A quest through diagnostics and predictive tools and the exploration of new treatment strategies in clinical trials to improve cancer therapy

The improved understanding of tumor biology has led to new diagnostic and therapeutic strategies in the treatment of cancer. The more personalized care resulted in an improved survival of cancer patients. The research in this thesis focusses on different strategies to further improve the treatment of cancer patients. In Chapter 1we showed that the self-learning algorithm ThromboSeg could discriminate sarcoma from controls with an accuracy of 87%. Our data also indicates that tumor-educated platelets RNA-based liquid biopsies may enable for sarcoma diagnostics. Chapter 2 we established a biobank of 22 sarcoma cell lines with a success rate of 69. We were able to predict treatment outcome accurately in 67% (n=12) for the normal cultured cell lines and in 71% of the cell lines cultured in human derived serum for systemic compounds (n=7), and in 64% (n=11) and in 80% (n=5), respectively, for radiotherapy. In Chapter 3 a potential new treatment strategy was discussed to enhance the efficacy of checkpoint inhibitors in patients with solid tumors, by combining them with chemotherapy. The majority of chemotherapeutic drugs has been shown to exert immunostimulatory effects, either by inhibiting immunosuppressive cells and/or activating effector cells, or by increasing immunogenicity and increasing T-cell infiltration. However, the timing, dose and sequence of administration of chemotherapy and immune checkpoint inhibitors seems important, but is still poorly understood. Chapter 4 described two clinical trials, in which checkpoint inhibitors are combined with new antibodies directed against costimulatory receptors of the T-cell. In Chapter 4.1 nivolumab was combined with anti-GITR. Anti-GITR had a manageable safety profile. However, the efficacy was comparable to historical data reported for nivolumab monotherapy. In Chapter 4.2 the new costimulatory antibody directed against OX40 was combined with or without nivolumab, with or without ipilimumab. Both the monotherapy and combination therapy treatment arms showed a manageable safety profile. There were no objective responses seen with monotherapy and the objective responses with combination therapy were not higher than expected for treatment alone with nivolumab and/or ipilimumab. Chapter 5.1 describes that fixed-dosing of nivolumab and pembrolizumab was rapidly implemented in most Dutch hospitals, but not for other monoclonal antibodies used in oncology. In Chapter 5.2 the economic impact was further analyzed of the implementation of fixed-dosing for all monoclonal antibodies used in oncology in the Netherlands Cancer Institute. Fixed-dosing resulted in substantial savings in health care costs, calculated between €0,8 and €3,1 million per year. Chapter 6.1 we investigated the effect of neoadjuvant systemic treatment in angiosarcoma patients. Neoadjuvant chemotherapy could be used to improve the resection margins. No definitive conclusions could be made about the effect on survival. Chapter 6.2 showed the study design of the proof of principle study in which we will evaluate the efficacy of propranolol in the treatment of angiosarcoma in the neoadjuvant setting. In Chapter 7 we compared proteomics and sequence data of metastatic tumor samples with samples of the primary tumor of the same patient to find potential new targets. Two potential targets were PARP-1 and ALDH1A1