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Combining radiotherapy with DNA repair inhibitors as novel treatment strategy for head and neck cancers

Boek - Dissertatie

Head and neck cancers are the 6th most frequent cancers worldwide and are divided in two groups according to their etiology, namely the alcohol and tobacco related and high-risk human papilloma virus (HPV) related. Despite enormous progress made in therapeutic efficacy, still up to 50% of patients die from local disease. Furthermore, the intense chemoradiotherapy schedules are currently at their maximum tolerated doses, indicating the urgent need for novel more selective treatment strategies. However, in general the progress in this field seems to be very slow. The low success rate of new selective treatment strategies can be ascribed to number of reasons but one important factor is the lack of rigorous design of preclinical studies in which the optimal scheduling and molecular interaction between different agents are studied. One of the biological reasons for the high local relapse is the DNA repair capacity of the irradiated cells, which can enable tumor cells to survive and provide a prominent mode of resistance and reduction in the therapeutic efficiency.In this PhD project, we propose a thorough preclinical assessment of novel DNA damage response targeting agents in combination with radiation treatment. First, we want to identify a subset of HNSCC patients that will be highly responsive to the combination of DNA repair inhibitors and radiotherapy and elucidate molecular mechanisms of the enhanced sensitivity. For this we will investigate if signatures can be defined which will predict therapy response in vitro. Therefore, we will look for specific gene alterations related to existing defects in DNA repair pathways. Next we plan to validate our in vitro observations using HNSCC PDX models. More specific, we propose to assess the efficacy, optimal therapeutic scheme and molecular alterations of combination of DNA repair inhibitors with radiotherapy. In the last step, we will also optimize the detection of the identified biomarkers using UH Leuven HNSCC tumor bank. A biomarker assay will be developed to detect response to DNA repair inhibition which can later be used in prospective trials using DNA repair inhibition. The results of our study will not only lead to a rational clinical trial design for HNSCC patients and improved patient outcome on the long-term.
Jaar van publicatie:2020