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Head and neck cancers include malignancies originating in the oral cavity, nasopharynx, oropharynx, hypopharynx and larynx. In Belgium, more than 90 % of head and neck cancers are squamous cell carcinomas (HNSCC), and more than 2500 patients were diagnosed with HNSCC in the year 2016. (Belgium Cancer Registry) The use of alcohol and tobacco, with a substantial synergistic effect, induces most HNSCC except for oropharyngeal (OPC) and nasopharyngeal cancer. These HNSCC subsites often have a viral aetiology, Human Papillomavirus (HPV) and Epstein Barr virus, respectively. In the Western world, the incidence of HPV positive OPC is rapidly increasing.The treatment of HNSCC depends mainly on the tumour subsite, tumour size, lymph node involvement and the presence of distant metastases, summarised in the TNM classification. Most early-stage HNSCC can be cured by surgery or radiotherapy (RT), which have similar locoregional control rates. The selection of treatment modality in early disease depends on patient characteristics, the expected post-treatment organ functionality and cosmesis. Unfortunately, the majority of patients with HNSCC have locally advanced disease at diagnosis and should, therefore, be treated with chemoradiotherapy (CRT) or with radical surgery followed by adjuvant (C)RT. Thus, RT is one of the cornerstones of the treatment of HNSCC. Since RT damages both normal and neoplastic cells, the clinical challenge in radical RT is to attain a high therapeutic ratio, which is the highest probability of cure with the least toxicity to surrounding healthy structures.Technical evolutions have made it possible to design high precision three dimensional (3D) conformal and intensity-modulated radiotherapy (IMRT) in which the high dose region is better sculpted around the target volumes, which made it possible to spare the healthy organs at risk (OAR) better. IMRT has become the prefered RT technique in the treatment of HNSCC since the randomised controlled PARSPORT trial has shown the ability and advantage of sparing the parotid salivary glands with IMRT. Despite the improved RT dose distribution on the OAR, acute and late toxicity such as dysphagia, remains a major problem. The risk of dysphagia is correlated with the dose to the swallowing muscles. With the current standard RT dose and fractionation, it is difficult to lower the dose on the swallowing muscles because of the proximity of the target volumes (tumour, nodes and elective neck). Therefore, the current RT procedure and protocol should be optimised in order to reduce treatment-related toxicity.We hypothesised that dose-de-escalation to the elective nodal neck (PTVelect) could lower the RT related toxicity such as dysphagia and lead to better QoL without compromising the oncological outcome. Therefore, a multicentre randomised controlled trial was set up comparing a lower dose to the PTVelect, EQD2 40 Gy, against the standard dose, EQD2 50 Gy. In previous publications, the dosimetric comparison, the effect on acute and late toxicity and the two-year tumour outcome were published showing a significant reduction in dose on several swallowing structures resulting in a substantial reduction in grade ≥3 dysphagia three months after radiotherapy. At later time points, only a trend toward less dysphagia was found. Regarding survival and tumour control, no statistically significant differences were found at two years. We assessed the long term oncological outcome with a special interest in the regional recurrence rate in the PTVelect and investigated the differences in QoL between the 40 Gy and 50 Gy arm.Since in this prospective randomised trial reduction of the dose to PTVelect did not result in a clear benefit in terms of decrease in late dysphagia, other factors may contribute to the development of severe dysphagia. We examined the role of patient and treatment characteristics on dysphagia scored on swallowing videofluoroscopy (VFS) as well as patient and physician scored dysphagia. Next, we evaluated if an existing prediction model for dysphagia, the total dysphagia risk score (TDRS), was also valid in our patient cohort.Besides efforts to reduce the treatment-related toxicity, we should also strive to tailor the treatment to the individual risk profile of the patient. Presently, all patients treated with curative RT receive a standard high dose of 70 Gy (in 35 fractions of 2 Gy), even though some tumours are more radiosensitive than others. The difference in radiosensitivity and prognosis is particularly proven in OPC. In general, HPV positive OPC have a better prognosis than HPV negative OPC. Treatment intensification, e.g. by dose escalation or hypoxia modification, may improve the oncological outcome for patients with poor prognosis while for others with excellent prognosis who might be overtreated, dose reduction could prevent long term toxicity. Good prognostic models are needed to individualise the patients' treatment. At the moment, these models are mostly based on the TNM classification in combination with patient characteristics such as smoking. We examined the prognostic impact of a few models and the new TNM classification in our patient population. Although the new TNM classification (8th edition) provides better OS stratification than the 7th edition, we are convinced that in the future genetic and radiologic information must be integrated to better select patients for de-escalation or escalation of the treatment. First, we examined the prognostic value of a 15-gene hypoxia classifier in OPC. Next, the role of diffusion-weighted (DW) MRI in OPC was investigated. We compared the DW-MRI first-order histogram and radiomic features between HPV positive and negative OPC.Thus, the objectives of this research project are twofold. The first aim is to reduce the treatment-related toxicity in HNSCC with particular focus on dysphagia. The second aim is to predict the prognosis for patients with OPC to tailor the treatment to the individual risk profile.

