Age-adjusted death rates the rate atwhich people of a certain agedie in a population -- whichcompensates for the facts that(1) Many diseases occur atdifferent rates at different ages(2) Different populations havediffering distributions of oldand young people.Mortality from heart diseasehas plummeted while thatfrom cancer has hardly changedTHE PROBLEM:An aging population. Therefore, more diseases of the oldSome age-adjusted deaths from cancer have declined while others have held constant or increasedIncidence of disease is very hard to interpret, i.e., we don’treally know how often certain diseases strike. The case of melanoma incidenceThe more you look, the more you find!Breast cancerThe better you can search, the more you findSuperficially similarly appearing tumor behave very differentlyif one stratifies them (segregates) them into subclasses based on their gene expression profilesUnder the microscope, they all look like thisSince the survival rates are so different, these are likely to bevery different diseases that needto be treated differently.One solution:Differentiation therapyWorks in acute promyelocytic leukemiaAlternative: Develop drugs that inhibit oncoproteinsplasma memb.outside cellcytoplasmNote that monoclonal antibodies can only be used to perturbproteins that are expressed on the outside of the cellNormal mammary epithelialcell surfaceSurface of ~30% ofbreast cancer cells ectodomainof HER2/NeuFigure 4.6c The Biology of Cancer (© Garland Science 2007)HER gene is amplifiedHER2 protein is overexpresseddifferent tumorsFigure 4.6b The Biology of Cancer (© Garland Science 2007)Figure 15.35b The Biology of Cancer (© Garland Science 2007)Monoclonal antibody(extracellular domain of receptor)Figure 15.38b The Biology of Cancer (© Garland Science 2007)Ectodomains of EGF-R and its cousin HER2/NeuFigure 15.37c The Biology of Cancer (© Garland Science 2007)radiationHerceptin potentiatesX-ray killing of cancercellsCopyright ©2006 AlphaMed PressBaselga, J. et al. Oncologist 2006;11:4-12Figure 3. Frequency of efficacy end point events in the Herceptin(R) Adjuvant (HERA) trial [8]Not bad!!Want about inhibiting intracellular oncoproteins?The case of chronic myelogenous leukemia Reciprocal translocation between chromosomes 9 and 22, whichdepends upon non-homologous recombination between these two chromosomes.The reciprocal translocation causes thefusion of two previously unaffiliatedgenes, one from chr. 22, the other fromchr. 9,resulting in the formation of afusion gene that encodes a novel fusionprotein(actually 3 alterative fusion proteins,depending on where the fusionbetween the 2 genes occurs.)(acute lymphocytic leuk.)(chronic myelogenous leuk.)(chronic neutrophilic leuk.)Let’s focus on the Bcr-Able fusion protein made in chronic myelogenous leukemia (CML)It has a number of functionally distinct domains, labeled here.The tyrosine kinase domain(TK) is most critical, since itis involved in omitting oncogenicsignals to the CML cell.If one can make a drug that inhibits firing by the TK domain, one canshut down Bcr-Abl signalingFigure 16.13a The Biology of Cancer (© Garland Science 2007)But there’s a major problem, since the Abl tyrosinekinase domain is only one of many TK’s encoded in human genome.A drug that shuts down the Abl TK may shut down many others. Thislack of specificity may cause many undesired side-effects.In fact, the human genomeencodes almost 600structurally related kinases,obviously evolved from a single evolutionary ancientKinase (through the process ofrepeated gene duplications followed by sequence divergence of duplicated genes). The tyrosine kinase branchof the “kinome tree” containsalmost 100 distinct, structurally related TK’s.(The remainder are threonine/serinekinases that attach phosphate groups to those amino-acid residues.)Here’s an example of another tyrosine kinase, in thiscase used as the signal-emitting domain of the EGF(epidermal growth factor) receptor; yet another TKis the Src oncoprotein of Rous sarcoma virus. tyrosine kinasedomainsHere’s a small sampling of growth factor receptors that usetheir tyrosine kinase domains to release growth-stimulatory signalsFigure 16.10a The Biology of Cancer (© Garland Science 2007)In fact, by screening many structurally related drug compounds,a drug molecule called “Gleevec” was developed that specificallyinhibits the TK of the Bcr-Abl moleculeFigure 16.10b The Biology of Cancer (© Garland Science 2007)Gleevec fits into the catalytic cleft of the Bcr-Abl tyrosine kinasedomain, preventing ATP from entering into the catalytic site3D structure of the TK domain of the Bcr-Abl fusion proteinNote that the interactionof Gleevec with thecatalytic cleft involvesthe formation of a number of stereo-specifichydrogen bonds withamino-acid residueslining the wall of the cleft.Catalytic cleft of the Abl TK domainof the Bcr-Abl fusion proteinGleevec achieves a 50% inhibition of the firing of the Abl (= c-Abl) TK at a concentrationof ~01. µM, whereas other TK’s are only inhibited at much higher (100x)concentrations!Hence, Gleevec should work against Abl when applied at al concentration that does notaffect the other kinases.Various tyrosinekinases (TK’s)TK of Roussarcoma virusNote: the concentrations given after each TK are those requiredto achieve 50% inhibition of firing by this TK.Use PCR to quantify how many leukemic cells in the blood beforeand after treatment of CML patientCycle no. ~29 ~39Therefore 210 -fold reduction in leukemic cells.Normal granulocyteserythrocytesleukemic cellsAfter a while, some patients’ tumors become resistant to Gleevec inhibition(and their CML reappears. . When they do so, often the Bcr-Abl proteins in the reappearing CML cells show amino-acidreplacements that sterically block Gleevec binding!Here the threonine-to-isoleucine Replacement introduces a sterically bulky a.a. side-chain that blocksGleevec bindingMutant Bcr-Abl proteinsResist inhibition by GleevecUnmutated Bcr-Ablfusion proteins continue to be inhibited by GleevecIn fact, amino-acidsubstitutions in a number of sites in theTK domain of Bcr-Ablgenerate Gleevec-resistantmutant proteins. These residues are shown hereas red balls. Since Gleevec wasdeveloped, pharmaceuticalcompanies have developed a numberof additional drugs that shut downGleevec-resistant Bcr-Abl proteinsand succeed in causing remission of disease.A major problem with Gleevec and similar
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