Research groups at MedUni Vienna receive substantial grants from the Ludwig Boltzmann Society

“Personalized targeted glioblastoma therapies by ex vivo drug screening: Advanced Brain Tumour Therapy Clinical Trial (ATTRACT)”
Anna Sophie Berghoff (Head) and Matthias Preusser (Mentor)
Glioblastomas are the most common malignant brain tumours in adults and are characterized by poor prognosis and high morbidity and symptom burden. Despite intensive research, treatment breakthroughs have not been realized, due in part to limited drug bioavailability and high intrinsic resistance rates. In approximately 60-70% of glioblastomas, the promoter of the O6-methylguanine methyltransferase (MGMT) gene is unmethylated, leading to particularly marked chemoresistance and poor outcomes. Therefore, the development of individualized therapeutic approaches based on tumour biology is urgently needed.

The "Personalized targeted glioblastoma therapies by ex vivo drug screening: Advanced Brain Tumour Therapy Clinical Trial" project, ATTRACT for short, aims to introduce the concept of functional precision medicine and thus enable patients to receive tailor-made therapy. This project is made possible by an interdisciplinary, Austria-wide consortium led by Matthias Preusser (Mentor), Anna Sophie Berghoff (Head KFG) and Maximilian Mair (Deputy Head KFG) in cooperation with CBMed, the Medical University of Graz, the Medical University of Innsbruck, the Karl Landsteiner University / University Hospital St. Pölten, the Johannes Kepler University / Kepler University Hospital, the Danube Private University and the Austrian Institute of Technology (AIT). At MedUni Vienna, in addition to the Division of Oncology (Department of Medicine I), the Department of Neurology, the Department of Neurosurgery, the Division of Neuroradiology and Musculoskeletal Radiology (Department of Biomedical Imaging and Image-guided Therapy) as well as the Institute of Medical Statistics and the Institute of Artificial Intelligence at the Centre for Medical Data Science are involved.

The cornerstone of ATTRACT is an innovative ex vivo drug screening platform developed by CBMed that analyses the response of patient-derived tumour cells (PDCs) to selected drugs. The clinical utility of this approach will be evaluated in a prospective, multicentre, randomized phase 2 trial involving 240 adults with newly diagnosed glioblastoma. The trial is supported by Austrian Cancer Aid, GPMed (Austrian Society for Pharmaceutical Medicine) and the Clinical Coordination Centre of MedUni Vienna and is supported by a high-calibre international Advisory Board consisting of Michael Weller (Clinic for Neurology, University Hospital Zurich), Priscilla Brastianos (Neuro-Oncology, Cancer Centre, Massachusetts General Hospital), Annette Kopp-Schneider (Division of Biostatistics, German Cancer Research Centre), Markus Zeitlinger (Department of Clinical Pharmacology, Medical University of Vienna), D. H. Nam (Samsung Medical Centre, Seoul), and Helen Bulbeck (Chair of the patient organization Braintrust, UK).

"The Ludwig Boltzmann Society's "Clinical Research Groups" grant is a unique funding opportunity in Austria for clinical academic research," explains study leader Anna Sophie Berghoff, "ATTRACT is a highly innovative study project that has been under consideration for many years, but until now there was no way to fund an academic study of this size in Austria." And "mentor" Matthias Preusser adds: "ATTRACT is also regarded by international colleagues as a leading research project and is the first to bring forward personalized therapy based on individualized drug screening to patients with newly diagnosed glioblastoma in a randomized trial here in Austria."

In addition, a unique biobank will be established to provide PDCs, drug response information, tumour tissue samples and detailed clinical information for further functional and translational research. Here, therapy resistance and sensitivity will be investigated using genetic, epigenetic and metabolic methods on PDCs and tumour tissue samples. By incorporating digitized histological sections as well as radiological data, the results will be correlated with clinical information. Integrative AI-based data analysis will enable the identification of novel, cross-platform biomarkers. ATTRACT will therefore provide comprehensive insights into the biology of glioblastoma and thus form the basis for the development of new treatment methods.

“Disease-driving mechanisms in patients with portal hypertension”
Thomas Reiberger (Head) and Michael Trauner (Mentor)
Portal hypertension (PH) is a serious complication in patients with liver disease and the leading cause of liver-related mortality, accounting for more than 2 million (4% of all) deaths worldwide. The only (off-label) therapy available is non-selective beta-blockers (NSBBs), although only about 60% of patients respond to this therapy. No other effective medical treatment has been established in clinical practice for >30 years. A better understanding of the molecular mechanisms involved in the progression and regression of PH in liver disease will help to find much needed PH treatments for those patients affected.

