Title Promoter Affiliations Abstract "Patient-centred and cost-neutral introduction of novel interventions in gynaecology" "Jan Deprest" "Urogenital, Abdominal and Plastic Surgery" "We aim to study the introduction of novel technologies, such as vNOTES and vaginal laser application, into our gynaecologic practice. For vNOTES hysterectomy, we will study the learning curve, perform a cost minimisation study, and measure the impact of an enhanced recovery protocol on hospital stay. In breast cancer patients under AI, we will perform a randomized controlled trial comparing fractional CO2 vaginal laser to hyaluronic acid application." "Translational research for optimization of preoperative diagnosis and minimally invasive surgical techniques in gynaecology." "Wouter Froyman" "Woman and Child" "Minimally invasive surgery is growing rapidly in various domains, including benign gynaecological surgery. This stems from the advantages for the patient, such as less morbidity, better postoperative quality of life and a shorter interval to regaining normal functioning. But also the societal burden diminishes by omitting or shortening the need for overnight hospitalisation, and by enhancing a quicker return to work. We strive to optimize already available as well as new techniques for benign gynaecologic operative interventions, focusing on surgical techniques, in need for high quality evidence. In particular, we will assess the outcome of these newly introduced procedures in terms of patient reported outcome measures (PROMs), patient reported experience measures (PREMs) and health economic impact. Pre-operative imaging (e.g. gynaecological ultrasonography) is essential in tailoring therapy for each individual patient. High-quality imaging helps to predict surgical difficulties, to choose the appropriate technique and to exclude underlying malignancy. We will specifically investigate the role of liquid biopsies and artificial intelligence to improve the subjective diagnosis by ultrasonography. This has been implemented in a growing number of fields, but rarely in gynaecology." "Developing better prevention strategies, faster detection methods and treatments in the following medical fields: cardiology, oncology, gynecology / fertility, infectious diseases, anesthesia / neurology, orthopedics." "Piet STINISSEN" "Immunology & Infection, Immunology - Biochemistry" "The Limburg Clinical Research Center (LCRC) is a unique collaboration between UHasselt, the Jessa Hospital and Hospital Oost-Limburg. By bridging the gap between academic research and clinical practice we want to improve healthcare. Through patient-oriented medical-scientific research we look for innovative solutions to needs from daily clinical practice. As an internationally oriented academic-medical knowledge center in Limburg, the LCRC wants to be an important stimulus for top medical care, academic education and healthcare innovation in Limburg and Flanders." "Improving treatment of rare women’s cancers and conditions." "Frédéric Amant" "Gynaecological Oncology" "This research is focusing on rare gynecological conditions, in particular on malignancies diagnosed during pregnancy and rare gynecological tumors. Altogether, rare women’s cancers account for more than 20% of all cancer diagnoses, but still present poorer clinical outcomes in comparison to other single common cancers. Similarly, though rare, the incidence of cancer in pregnancy has been increasing in recent decades, resulting in more complex oncologic–obstetric decision making processes. However, due to the low incidence and the limited (pre)-clinical data available with regard to these conditions, pharma companies are reluctant to invest resources, despite their high clinical need. In this research project, I aim to improve treatment options and quality of life for women with such rare cancers or disease conditions. In particular, given my position in the clinic, I have identified specific and urgent medical needs for women with these rare conditions. Via clinical studies and unique patient-derived models of gynecological cancers, and the implementation of innovating, cutting-edge approaches I aim to translate cutting-edge research data into clinical benefit for patients suffering from these conditions." "Improving treatment of rare women’s cancers and conditions." "Frédéric Amant" "Gynaecological Oncology" "This research is focusing on rare gynecological conditions, in particular on malignancies diagnosed during pregnancy and rare gynecological tumors. Altogether, rare women’s cancers account for more than 20% of all cancer diagnoses, but still present poorer clinical outcomes in comparison to other single common cancers. Similarly, though rare, the incidence of cancer in pregnancy has been increasing in recent decades, resulting in more complex oncologic–obstetric decision making processes. However, due to the low incidence and the limited (pre)-clinical data available with regard to these conditions, pharma companies are reluctant to invest resources, despite their high clinical need. In this research project, I aim to improve treatment options and quality of life for women with such rare cancers or disease conditions. In particular, given my position in the clinic, I have identified specific and urgent medical needs for women with these rare conditions. Via clinical studies and unique patient-derived models of gynecological cancers, and the implementation of innovating, cutting-edge approaches I aim to translate cutting-edge research data into clinical benefit for patients suffering from these