Therapeutic Strategies for Mesenchymal Type Colorectal Cancer

Abstract

Colorectal cancer is a heterogeneous disease. We are unable to predict which colorectal cancer patients will develop metastases, and which adjuvant therapy is required to prevent outgrowth of metastases in the individual patient. Analysis of molecular characteristics of colorectal cancer could contribute to improved patient selection and targeted therapies. Based on gene expression profiles, four Consensus Molecular Subtypes (CMS1-4) of CRC are distinguished, which vary in activation of cellular signaling pathways and in the composition of the tumor microenvironment consisting of non-neoplastic cells and extracellular matrix. Besides, the CMSs differ in terms of prognosis and show variable response to adjuvant chemotherapy. The mesenchymal type (CMS4) has the worst prognosis and responds poorly to currently used chemotherapies. Identification of this subtype and development of novel therapies against CMS4 are therefore of utmost importance. The aims of studies described in this thesis were to implement CMS classification in clinical practice, to test novel CMS4-targeted therapies in preclinical models and in a clinical trial, and to study molecular classification and surgical treatment of metastatic colorectal cancer. We made use of organoids (three-dimensional cell culture models of tumors), tissue material from colorectal cancer, and clinical data from patients with colorectal cancer in various stages of the disease. A diagnostic test was developed that allows selection of CMS4 tumors for therapeutic purposes. With this test, multiple regions within a single cancer were tested, and it was found that one tumor can contain multiple molecular subtypes. Furthermore, primary cancers and metastases can differ in molecular subtype, and chemotherapeutic treatment can influence the subtype. Finally, with the use of organoids, two promising novel treatments against poor-prognosis colorectal cancer were discovered. The tyrosine kinase inhibitor dasatinib attenuates invasion of tumor cells driven by the microenvironment and could thus improve treatment of CMS4 cancers. Inhibition of the protein ATR increases the efficacy of intraperitoneal chemotherapy treatment by preventing DNA damage repair in tumor cells. Molecular classification of colorectal cancer can be implemented in clinical practise, and can contribute to the development of novel (subtype-targeted) therapeutic strategies against poor-prognosis colorectal cancer