健康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转化医学概念美国已经在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45 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转化医学发展现状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 中国的转化医学转化医学与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Personalized Prevention Early Detection Lifestyle changes Screening Chemoprevention Prophylactic Surgery Average ModerateHighVery High RISK Personalized Medicine 个体化治疗No one size fits alldrug Most drugs work for 30 to 70 of patients Multiple factors determine drug responses Phamacogenetics is essential for individualized therapy Herceptin the first marketed personalized medicine was approved using a coordinated drugdiagnostic approval process that will become more common Personalized Medicine 个体化治疗Our Study Molecular Docking HAb18G Its Antibodies HAb18GCD147 HAb18 6H8 5A12 Antibodies HAb18GCD147 I Set Our Study Crystal Structure of HAb18GCD147 C2 I Xiao-Ling Yu Zhi-Nan Chen J Biol Chem 283 26 2008 National patent 200710018514X PCT patent PCTCN2007003034 PDB ID 3B5H HAb18GCD147 Our Study Tissue Atlas - HAb18GCD147 HAb18GCD147 Our Study Tissue Atlas - HAb18GCD147 Our Study Tissue Atlas - HAb18GCD147 Shao-Hui Hu Zhi-Nan Chen et al Proteomics 7 13 2007 Lung Liver Fetal Normal Cancer Case Positive Positive Rate P Fetal 67 1 149 00001 Normal 196 16 816 00001 Cancer 1565 1040 6645 Yu Li Zhi-Nan Chen et al Histopathology 2009 Our Study Tissue Atlas - HAb18GCD147 组织类型病例数阳性率灵敏度真阳性率特异度真阴性率肝癌147 例7766 7766 100 良性病变肝组织44 例000 肺癌186 例9504 9504 98 良性肺疾病100 例200 乳腺癌200 例6535 6535 91 良性乳腺疾病100 例900 食管癌199 例8622 8622 975 良性食管疾病80 例277 卵巢癌101 例7623 7623 8367 良性卵巢疾病52 例1633 胃癌193 例7 668 7 668 8 337 良性胃疾病98 例1 663 宫颈癌120 例7 184 7 184 8 846 良性宫颈疾病55 例1 154 直肠癌195 例7768 7768 9393 良性直肠疾病100 例607 平均值7 875 9 173 Cancer Biol Ther 5 7 2006 Our Study Iodine 131I Metuximab Injection LICARTINTM Anti-recurrence Treatment after Liver Transplantation recurrence rate 3042survival rate 2062AFP 4408 5709 2667 8250 6188 P00174 P00289 P00016 Control group Treatment group 60 cases HCC III IV stage 8782 Our Study Iodine 131I Metuximab Injection LICARTINTM Hepatology 45 2 269-276 2007 Our Study Iodine 131I Metuximab Injection LICARTINTM 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与排名第一的脑血管病仅有013 的差距属于世界较高水平而且呈持续增长的趋势与70 年代中期相比死亡率增加了831 与90 年代初期相比也增加了225 其中食管癌胃癌宫颈癌鼻咽癌死亡率及其构成呈明显下降趋势宫颈癌下降幅度最大而与环境生活方式有关的肺癌肝癌结直肠癌乳腺癌膀胱癌死亡率及其构成呈明显上升趋势以肺癌和乳腺癌上升幅度最大过去30 年分别上升了465 和96 原发性肝癌primary liver cancer 所致的死亡率在世界范围内居于第三位而在我国一直高居首位尽管2008 年我国死亡原因调查显示肺癌已代替肝癌成为我国首位恶性肿瘤死亡原因占全部恶性肿瘤死亡的227 但肝癌的死亡率依然呈上升趋势另据WHO 估计到2030 年我国因恶性肿瘤所致死亡率将由2005 年的202 上升至23657 可见不管是在世界范围内还是在我国恶性肿瘤依然是威胁人类健康和生命的重大疾病对其发病机制早期诊断方法及有效治疗措施的研究仍是全球生物医学研究领域的重中之重but that only a subset of these contribute to the neoplastic process Using stringent criteria to delineate this subset vast majority unknown and predicted to affec