Molecular analysis of aggressive colorectal cancer

Abstract

Over 1.8 million new colorectal cancer cases and 881,000 deaths are estimated to occur in 2018. Death due to CRC is mainly the result of distant metastases, which occur in 50% of cases. Despite improvements in surgical procedures, systemic therapy and local radiation techniques, the prognosis of patients with metastatic colorectal cancer remains poor with a five-year survival of only 15%. To date surgery is the only curative option, but only 25% of patients are eligible surgical candidates at disease presentation. Treatment options for the remaining 75% of patients are limited to systemic therapy or local ablation/radiotherapy. For these patients the current adjuvant systemic therapy prolong life expectancy approximately 2 years. So new therapeutic strategies are urgently needed. This thesis promotes further delineation and characterization of molecular signatures in cancer in general and CRC in particular. It provides new insights into the molecular background of the poor prognosis subtype CMS4 and its interaction with the ECM and stromal cells. It emphasizes the potential of targeted therapy in conjunction with standard chemotherapy regimens to optimize treatment and confirms the promising results of disrupting the tumor-ECM-stroma interaction. It contributes to further insights into how CRLM react to chemotherapy at the molecular level and presents cellular energy metabolism as a novel strategy to reduce chemotherapy resistance in metastatic CRC patients. It provokes the use of lymphatic gene expression in the context of CRLM and presents RAF1 as a novel target in the treatment of metastatic CRC. The response to systemic therapy remains limited in metastatic CRC and with rapidly expanding treatment options patient selection and therapy prediction will become essential. Molecular signatures of CRC have great potential in optimizing treatment outcome by guiding the design of targeted therapies.