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Head-and-neck squamous cell carcinoma (HNSCC) is the fifth most common malignancy worldwide, responsible for approximately half a million new cases every year. The treatment of this disease is challenging and characterized by high rates of therapy failure and toxicity, stressing the need for new innovative treatment strategies. In this work we primarily aimed to identify potential starting points for new therapeutic targeting strategies. We therefore performed a high throughput shRNAmir based screen on HNSCC cells with the aim to identify tyrosine kinases that are mediating radiotherapy resistance. Using this screen setup we identified the receptor tyrosine kinase FLT1 (VEGFR1) as an important driver of cell survival and radioresistance, and demonstrate receptor activation through autocrine production of FLT1 ligands. Immunohistochemistry on HNSCC patient samples demonstrated FLT1 and ligands to be uniformly expressed. Interestingly, FLT1 was selectively overexpressed in tumour tissue as compared to non-cancerous epithelium. Remarkably, we found only membrane permeable FLT1 kinase inhibitors to be effective, which was in agreement with the intracellular localization of FLT1. Taken together, we document expression of FLT1 in HNSCC and demonstrate this kinase to modulate radioresistance and cancer cell survival. Given the fact that FLT1 kinase is selectively upregulated in tumour tissue and that its kinase function seems expendable for normal life and development, this kinase holds great promise as a new potential therapeutic target. Nonetheless several scientific questions still need to be resolved before FLT1 targeted therapy can be transferred from bench to bedside. Most crucial is the development of a good FLT1 targeting drug, which is able to shut down FLT1 activity at concentrations which are maintainable in a clinical setting. Also further validation of such a FLT1 targeting strategy is recommended in different patient derived HNSCC xenograft models to evaluate therapy responses as well as to validate prognostic biomarkers like for example (semi) quantitative VEGFA expression or Human Papilloma Virus (HPV) status. A subgroup of HNSCC is etiologically related to HPV infection. These HPV related tumors present a different clinical behavior as compared to classical HPV unrelated HNSCC which seems rather paradoxical: they tend to have a better prognosis and show a better response to radio/chemotherapy although these tumors are undifferentiated and show more advanced clinical stages. Additionally in contrast to HPV unrelated HNSCC they seem not responsive to hypoxia targeted therapy although the level of hypoxia between these tumors is comparable. To date these characteristics are unexplained on a molecular level. As a starting point to shed light on this intriguing radiobiologic behavior, we started from observations done on breast cancer cells where it was shown that p16 suppresses the expression of VEGFA (a FLT1 activating ligand), through inhibition of HIF1a, the key regulator of hypoxic metabolism. If wecould show that p16 is suppressing HIF1a in HPV positive HNSCC, a resulting reduction of VEGFA expression could maybe explain part of the increased radiosensitivity through impaired FLT1 activity. Additionally, an impaired HIF1a function could lead to hypoxia intolerance, owing to impaired adaptation to cellular hypoxia related metabolic stress. This hypoxia intolerance could then severely impact cellular survival under oxygen deprivation, and therefore lead to increased radiosensitivity in vivo, since these cells would be unable to rely on hypoxic niches within a tumor to protect them from radiation. We clearly demonstrated p16 related HIF1a suppressive activity in HPV positive HNSCC resulting in suppressed VEGFA expression. However we also showed that this suppressive activity did not suffice to prevent a HIF1a mediated metabolic shift nor hypoxia intolerance in these cells. The reason why