15 General Introduction THESIS OUTLINE AND SCOPE Clinical implementation of precision oncology for patients with advanced solid tumors continues to be challenging. This thesis focused on optimizing the approach to targeted treatment selection (patient-based approach) and on identification of predictive tissue-based biomarkers for treatment benefit (drug-based approach), while contributing to an optimized infrastructure as a basic requirement for multi-omics analysis. Chapters 2 and 3 focus on the Drug Rediscovery Protocol (DRUP), an ongoing prospective, multicenter, non-randomized basket trial, in which patients with advanced solid tumors are being treated based on their tumor genomic profile, with targeted- or immunotherapy outside their registered indications. Chapter 2 describes the design and feasibility of the DRUP trial, including treatment outcomes of the first 215 patients treated in the trial. The clinical benefit rate in the first completed cohort “Nivolumab for MSI tumors” is highlighted, as well as the value of WGS in identifying targeted treatment options for patients with advanced cancer. In chapter 3 we present the results of the DRUP cohort “Olaparib for tumors with a BRCA1/2 mutation”, in which 24 patients with treatment refractory cancer with BRCA1/2 loss of function mutations were treated with the PARP inhibitor olaparib. Clinical outcome of these patients is interpreted in the context of their tumor genomic characteristics, attempting to identify potential indicators of (lack of) treatment benefit to olaparib, with special emphasis on patients with non-BRCA-associated tumor types. Chapter 4 focuses on the use of mass spectrometry-based phosphoproteomics for the identification of predictive biomarkers for response and resistance to the tyrosine kinase inhibitor sunitinib in patients with renal cell carcinoma. Using this functional read-out, we aimed to describe differences in biology between sensitive and primary resistant patients and to define a phosphosite signature for prediction of treatment outcome. In chapter 5 we describe a new liquid nitrogen-free snap freezer for snap freezing biospecimens, which was developed to conserve molecular profiles under standardized and optimized pre-analytical conditions. We compare the performance of the new snap freezer to the current golden standard for snap freezing (quenching in liquid nitrogen) in terms of conservation of phosphoproteomics- and transcriptomics profiles of samples, hypothesizing that a liquid nitrogen-free snap freezing method may advance implementation of precision oncology. The main findings of this thesis are summarized and discussed in chapter 6. With special emphasis on the approaches we used for improving patient selection and prediction of treatment outcome, we place our findings in the broader context of multi-omics for improving effective and personalized care for patients with cancer, and give recommendations for future research. 1
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