conditions." "Fulvestrant in gynecological cancers that are potentially hormone sensitive: the FUCHSia study" "Frédéric Amant" "Gynaecological Oncology" "Here, we aim to set up a Phase II, multicenter study to test the efficacy of Fulvestrant in patients with ER-positive low-grade gynecological cancers. Fulvestrant is an anti-ER drug already approved for ER-positive metastatic breast cancer in postmenopausal women progressing under previous endocrine treatments. Because of its peculiar mechanisms of action, there are indeed highchances that tumors developing resistance to other hormone therapies would still respond to Fulvestrant, making it a valuable alternative therapeutic strategy. We will assess the feasibility of18F-FES-PET/MRI technique to monitor disease’s response and evolution during treatment in order to assess its potential use as a predictive/prognostic biomarker. Results from this study will help to introduce molecular-based stratification approaches in the design of clinical trials for hormone therapies and potentially accelerate the approval of Fulvestrant for treatment of selected low-grade gynecological cancer patients. " "Three dimensional ultrasound and artificial intelligence in the characterization of adnexal masses" "Wouter Froyman, Dirk Timmerman" "Woman and Child" "The objective of the thesis is to develop knowledge on gynecologic ultrasound. Specifically I will concentrate myself on the fields of artificial intelligence and three- dimensional ultrasound applied to the ovarian cancer first and later also focus on the three- dimensional ultrasound to endometrial cancer and uterine malformations. I will participate in the already ongoing research projects and take the chance to start new projects based on them. Once completely developed and well-established, artificial intelligence will permit the automatic pattern recognition of basic sonographic features of ovarian masses, and this will probably help sonographers in the selection of malignant masses, according to what is nowadays known on this area, and sort the cases that need particular follow up or secondary care. On the other hand, three- dimensional ultrasound is a challenging skill that could eventually help gynecologists to better understand the nature of ovarian masses, endometrial cancers and uterine malformations compared to the two-dimensional ultrasound, and therefore it may improve the specificity of the diagnosis. However further studies are needed in order to evaluate this.   Artificial intelligence and three-dimensional ultrasound is a continuously growing branch of gynecologic ultrasound, and many improvements are expected to increase diagnostic confidence and optimal clinical workflows." "An In-vitro and In-vivo Study on the Effect of alpha PLGF in Gynaecological Tumours" "Frédéric Amant" "Gynaecological Oncology" "Angiogenesis (the process of new blood vessel formation) is essential for tumour growth and metastasis to lymph nodes and other organs in the body. Inhibition of angiogenesis is a new discovery in the treatment of cancer. However, current angiogenesis therapy used in a clinical setting have serious side effects and do not have the desired efficacy. For this reason, there is a need to discover and develop new and complementary angiogenesis inhibitors. Very recently, a new anti-angiogenesis inhibitor, anti-PlGF, was discovered. Anti-PlGF slows down the angiogenesis, lymphangiogenesis, growth and metastasis of the tumours and does not have the serious side effects associated with current anti-angiogenesis therapy. The effect and therapeutic potential of anti-PlGF has not yet been evaluated and researched for gynaecological tumours. Therefore, this project aims to research PlGF and PlGF inhibition in endometrial, uterine, cervical and ovarian cancer. In this project, there will be a combination of pre-clinical and clinical studies. In-vitro and in-vivo experiments will aim (i) to evaluate the role of PlGF in gynaecological tumour biology en (ii) to establish the pre-clinical potential of anti-PlGF in both a homologous and a heterologous tumour model system. In complementary clinical studies, the prognostic value of (i) plasma PlGF levels, (ii) PlGF immunohistochemistry in the tumour and (iii) genetic variations in the PlGF gene will be determined for  relapse, response to therapy and resistance to the therapy. This project aims to create a scientific background for future use of anti-PlGF in the treatment of patients with gynaecological tumours. " "Serine auxotrophy: a novel metabolic vulnerability of platinum resistant ovarian cancers?" "Frédéric Amant" "Gynaecological Oncology, Laboratory of Cellular Metabolism and Metabolic Regulation (VIB-KU Leuven)" "Ovarian cancer is the eight most common type of cancer in women and accounts for the second highest number of gynecological cancers associated deaths in the developed world. While for many cancer types the overall survival increased over the last years, this is unfortunately not true for ovarian cancer, showing a stagnation over the last decades. For over 40 years standard of care consists out of platinum-based chemotherapy, with or without taxanes. The high mortality rate is mainly attributed to the development of resistance to conventional platinum-based therapies. Although a lot of research has been done on chemoresistance, translation into the clinic has been failed. In addition, there are no trustworthy biomarkers to distinguish platinum resistant from platinum sensitive tumors, often leading to ineffective platinum treatment. That is why the identification of