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Department of Dermatology and Veneral Diseases

Projects

  • Biomarker for the early detection of melanoma

    Compartment specific in depth analysis of blood plasma nucleic acids for highly sensitive detection of early metastic events in melanoma disease

    • Project Number: LSC15_020
    • Project Lead: Jörg Burgstaller, University of Veterinary Medicine Vienna / IFA Tulln (VetMed)
    • Project Partner: Karl Landsteiner University of Health Sciences / Division of Dermatology and Venereal Diseases (University Hospital St. Pölten), University of Veterinary Medicine Vienna / Clinical Department of Equine Surgery
    • Duration: 48 months starting from 01.05.2017

    Background

    Biomarkers as indicators for therapeutic mode, onset, and response to treatment are rapidly gaining importance in clinical cancer management. Cancer biomarkers are tumour- or patient-related factors, which reflect the biological behaviour of a tumour and thus constitute a prognostic tool. Cutaneous malignant melanoma is a highly aggressive and metastatic tumour arising from cutaneous pigment cells termed melanocytes. Although incidence of melanoma and related mortality are continuously increasing, it is still impossible to predict the metastatic behaviour of melanoma in individual patients.
    In the past five years, the field of "liquid biopsies", i.e. the gain of important information on tumour development via nucleic acid (NA)-based analysis of blood samples, has tremendously progressed. It is now evident that in the blood, tumour-cell derived NAs reside in three different compartments, i.e. (i) intracellular NAs in circulating tumour cells, (ii) NAs in extracellular vesicles, and (iii) freely circulating protein-bound DNA in the plasma. Importantly, extracellular NAs are more abundant in blood, and therefore more accessible.Currently, the clinical applicability of blood-based tumour detection and monitoring methods is still limited to patients with progressive (metastatic) disease. Based on the hypothesis that a compartment-specific NA analysis will considerably aid in improving blood test sensitivity in comparison to holistic approaches, the overall objective of the herein presented study is to exploit the compartmentalization of tumour-derived blood NAs in order to establish a novel strategy for highly sensitive blood-based detection and monitoring of early stage human melanoma disease and metastasis. The applicant and cooperation partners aim at achieving this goal by (i) addressing the amount and composition of extracellular vesicular nucleic acids and circulating free DNA in vitro in order to comparatively evaluate vesicles as a reservoir of potential NA-type biomarkers, (ii) addressing the presence and amount of tumour-derived NA per compartment and possible changes of these parameters over time in a clinical study involving late stage melanoma patients, and by (iii) addressing the presence and amount of the most promising tumour-derived NAs identified in (ii) in a clinical study involving patients with high risk of melanoma recurrence as to achieve earliest possible detection of disease recurrence.

  • CSPG4

    The role of chondroitin sulfate proteoglycan 4 in the development of multidrug tolerance in melanoma cells

    • Project Number: LSC15_007
    • Project Lead: Christine Hafner, Karl Landsteiner University of Health Sciences / Division of Dermatology and Venereal Diseases (University Hospital St. Pölten)
    • Project Partner: Karl Landsteiner University of Health Sciences / Institute of Pathology (University Hospital St. Pölten), Karl Landsteiner University of Health Sciences / Institute of Pathology (University Hospital Krems), Medical University of Vienna / Institute of Pathophysiology and Allergy Research, University of Queensland / Dermatology Research Centre
    • Duration: 48 months starting from 01.11.2016

