1、癌症的生物治疗,癌症的传统治疗方法： 手术治疗 放射治疗 化学治疗 癌症的生物治疗方法： 基因治疗免疫治疗细胞治疗 抗体治疗分子靶向治疗,癌症治疗现状,Progress in Gene Therapy of Liver Cancers,May 4, 2007,Genetic Material,Gene Transfer (vectors),Biological Effect,Target Cell,Gene Therapy,Multistage model of carcinogenesis,Chemical,Radiation,Virus,Normal cell,Preneoplastic
2、lesion,Malignant tumor,Metastasis,Positive,OncogenesGrowth factors,ProteasesAdhesion receptorsMotility cytokines,Negative,Tumor suppressor genesGrowth inhibitors,Metastasis suppressor genes,Gene therapy strategies for treatment of liver tumors,Gene Therapy for HCC,1. Gene Replacement Wild-type p532.
3、 Antisense Strategies Antisense RNA, Ribozymes, siRNA,shRNA,miRNA against Oncogenes and Growth Factor (ras, myc, BCL-2, IGF-2, TGF-a)3. Anti-angiogenic therapy,Tumor Suppressor Genes,GenesLocationCancers,p5317p13Small cell lung cancer Colorectal carcinoma Hepatocellular carcinoma breast cancer Leuke
4、mia,RB113q14Retinoblastoma Small cell lung cancer Osteosarcoma Breast cancer,WT111p13Wilms tumor Nephroblastoma,DCC18q21Colerectal carcinoma,NF117qNeurofibromas,APC5q21Colorectal carcinoma,Antitumoral mechanisms induced by tumor suppressor genes,Nat. Bio. Tech. 2004,Antitumoral mechanisms induced by
5、 inhibition of oncogenes,Mechanisms of inhibition of oncogenes by shRNA and miRNA,Co-expression of shRNA and therapeutic genes for therapy of cancer,Mechanisms of Drug Sensitivity by HSV-tk,Ganciclovir (GCV),MonophosphateGCV,Triphosphate GCV,DNA,DNA polymerase,Chain termination,Cell death,replicatio
6、n,CMV-HSV-tk-pA,AdCMVtk,Bystander effect induced by suicide gene,Introduction of HSV-tk in tumor cells,Ganciclovir,Effect 1:Death of tranduced cells,Effect 2:Death of nearby cells,Can cancer be treated by targeting MET signal transduction pathway,Involvement of cytokines and growth factors in pathog
7、enesis of cancer,Hepatocyte growth factor (HGF),MET (c-met),Hepatocyte growth factor (HGF),MET (c-met),HGF,The signaling pathways for MET-dependent invasive growth,Expression of c-met in HCC,Ueki T Hepatology. 1997 Mar;25(3):619-23.,HGF-dependent invasive growth and angiogenesis,MET overexpressionOv
8、erexpressed receptors, located at the cell surface, undergo spontaneous dimerization and subsequent activationMET gene amplificationenhanced MET transcription by oncogenestransient MET overexpression by hypoxia-activated transcriptionMET structural alterationschromosomal translocation point mutation
9、HGF-dependent autocrine/paracrine activationHGF-independent mechanisms,Mechanisms of Met activation in cancer,Strategies to target Met signaling,A lesson from anti-angiogenic therapy of cancer via a gene transfer approach,Angiogenesis Formation of new blood vessel from a pre-existing vascular networ
10、k.,Most solid tumors ( 1 mm 3) receive blood supply from normal tissue to support of nutrients, oxygen etc. Oxygen diffusion is limited to 100 to 200 mm between capillary and perfused cells. This corresponds to 3 to 5 cellular lines around a vessel If tumors are more than this size, they need their
11、own vascularization.,The role of angiogenesis in tumor growth,Balance of angiogenic and anti-angiogenic factors in tumor progression,angiogenesis,+,-,The switch from a quiescient, dormant tumor stage to tumor neo-vascularization is regulated by an alteration of the balance of positive and negative r
12、egulators of angiogenesis,Endogenous regulators of Angiogenesis:,Stimulating factors,Inhibitory factors,aFGF/bFGF VEGF IL-8 TNF-alpha TGF-alpha/beta Angiogenin Heparinase etc.,Angiostatin (K1-3; K4; K5) Endostatin PEDF IFN-alpha/beta IL-12 PF4 Thrombospondin etc.,Characteristics/Advantages of an ant
13、iangiogenic antitumor therapy,keep the tumor in a dormant stage /no elimination of all of the tumor cells prevention of metastasis no/few side effects because of minor physiological role of angiogenesis in the adult combination with other therapies (surgery/chemotherapy etc.),Anti-angiogenic factors
14、,1. Angiostatin (1994)2. Endostatin (1997)3. Pigment epithelium derived factor (PEDF) (1999),Vector construction,Summary,1. Three vectors have been constructed2. Transgenes have been expressed 3. The expressed factors have biological effect4. They have anti-tumor effect5. They induce inhibition of angiogenesis in vivo,Gene transfer-mediated anti-angiogenic therapy,Adenovirus:Angiostatin, endostatin, PF-4, soluble Flt-1 Retrovirus: PF-4, dominant-negative FLK-1 mutant receptorAAV: angiostatin, endostatinLentivirus: PEX,Gene therapy strategies for treatment of liver tumors,
