Introduction to Cancer

Transcription

1 Introduction to Cancer Clonal Evolution Theory of Tumor Development,2,2,,2,2,,2, Numbers represent sequential mutations to cellular genes

2 Oncogenes and Tumor Suppresser Genes On Oncogenes Tumor Suppresser Genes Off NORMAL CELL In normal breast tissue cells, the HER2 gene produces a protein receptor on the cell surface. These growth factorlike receptors are thought to play a role in normal cell growth by signaling the cell to divide and multiply HER2 O VEREXPRESSING CANCER CELL Cancerous breat tissue cells that overexpress or overproduce the HER2 gene produce extra protein receptors on the cell surface. The higher density of receptors triggers the cell to divide and multiply at an accelerated rate, thus contributing to tumor growth. About 25-0% of all women with metastatic breast cancer overepxress the HER2 protein. Herceptin It is thought that Herceptin (a HER2 antibody) binds to numerous HER2 receptor sites found on the cell surface, blocking the receptor sites and possibly preventing further growth by interrupting the growth signal. As a result, the HER2 antibody may slow progression of the disease 2

3 Another success story CML: Chronic Myeloid Leukemia Leukemia is a type of cancer of the blood and the bone marrow. Normally: Signals turn stem cells on and off as necessary to produce the various blood cells the body needs throughout life (>80 years). In CML: A mutation causes a signal to stay on, thereby producing more and more abnormal white blood cells.

4 The disease was first traced decades ago to a shortening of chromosome 22. The shortening was subsequently shown to be due to a translocation with chromosome 9. The shortened chromosome 22, called the Philadelphia chromosome, forms a gene called BCR-ABL The product of the ABL gene is a tyrosine kinase, an enzyme that helps control growth and division. The abnormal fusion protein retains the tyrosine kinase activity of ABL but the signals are not regulated in any way. The white blood cells therefore divide continuously, and massive numbers of cells are produced. 4

5 By 990, 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 STI57, 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 200. The results of the phase III trial showed that Gleevec is four times more effective than standard therapy, with only 25 per cent of patients treated at the chronic stage progressing to blast crisis. Some other forms of cancer with mutations in related kinase genes are also responsive to Gleevec. Gleevec is highly specific for the BCR-ABL tyrosine kinase, therefore blocking any growth signals the abnormal protein generates and preventing cell proliferation. Gleevec also inhibits the normal version of ABL, but this does not seem to have any clinical side effects on normal cellular processes, probably because alternative signaling pathways can be used. 5

6 BCR-ABL kinase domain x P C A M244V E255K Q252H/R G250E Y25F/H T5I M5T F59V L87M F7L E55G H96R Sites of missense mutations leading to Gleevec resistance The drug Gleevec, or STI-57 (orange),can shut down the overactive BCR-ABL protein (purple), except during blast crisis, when a mutation (red circle) changes the shape of the protein's active site. When this happens, the drug can no longer bind tightly and is less effective. Image: Lore Leighton, Laboratory of John Kuriyan 6