HPV positive HNSCC is not responsive on hypoxia targeted therapy therefore remains elusive. Recent work, however, by the DAHANCA group shows HPV positive HNSCC cells are sensitive to hypoxia targeting but only in vitro. It is therefore possible that the true explanation of this strange radiobiological behavior might come from studies investigating the tumor microenvironment like the tumor vasculature or the immune system. HPV associated HNSCC is currently becoming a global epidemic. According to American SEER data, the incidence of this type of cancer is increasing with 2-3% each year. American studies have shown that 40 to 65% of HNSCC arising from the base of tongue or tonsil could be attributed to HPV16. As already mentioned these tumors are more radiocurable but are not responsive to hypoxia targeted therapy. These factors could probably have an impact on treatment selection. Currently, locally advanced stage oropharyngeal cancers are being treated in the same way as the classical HNSCC with radio-chemotherapy schedules. These intense treatment regimens come however at the cost of severe acute and late toxicity (like dysphagia and PEG-tube dependency). Patients with HPV-associated HNSCC might not need these intense treatment regimens, and perhaps more function sparing therapies lead to equal survival numbers in this population. To set up new clinical studies, we need to have an idea about the prevalence of HPV in oropharyngeal cancer in our patient population in Flanders (Belgium), certainly because large geographical differences seem to exist. Therefore a multicenter cooperative study was undertaken between the radiation-oncology departments of the Flemish universities. We found indeed an increasing incidence of oropharyngeal carcinoma increases in males as well as females. The prevalence of HPV(+) oropharyngeal carcinoma was found to be 24.78% (19.93-30.36%). HPV status remained a strong predictor of better locoregional control after multivariate analysis. Regarding locoregional control we found the addition of concurrent chemotherapy to be of equal benefit in HPV(+) and HPV(-) patients suggesting that treatment de-escalation by omitting concurrent chemotherapy is probably not a good idea.

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Introduction: HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC) differ in their response to radiotherapy (RT). Despite these differences, all HNSCC patients are treated with the same highly toxic cRT treatment schedules. Currently, up to 50% of HNSCC patients relapse after treatment, which indicates the need for novel tumour selective radiosensitizing strategies. In addition, HPV+ and HPV- HNSCC show the same metastasis rate, but differ in their dissemination pattern to distal organs. We focus on unravelling the biological processes of metastasis in HPV+ and HPV- HNSCC. Material and methods: 36 DNA repair genes were assessed for their synthetic lethal interaction with RT in HPV+ and HPV- HNSCC cells via loss of function CRISPR-Cas9 screen. The efficacy of DNA-PK inhibitor NU-7441 with(out) RT was tested in vitro and in vivo PDX models. Differences between the dissemination patterns of HPV+ and HPV- HNSCC were assessed by migration and invasion assays. The role of p16 in the dissemination patterns was determined in xenograft mouse models by investigating angiogenesis (CD31) and lymphangiogenesis (LYVE-1). Results: Our results show differences and similarities in DNA repair machinery of HPV+ and HPV- HNSCC. Both types rely on NHEJ and targeting the key modulator DNAK-PK results in radiosensitization. Moreover, we found that p16 regulates invasiveness and metastasis through inhibiting angiogenesis, but also regulates nodal spread by stimulating lymphangiogenesis through upregulation of integrins. Discussion: Our findings provide new molecular insights in HNSCC and provide possible new treatment options which can improve outcome of HNSCC patients.

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