Abstract
Curative treatment of most solid tumors includes surgical interference. However, the incidence of local recurrence or distant micrometastases is significantly lower when patients are treated with systemic or locally administered chemo- or targeted therapy. In the last decade, many novel targeting strategies have been developed for several tumor types. This thesis aims to identify promising targeting strategies for glioma and colorectal carcinoma and reveals resistance mechanisms for these new promising strategies. In the first part, the therapeutic effects of oncolytic viral vectors on glioma and colorectal cancer are explored. Infectivity and cell killing properties of transductional and transcriptional targeted adenoviral vectors is evaluated on glioma cell lines and freshly derived glioma tissue from patients. In this part, a very selective, conditionally replicating adenovirus based on the survivin promoter is presented for the treatment of glioma. In colon cancer samples, this thesis describes efforts to overcome infectivity limitations observed in reovirus treatment of primary colorectal cancer samples. In the second part, we evaluate EGFR and MEK targeting in KRAS mutated colorectal cancer cells. For EGFR, we focus on the effects of KRAS mutations on EGFR signaling and inhibition. In line with the growing evidence in large clinical studies, we find that both extracellular and intracellular EGFR targeting agents are ineffective in colorectal cancer cells with an activating mutation in KRAS. In search for explanations for this striking resistance, we show that mutant KRAS causes intracellular retention of the EGFR which diminishes the tumor cell response to both EGF induced activation and EGFR inhibition. These results add an alternative explanation for resistance to EGFR targeted therapy. For MEK targeting, we demonstrate that mutant KRAS allows cells to bypass MEK/ERK inhibition by activating the p38 MAPKinase pathway. This allows activation of transcriptional targets that are shared by the MEK/ERK and the p38 MAPK pathway. Therefore, we state that KRAS mutations in colon cancer cells are associated with resistance to MEK inhibition. Finally, we explore strategies to target colorectal cancer stem cells. Therefore, a novel model for culturing colorectal cancer stem cells from freshly resected colorectal tumors or liver metastases was developed. With this model, we identify two different mechanisms of resistance of cancer stem cells to common chemotherapeutic drugs. First, we show that one of the ABC transporters, ABCB1, plays an important role in resistance to irinotecan treatment. However, our results indicate that colorectal cancer stem cells do not display intrinsic resistance to irinotecan. Instead, the drug-sensitive cancer stem cells appear to be protected by a drug resistant, differentiated cell population originating from the cancer stem cells. Second, we used a proteomics based approach to identify BIRC6, an inhibitor of apoptosis protein, as a key player in resistance of cancer stem cells to oxaliplatin and cisplatin resistance in cancer stem cells. In conclusion, we describe several new targeting strategies for glioma and colorectal cancer. Our studies identify some striking resistance pattern for targeted therpeutics, but also suggest strategies for circumventing resistance and reveal new options for tumor targeting
Original language | English |
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Qualification | Doctor of Philosophy |
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Award date | 14 Jun 2011 |
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Print ISBNs | 978-94-6108-176-6 |
Publication status | Published - 14 Jun 2011 |