    Background

    Malignant melanoma is the most frequent cause of skin cancer-related deaths. Despite the progress in understanding the biology of this disease, it still remains a significant clinical problem. Melanoma is often associated with activating mutations in the BRAF gene at the amino acid position 600, which results in an uncontrolled activation of the MAP-kinase pathway and - as a consequence - leads to increased cell proliferation and migration. Although several BRAF inhibitors, such as vemurafenib, have been proven to be highly effective in inhibiting BRAFV600 mutated melanomas, resistant-associated secondary mutations, which reactivate alternative survival pathways, often occur. We have recently reported on the response of chondroitin sulfate proteoglycan 4 (CSPG4)-specific Abs to enhance the anti-proliferative effects of vemurafenib. These data implied that the microenvironment is important in determining the effect of targeting CSPG4 on cell migration and invasion and suggest a role for CSPG4 in the phenotypic plasticity of melanoma cells and the emergence of a transient drug-resistant state. Central to the model of stress-induced drug tolerance resulting in multi-drug resistant cancer cells called induced-drug tolerant cells (IDTCs) is their propensity to develop colonies for which cell adhesion is crucial. Based on these findings of cell adhesion and cell motility being crucial for early drug resistance we propose that anti-CSPG4 antibodies, which have shown promising results in two different animal models, prevent or delay IDTC formation in mutant BRAF melanoma cells if combined with standard treatment modalities such as BRAF and MEK inhibitors. During this project we will validate this hypothesis with in vitro and in vivo models of melanoma, we will analyse changes on protein and gene expression levels induced by these treatment modalities and we will validate these experimental data on patients´-derived melanoma samples. Targeting IDTCs with anti-CSPG4 antibodies could be a crucial step for the prevention of acquired drug resistance.

  • NRF2 Melanoma

    The role of NRF2 for Melanoma Progression - Insights into the mechanimsm of metastasis

    • Project Number: LSC14_007
    • Project Lead: Harald Hundsberger, IMC University of Applied Sciences Krems
    • Project Partner: Karl Landsteiner University of Health Sciences / Division of Dermatology and Venereal Diseases (University Hospital St. Pölten), Medical University of Vienna / Institute of Medical Genetics
    • Duration: 36 months starting from 01.03.2016

    Background

    Melanoma is one of the most frequent tumors in young adults and despite it only accounts for 4% of all cases of skin cancer, melanoma is responsible for 79% of all skin cancer related deaths. Despite progress has been achieved in treatment of Melanoma (e.g with B-raf inhibitors), finally patients succumb due to resistance mechanisms acquired by the tumor. Many lines of evidence have shown that especially metastatic melanoma exhibits a strong metabolic turnover, which is needed to fuel cell proliferation and anabolic pathways. This increased cellular turnover also results in an increased demand to maintain the redox homeostasis. Here we propose to analyze this high metabolic and therefore also ROS (Reactive Oxigen Species) generating stress as a possible Achilles heel of melanoma. One of the major regulators of stress response in cancer is NRF2. It plays a central role in protection of cells against oxidative and xenobiotic stresses. Therefore the inhibition of NRF2 or its target genes might re-establish the sensitivity of melanoma to apoptosis driven by ROS. Furthermore this mechanism could prevent resistance mechanisms frequently observed in metastatic melanoma and it might abolish the frequently observed activation of endothelial cells, which surround tumor cells. It is highly likely that a combination of state of the art melanoma treatment with compounds that inhibit the generation of ROS scavengers, potentiates the effectiveness of the current treatment regiments. We will use CRISPR based methods as well as pharmacological inhibition to elucidate the mechanistic role of NRF2 in melanoma cells and on endothelial cells. Furthermore we will transfer knowledge gained from our model by closely cooperating with clinicians, who routinely care for melanoma patients. Concluding, we propose that abolishing the antioxidative response by suppressing NRF2 directly or its targets will be an effective contribution in the battle to fight metastatic melanoma.

Events

  1. 14 Mar

    Open House at KL University - March 2020

    14. March 2020, 10:00 - 14:00
    Karl Landsteiner University, Dr.-Karl-Dorrek-Straße 30,3500 Krems, Trakt Y, Erdgeschoß
  2. 27 Mar

    International Skills Lab Symposium 2020

    27. March 2020, 09:00 - 28. March 2020, 18:00
    Karl Landsteiner Privatuniversität für Gesundheitswissenschaften, Skills Lab, Trakt Y
  3. 16 Nov

    Open House at KL University - November 2019

    16. November 2019, 10:00 - 14:00
    Karl Landsteiner Privatuniversität, Dr.-Karl-Dorrek-Straße 30,3500 Krems, Trakt Y, Erdgeschoß