PhD defence M.A. (Melinda) Pruis

Summary:

Cancer originates in abnormalities of the cell's hereditary material; the DNA. Errors in DNA are called mutations and usually arise from exposure to substances or radiations harmful to DNA, such as smoking, UV radiation, asbestos
and heavy metals. If enough errors arise in the DNA, a healthy cell can derail into a cancer cell. For this to happen, DNA must be damaged in places that affect cell growth and cell division. In addition, there are numerous mutations that contribute to sustained growth of cancer cells, for example mutations for additional blood supply for the tumour or mutations that ensure that the cancer cell is not visible to the immune system. The emergence of these oncologically beneficial mutations is subject to a random process and it therefore takes decades for a
cell dysregulates based on these mutations. Most cancer types are therefore also associated with advanced age and possess many mutations. In a minority of patients with cancer, about 20 -30%, cancer is driven by a single
dominant mutation. These types of cancers generally occur in a younger population and do not appear to be caused by smoking, for example. These involve mutations in one of the genes that play an important role in cell growth, such as Anaplastic Lymphoma Kinase (ALK), Epidermal Growth Factor Receptor (EGFR) and Mesenchymal Epithelial Transition (MET). A mutation that causes the product of this gene, namely a growth receptor, is continuously active can lead to a malignant cell. It is unclear why these mutations occur. The advantage of this type of cancer, mutation-driven cancer, is that it is susceptible to targeted treatments (genotype-targeted) that
block the specific growth receptor. These mutations are not organ-specific, but some mutations do occur more in one organ than another. Diagnosis of these mutations (molecular diagnostics) has only been technically
feasible in clinical practice. The emergence of molecular diagnostics and its rapid development also require combined efforts of experts to ensure that patients receive the right treatment and information. Therefore, patients in whom such mutations are found are discussed in so-called 'molecular tumour boards' which consist of, among others, (pulmonary) oncologists, clinical molecular biologists in pathology clinical geneticists, pathologists and pharmacists. In this thesis, various aspects of genotype-targeted treatments are highlighted. The introduction contains a comprehensive account of the role of DNA in cancer, the history of DNA diagnostics and the emergence of genotype-targeted treatments, followed by an introduction for each chapter. The first part of this thesis describes studies aimed at are aimed at optimising patient inclusion for early clinical trials of genotype-targeted treatments and a Phase I study of OMO-1, a MET inhibitor. The second part consists of 2 chapters on DNA diagnostics and its role in identifying patients for targeted therapy and associated prognostic factors. The final section examines clinical implications of targeted treatments are examined, including side effects and resistance mechanisms.