11 General Introduction protein kinase inhibitors (PKI’s)) or the immune system (i.e. immune checkpoint inhibitors (ICI)), or that target specific weaknesses in cancer cells caused by genetic aberrations (e.g. PARP inhibitors), have proven to be effective. For patients with metastatic melanoma or renal cell carcinoma for example, these new treatment options have dramatically improved the overall survival and quality of life. Historically, patients with advanced melanoma, an aggressive and chemotherapy-resistant form of cancer, had a median overall survival of around 8 months and a 5-year survival of 10%. With the introduction of immune checkpoint inhibitors ipilimumab (monoclonal antibody (mAb) directed against CTLA4), nivolumab and pembrolizumab (mAb directed against PD-1) and combinations of these drugs, the overall survival has improved to several years, with a 5-year survival of 52%8. Approximately 50% of patients with advanced melanoma has a pathogenic mutation in the V-Raf Murine SarcomaViral Oncogene Homolog B (BRAF) gene in their tumor DNA. Treatment of these patients with an inhibitor of BRAF combined with an inhibitor of mitogen-activated protein kinase 1 (MEK1 or MAP2K1) resulted in a median progression free survival of 9.9 months, with an objective response rate of 68%9. Treatment strategies combining these BRAF/MEK inhibitors with ICI are currently under investigation10. For patients with metastatic clear cell renal cell carcinoma, the introduction of anti-angiogenic tyrosine kinase inhibitors (TKI’s), such as sunitinib, sorafenib, axitinib, pazopanib and cabozantinib, has also dramatically improved survival. Since their introduction, the median overall survival (OS) has improved from 15-17 months before 200411-14 to 23-29 months with TKI monotherapy15-17. Combining TKI’s with ICI has further improved the 12-month overall survival rate from 72%18 to 90%19,20. MOLECULAR PROFILING TO ASSESS TUMOR BIOLOGY A corner stone for successful targeted treatment of patients with cancer is the presence of a biomarker that is associated with sensitivity for a certain targeted agent. Targets for treatment can be identified in multiple layers of cancer cell biology, but the challenge remains where to look for the most reliable biomarkers that best predict the treatment outcome to a targeted therapy. DNA holds a permanent copy of the genetic information. The genes in DNA encode proteins, the driving force of cellular function, including intracellular signaling and immune response. All genetic information together is called the genome. The conversion of the genetic information stored in DNA to a functional product, such as a protein, is a complicated process that has two major steps. First, during transcription, the information in the double-stranded DNA is transferred to a messenger RNA (mRNA) molecule, which is a single-stranded temporary copy of the gene26. The sum of all the mRNA molecules expressed from the genes is called the transcriptome. During the process of translation, the second major step, the transcribed code on the mRNA molecules is used to assemble a chain of specifically sequenced amino acids 1
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