resistance biomarkers and development novel therapeutic strategies is of crucial importance in translational cancer research.In recent years it has become clear that cellular metabolism is of major importance in the regulation of cell survival and cell death signaling, that is why we in this PhD project we aimed to investigate metabolic changes that are potentially linked to the resistant phenotype. To underline the clinical importance of our findings we combined state-of-the-art molecular technologies and relevant pre-clinical patient derived xenograft (PDX) mouse models and patient derived data.By applying unbiased metabolomics and isotope labeled tracer analysis in vitro, we managed to identify changes in serine metabolism in platinum resistant cells compared to its platinum sensitive counterpart. Moreover, we found that resistant cancer cells down regulate serine biosynthesis by reducing the intracellular amounts of its rate limiting enzyme phosphoglycerate dehydrogenase (PHGDH).Based on this finding we hypothesized that PHGDH can potentially be used as biomarker for platinum sensitivity. In addition, we also showed that platinum resistant cells are auxotroph for serine in vitro.Next, we investigated the underlying mechanism of PHGDH downregulation by integrating our metabolic findings and we found that serine synthesis down regulation is a part of global metabolic changes in central carbon metabolism towards a NAD+ generating phenotype. We found that NAD+ availability is required to sustain poly-(ADP)ribose-polymerase (PARP) activity under platinum treatment. PARPs are enzymes needed for many cellular functions, including DNA repair. By combining PARP inhibitors and carboplatin we managed to overcome platinum resistance in vitro.  To further investigate if our findings are clinically relevant we used patient-derived xenograft mouse models (PDX), their derived organoid cultures and patient data. We showed that PHGDH are also reduced in resistant models in vivo. These findings are in concordance with TCGA derived data. In addition, we showed that PHGDH gradually decrease and PARP1 levels increase after platinum-based treatment in different PDX models, suggesting that this is an adaptive mechanism to platinum exposure. Finally, we were able to acquire matched primary and recurrent tumor biopsies from patients from the clinic and we showed that, also in patients, PHGDH levels decrease when tumors became resistant to platinum after different cycles of platinum exposure. The identified changes in PHGDH can subsequently potentially be used as biomarker to distinguish platinum sensitive from resistant tumors. Our data provide evidence that combining platinum-based chemotherapy and PARP inhibitors might be a relevant method to overcome platinum resistance. Eventually we validated these results in PDX derived organoid models where we observed a synergistic effect of combining platinum with olaparib.To conclude, with this PhD project we managed to identify a novel potential biomarker for platinum resistance. We showed that resistant cancer cells down regulate serine biosynthesis by specifically decreasing PHGDH levels compared to sensitive cells. Investigation of the underlying mechanism led to a novel potential metabolic target, moreover PARPs, to overcome platinum resistant. We were able to overcome platinum resistance by combining PARP inhibitors with carboplatinum in vitro and in different ex vivo organoid models. These findings need further confirmation in clinical settings in future studies." "A drug strategy targeting stabilised mutant p53 to fight metastatic plantinum-resistant ovarian cancer." "Ignace Vergote" "Gynaecological Oncology" "Epithelial ovarian cancer (EOC) is the most lethal gyncaecological malignancy causing 41900 deaths annually in Europe. The predominance of aggressive Type II tumours, which are characterised by a high frequency of p53 mutations, and primary or acquired resistance to platinum-based chemotherapy profoundly contribute to the high mortality rate. With current standard therapy the median overall survival of metastatic platinum-resistant (Pt-R) ovarian cancer patients is only 14 month. There is a pressing need for more effective, innovative treatment strategies to particularly improve survival in this subgroup of EOC patients. The GANNET53 trial aims to achieve this goal by applying a highly innovative concept that has grown from solid basic research findings made by members of the GANNET53 consortium. This is a drug strategy targeting a central driver of tumour aggressiveness and metastatic ability, namely mutant p53, via an innovative new Hsp90 (heat shock protein 90) inhibition mechanism. The most advanced, second-generation Hsp90 inhibitor will be used, Ganetespib. The first part (Phase I) of the GANNET53 trial will test the safety of Ganetespib in a new combination with standard chemotherapy (Paclitaxel weekly) in Pt-R Type II EOC patients. The second part (randomised Phase II) will examine the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone in EOC patients with Pt-R Type II tumours. We established a highly efficient consortium with previously proven capability and manpower to perform this multicentre clinical trial and assess our innovative therapeutic concept in this deadly disease. Our consortium consists of national clinical trial groups in gynaecological oncology and high-volume University centres as well as noted p53 scientists and 3 innovative SMEs. Since ovarian cancer is defined as a rare cancer a scale at the European level is crucial for the planned clinical trial."