药理学专题肿瘤细胞代谢改变与抗肿瘤药物靶点发现邢美春副本.pptx

higher proliferative ratesMetabolic activities in cancer cells are dramatically fast.more nutrient hungry and excrete more waste productsresulting in a build-up of metabolites inside the cell and the formation of a more hostile environment outside the cellIn order to divide,a cell needs to both increase its size and replicate its DNA processes that are hugely metabolically demanding and which require large quantities of proteins,lipids and nucleotides,as well as energy in the form of ATPABOUT METABOLIC ALTERATION OF CANCER CELL第1页/共13页Drivers(A and B).The metabolic derangements in cancer cells may arise either from the selection of cells that have adapted to the tumor microenvironment or from aberrant signaling due to oncogene activation.Advantages(CE).The altered metabolism of cancer cells is likely to imbue them with several proliferative and survival advantages,Potential Liabilities(F and G).This altered metabolism,however,may also confer several vulnerabilities on cancer cells.Warburg effect第2页/共13页When glucose enters the cell through a glucose transporter,it is phosphorylated by HK to glucose-6-phosphate,which is further metabolized by glycolysis to pyruvate in the cytosol.Under aerobic conditions,normal cells use pyruvate dehydrogenase(PDH)to convert most pyruvate to acetyl-CoA.The acetyl-CoA is then oxidized via the TCA cycle,providing sources of ATP synthesis.In contrast,the metabolic pathways of glucose utilization in cancer are changed from ATP generation by oxidative phosphorylation to ATP generation through glycolysis.Also,for cell proliferation to occur,cancer cells require the synthesis of new macromolecules(for example,nucleic acids,lipids,proteins).Key enzymes that may be promising targets for cancer therapy are highlighted in red.TCA enzymes that are known to be mutated in cancer are shown in purple:IDH2,SDH,and FH.The regulation of glucose metabolism in cancer cellsWarburg EffectMiran Jang et al.Cancer cell metabolism:implications for therapeutic targets.Experimental&Molecular Medicine(2013)Oct 4;45:e45第3页/共13页Daniel A.Tennant et.al,Targeting metabolic transformation for cancer therapy.Nature,10 267-277(2010)have been usedas chemotherapeutic agents for several yearsUsed as chemotherapeutic agents for several yearstarget the final stages in the nucleotide synthetic pathwaylack of tumour specificityfew new agents in the clinic that directly target this pathwaydirected towards the pathways that supply intermediates to be used in nucleotide biosynthesis(PPP,TCA)1.Targeting nucleotide biosynthesisIt is possible that the nucleotide building blocks necessary for normal proliferating cells can be supplied by the exogenous pool of nutrients,such as nucleosides.But owing to poor vascularization and the high proliferative burden of cancer cells,tumors might rely more on endogenous synthesis from glucose and glutamineBlocking early stages of nucleotide biosynthesis such as ribose-5-phosphate(R5P)production could provide a better therapeutic window than that shown by previous antimetabolic therapies.do not seem to have as significant an effect on tumour growth as monotherapyBut can resensitize tumors to other chemotherapeutic agents(such as paclitaxel)Agents used in combination with glycolysis inhibitors include both chemotherapy and radiotherapy2.Targeting glycolysis3.Targeting amino acid metabolismseveral uses in the tumor cella substrate for protein synthesisnon-essential amino acids(through transamination)replenish TCA cycle metabolite levelsan essential starting point for nucleotide biosynthesisinhibits the proliferation of tumor cells and promotes their differentiation；but were found to be toxic or raised an immune reactionmore specific inhibitors of this enzyme are important in treating glutamine-dependent tumors第4页/共13页Direct targets consist of the metabolic enzymes themselves.Indirect targets include signaling pathways that are activated or repressed in tumors,resulting in aberrant metabolic control.第5页/共13页Oncogenes and metabolismOncogenesis generally proceeds via the progressive acquisition of genetic and epigenetic alterations that together influence various cellular processes,including metabolic pathways.Such alterations,which generally involve either the inactivation of oncosuppressor genes or the hyperactivation of oncogenes,not only allow for malignant transformation but also support the survival of established tumours.Inhibition of oncogenic drivers and/or the reconstitution of(previously lost)oncosuppressive functions normally results in robust antineoplastic effectsfrequently involves stress response pathways,offers an attractive approach for the development of novel therapeutic strategies against cancer.第6页/共13页 Molecular Mechanisms of Cancer-Specific Metabolic ReprogrammingAs a result of oncogenic gain-of-function events(pink)or the loss of tumor suppressors(green)affecting the PI3K/Akt/mTOR/HIF axis and/or inactivation of the p53 system,a stereotyped pattern of metabolic changes is induced,leading to cancer-associated alterations in metabolism.第7页/共13页mTOR is regulated by the PI3KPTENAKT pathway(see the Figure),which is overactivated in many types of both sporadic and hereditary cancer.This limited success can be explained by the negative feedback loop downstream of mTOR and by the specificity of rapamycin for mTOR complex 1.As a consequence,rapamycin treatment leads to the overactivation of the PI3KPTENAKT pathway.New approaches should focus on inhibiting both mTORC1 and mTORC2 complexes,and on treatments that combine mTOR inhibitors with other signalling pathway inhibitors(particularly the PI3KPTENAKT pathway).The clinical outcome in trials using mTOR inhibitors as monotherapy has shown only modest results.mTOR and cancer therapy第8页/共13页1.Bryan T.Oronsky,Follow the ATP:tumor energy production:a perspective.Anticancer Agents Med Chem.2014;14(9):1187-98.2.W.J.Israelsen et al.Cell 155,397409;2013Special enzymeAltering dietA further strategy targeting energy generation in tumors is the use of the ketogenic diet:a low-carbohydrate and high-fat(specifically medium-chain triglyceride)diet.Although normal cells can adapt to using ketone bodies to produce ATP,tumor cells that rely on high glycolytic flux would not be expected to survive on this alternative fuel source.Although this change in diet is not likely to be a monotherapy,it may well prove to be a useful addition to other antimetabolic therapies第9页/共13页第10页/共13页Simultaneously targeting oncogene and nononcogene addiction,which often manifests at the level of metabolism or stress responses,is also a promising approach.Cancer is defective in mitochondrial respiration,which drives a switch to an alternative energy source.The basis of several mechanisms of tumor resistance to both radiotherapy and chemotherapy is in the aberrant metabolism of a tumor,and so the reactivation of a more normal metabolism could revert tumors to being sensitive to these agents.Problem:As with most other chemotherapies,it is the ability of a drug to distinguish between tumor cells and the proliferating normal cells in the body that often determines its therapeutic index.By targeting tumor-specific enzyme isoforms or by suppressing the activity of an enzyme or the concentration of a substrate instead of completely abolishing it,it may be possible to more selectively attack tumor cells.Summery123We require more analytical work to understand which pathways are activated in different tumor types,so that we can more efficiently identify targets that are efficacious and specific for tumors with minimal toxicity for normal organs.Others第11页/共13页The EndThe EndThanks Thanks For Your AttentionFor Your Attention第12页/共13页感谢您的观看！第13页/共13页