The clinical research group (KFG) MOTION consists of a team of clinical experts in hepatology, radiology, and anaesthesiology from the Medical University of Vienna with an intensive care focus on coagulation disorders, as well as principal investigators from the Centre for Molecular Medicine (CeMM) and the Division of Gastroenterology and Hepatology (Department of Internal Medicine III). Based on the experience of ongoing prospective biobank registry studies involving patients with liver cirrhosis (VICIS: Vienna Cirrhosis Study, clinicaltrials.gov NCT03267615) and vascular liver disease (VALID: Vienna Vascular Liver Disease Study, clinicaltrials. gov NCT03541057) are included, the severity of PH is characterized using invasive gold standard, hepatic vein pressure measurement (HVPG) and modern non-invasive techniques, such as liver (LSM) and spleen elastography (SSM). The Vienna Hepatic Hemodynamic Lab at the Division of Gastroenterology and Hepatology at the University Hospital AKH Vienna under the direction of Mattias Mandorfer (Deputy-Head of KFG MOTION) has been an international pioneer in refining these methodologies for many years.

Within KFG, three investigator-driven clinical trials are being conducted involving patients with (i) compensated cirrhosis (cACLD), (ii) decompensated cirrhosis (dACLD), and (iii) vascular liver disease (PSVD), which are testing promising new therapies for PH: The TECA study is investigating the effects of the renin-angiotensin system (RAS) blocker telmisartan on HVPG in cACLD patients, given the central role of the RAS in the liver scarring (fibrosis) process. In the NOPE study, the effects of norfloxacin, which primarily targets the gut microbiome and bacterial translocation, on HVPG will be investigated. Using norfloxacin therapy, researchers also hope to inhibit systemic inflammatory processes, resulting in a lower rate of serious complications in dACLD patients. The EXPOSURE study will evaluate the safety and preclinical efficacy of the direct anticoagulant edoxaban in PSVD patients because vascular liver disease often presents with a prothrombotic tendency.

In a total of 8 work packages, KFG MOTION is studying basic pathomechanisms of portal hypertension, using modern peptide and enzyme assays to characterize classical and alternative RAS, gene expression analysis by RNA sequencing of liver tissue and intestinal biopsies, assessment of the intestinal microbiome, and studies of blood metabolites in the CeMM Core Facility for Metabolomics. In addition, detailed analyses of the blood coagulation cascade in cACLD, dACLD and PSVD patients will be performed, which will also be used to monitor the effects of edoxaban therapy in the EXPOSURE study. In a dedicated radiomics work package, machine-learning models are used to process and analyse the enormous data input of modern CT cross-sectional imaging techniques. In another work package, vascular changes in PH are being investigated using single-cell sequencing of isolated circulating endothelial cells, among other methods, and systemic angiogenesis messengers are being mapped using multiplex ELISAs and structural changes in liver sinusoids are being analysed using histologic staining.

In summary, the KFG Motion team seeks to explore specific pathophysiological mechanisms of PH in compensated (cACLD) and decompensated (dACLD) cirrhosis, as well as in PSVD, through advanced technology and state-of-the-art methodology to improve the diagnosis, non-invasive monitoring, therapy, and prognosis of patients with PH.

Research programmes with a clear focus on patient-centred, medically relevant topics
The call for LBG Clinical Research Groups (KFG) aims to fund medium-term collaborative research programmes with a clear focus on patient-centred, medically relevant topics in the field of non-commercial clinical research.

The development of innovative research results in disease- or patient-oriented clinical research within the framework of investigator-initiated clinical studies is supported, with the possibility of integrating translational aspects. At the same time, with a view to promoting young researchers, high-quality training opportunities will be offered to young clinical researchers. The KFG will focus on a coherent research programme consisting of several work packages/subprojects.

The total budget for the 2022/23 call is 24 million euros (16 million from the Federal Ministry of Education, Science and Research (BMBWF) and 8 million euros from the Austrian Future Fund). Participating institutions are required to contribute at least 10% of the KFG costs from their own funds. Duration: 4 + 4 years (second funding period after successful interim evaluation).

44 applications were submitted during the short application period for the first call. After the evaluation by the international expert commission, 8 groups were invited to the full proposal round and to present their projects to the expert commission, and finally 3 proposals were selected for funding by KFG.