1Introduction to CancerClonal Evolution Theory of Tumor Development11,21,21111,2,31,2,3111,2,3Numbers represent sequential mutations to cellular genes2Oncogenes and Tumor Suppresser GenesOncogenesTumor Suppresser GenesOnOffNO RMAL CELLIn normal breast tissue cells, the HER2gene produces a protein receptor onthe cell surface. These growth factor-like receptors are thought to play a rolein normal cell growth by signaling thecell to divide and multiplyHER2 O VER EXPRESSING CANCER CELLCancerous breat tissue cells that overexpress oroverproduce the HER2 gene produce extra proteinreceptors on the cell surface. The higher density ofreceptors triggers the cell to divide and multiply at anaccelerated rate, thus contributing to tumor growth.About 25-30% of all women with metastatic breastcancer overepxress the HER2 protein.HerceptinIt is thought that Herceptin (a HER2 antibody) bindsto numerous HER2 receptor sites found on the cellsurface, blocking the receptor sites and possiblypreventing further growth by interrupting the growthsignal. As a result, the HER2 antibody may slowprogression of the disease3Another success storyCML: Chronic Myeloid LeukemiaLeukemia is a type of cancer of theblood and the bone marrow.Normally:Signals turn stem cellson and off as necessaryto produce the variousblood cells the bodyneeds throughout life(>80 years).In CML:A mutation causes asignal to stay on,thereby producing moreand more abnormalwhite blood cells.4The disease was first traced decades ago to ashortening of chromosome 22.The shortening was subsequently shown to be dueto a translocation with chromosome 9.The shortened chromosome 22, called thePhiladelphia chromosome, forms a gene calledBCR-ABLThe product of theABL gene is atyrosine kinase, anenzyme that helpscontrol growth anddivision.The abnormal fusionprotein retains thetyrosine kinaseactivity of ABL butthe signals are notregulated in any way.The white blood cellstherefore dividecontinuously, andmassive numbers ofcells are produced.5• • By 1990, the inhibitory activity of phenylaminopyrimidines was analyzed in screens to identify compounds that interact with the BCR-ABL tyrosine kinase.• Lead compounds were optimized, eventually resulting in STI571, or Gleevec.• Preclinical testing demonstrated that Gleevec could inhibit BCR-ABL both in the test tube and in living cells. Gleevec was shown to inhibit the proliferation of cells containing the Philadelphia chromosome without affecting normal cells.• The drug was FDA approved in 2001. The results of the phase III trial showed thatGleevec is four times more effective than standard therapy, with only 25 per cent of patients treatedat the chronic stage progressing to blast crisis.• Some other forms of cancer with mutations in related kinase genes are also responsiveto Gleevec .Gleevec is highly specific for the BCR-ABL tyrosine kinase,therefore blocking any growth signals the abnormal proteingenerates and preventing cell proliferation.Gleevec also inhibits the normal version of ABL, but this does notseem to have any clinical side effects on normal cellularprocesses, probably because alternative signaling pathways canbe used.6xxPCABCR-ABL kinase domainM244VG250EQ252H/RY253F/HE255KT315IF359VF317L E355G H396RM351TL387MSites of missense mutations leading to Gleevec resistanceThe drug Gleevec, or STI-571 (orange),can shut down the overactive BCR-ABLprotein (purple), except during blast crisis,when a mutation (red circle) changes theshape of the protein's active site. When thishappens, the drug can no longer bind tightlyand is less effective.Image: Lore Leighton,Laboratory of John
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