The use of existing medications for diseases they were not originally developed for is called drug repositioning. A popular drug repositioning method to find new drugs against specific cancer types... Show moreThe use of existing medications for diseases they were not originally developed for is called drug repositioning. A popular drug repositioning method to find new drugs against specific cancer types is to search for drugs which are expected to bring back the gene expression activity of cancer cells to that of healthy cells (‘normalization’). One of the main research goals of this thesis was to investigate of this method could also be used on the gene expression profiles of individual tumors, enabling personalization of drug repositioning candidates for each patient. We initially had some success with this approach but this eventually lead to a systematic validation of the underlying principle using almost 10,000 tumor samples across 18 different tumor types. Unfortunately, the predictive power of the method was found to be much lower than previously reported and the part that remained could be nullified by correcting the gene expression profiles of the drugs for the downstream effects of reduced cell division. These results indicate that the current use of the method does not result in drug repositioning candidates specific for a tumor type but is only able to select generally cell-toxic drugs. Show less
DNA damage, mutations and genomic instability are established driving forces of cancer and other age-related diseases. Mutations in tumor suppressor genes and oncogenes are very frequently found in... Show moreDNA damage, mutations and genomic instability are established driving forces of cancer and other age-related diseases. Mutations in tumor suppressor genes and oncogenes are very frequently found in tumors and genomic instability is the most common enabling characteristic of cancer. Aging is also believed to be enabled, amongst others, by genomic instability. DNA repair pathways, like the nucleotide excision repair (NER) pathway and cell cycle control (e.g. p53-dependent) processes are therefore vital to organisms, since these processes counteract or prevent genomic instability, and are thought to underlie, when affected, aging and age-related diseases like cancer. To unravel the functions, mechanisms and pathways involved in the onset of aging and age-related diseases we have investigated several mouse models deficient in either DNA repair (NER) capacity (Chapter 3, 4), cell cycle control (p53) (Chapter 6) or both (Chapter 5), and compared this to a wild type situation (Chapter 2). The use of mouse models enabled us to investigate cancer and aging in a controlled environment, minimizing possible confounding factors. Additionally, the mouse models can be useful as an alternative tool to identify genotoxic and non-genotoxic carcinogens that can be harmful to the society and the environment (Chapter 5). Show less
