Lecture 19: Cancer Prevention and Treatment

Cancer prevention and treatment Epidemiology reveals that many cases of cancer are preventable Migrant populations tend to adopt cancer statistics typical to their new destination 80-90% of cancers should be avoidable, at least postponable Which of the following metabolically activates carcinogens in the Ames test? • A. Liver extract • B. Salmonella • C. Test compound Carcinogens In foods: Chemicals used in processes and cured meat such as bacon, sausages, and ham Nitrites used as food preservatives in cured meat such as bacon are linked to colon cancer Cooking food at high temperatures, for example grilling or barbecuing meats Acrylamide is generated in fried or overheated carbohydrate foods (such as French fries and potato chips). Studies on whether the level of acrylamide in those foods is dangerous are underway In the lab: Ethidium bromide Formaldehyde Chloroform (in oral exposure) Viruses cause cancers by _____ • A. Promoting excessive proliferation • B. Introducing mutations • C. Both HPV causes cancers of uterine cervix HPV is the most common STI Only certain types of HPV cause cancer; 70% of HPV are caused by HPV 16 and HPV 18 Cancers of the uterine cervix can be prevented by vaccination. against human papilloma virus Only persistent infections by HPV that last for years cause cancer; in most cases the symptoms disappear within a year Regular testing of women by pap smear test significantly reduced the occurrence of the uterine cervix cancer In a wart or other benign infection HPV chromosomes are stably maintained in the basal cells of the epithelium as plasmids Rare accidents can cause the integration of a fragment of such a plasmid into a chromosome of the host, altering the environment of the viral genes This (or possibly some other cause) disrupts the control of viral gene expression The unregulated production of viral replication proteins interferes with the control of cell division, thereby helping to generate cancer PARP inhibitors kill cancer cells that have defects in Brca1 or Brca2 genes PARP is a polymerase involved in DNA repair BRCA1 and BRCA2 that are commonly mutated in breast cancer, are also involved in DNA repair Normal cells have all those proteins and if PARP is inhibited, BRCAs help to repair DNA Since BRCAs are commonly mutated in breast cancers, inhibition of PARP results in inability of PARP.results in inability to seal single stranded breaks forming in replay action and death of cancer cells Normal cells survive PARP inhibitors because of alternative pathways based on homologous recombination that involve BRCAs What happens in normal cells when PARP is inhibited? • A. BRCA proteins can compensate for the loss of PARP because it has similar structure • B. BRCA proteins repair DNA in an alternative pathway Chronic Myelogenous Leukemia (CML) cause by Philadelphia chromosome Bcr-Abl fusion protein is. cytoplasmic tyrosine kinase, which is always in “on” conformation, independent of cytokine signaling Drug Gleevec (imatinib) inhibits the fusion Bcr-Abl kinase Cancer if early stage are successfully treated with Gleevec at 80% rate Cancer at later stages get resistance by introducing additional mutations in the fusion proteins n Combination of inhibitors seems promising for curing later stage cancers Gleevec also inhibits normal Abl kinase but normal cells have alternative kinases to compensate Treatments with antibodies Injections with antibodies against receptors that are over expressed on the surface of cancer cells (approved for some breast cancers) Antibodies to the surface proteins overexpressed on cancer cells can also be linked to toxins Cancer cells escape immune response Cancer cells have on average 50 mutated proteins; some of them are displayed on the cell surface Mutant proteins can be recognized by immune system as foreign, resulting in elimination of the cells Cancer cells develop the resistance to immune system by expressing inhibitors of immune system cells on their surface A new approach to treatment is removing the immunosuppressive environment Cancers evolve resistance to therapies Drugs can initially provide remission but cancer may still come back by developing extra mutations that overcome the effect of the drug PARP inhibitors can become inactive because cancer cells restore the BRCA proteins by compensatory mutations Small fraction of cancer cells that were not destroyed by the drug can result in tumors years later Some cancer cells amplify the genes that code for ABC transporters which can pump lipophilic drugs out of the cells