Salzburg Cancer Research Institute SCRI

Salzburg, Austria

Salzburg Cancer Research Institute SCRI

Salzburg, Austria
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Aberger F.,University of Salzburg | Hutterer E.,Salzburg Cancer Research Institute SCRI | Hutterer E.,Paracelsus Medical University | Sternberg C.,University of Salzburg | And 3 more authors.
Cell Communication and Signaling | Year: 2017

Treatment of acute myeloid leukemia (AML), an aggressive and heterogeneous hematological malignancy, remains a challenge. Despite advances in our understanding of the complex genetics and biology of AML pathophysiology, these findings have been translated to the clinic with only limited success, and poor outcomes persist for the majority of patients. Thus, novel treatment strategies are clearly needed for achieving deeper and prolonged remissions and for avoiding the development of resistance. Due to its profound role in (cancer) stem cell biology and differentiation, the Hedgehog (HH)/Glioma-associated Oncogene Homolog (GLI) signaling pathway may be an attractive novel therapeutic target in AML. In this review, we aim to provide a critical and concise overview of the currently known potential and challenges of HH/GLI targeting. We describe the biological role of the HH/GLI pathway in AML pathophysiology. We specifically focus on ways of targeting non-canonical HH/GLI signaling in AML, particularly in combination with standard treatment regimens, which may overcome some hurdles observed with approved HH pathway inhibitors in solid tumors. © 2017 The Author(s).

Greil R.,Paracelsus Medical University | Greil R.,Salzburg Cancer Research Institute SCRI | Obrtlikova P.,Charles University | Smolej L.,Charles University | And 35 more authors.
The Lancet Haematology | Year: 2016

Background In many patients with chronic lymphocytic leukaemia requiring treatment, induction therapy with rituximab plus chemotherapy improves outcomes compared with chemotherapy alone. In this study we aimed to investigate the potential of rituximab maintenance therapy to prolong disease control in patients who respond to rituximab-containing induction regimens. Methods In this randomised, international, multicentre, open-label, phase 3 clinical trial, we enrolled patients who had achieved a complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) to first-line or second-line rituximab-containing chemoimmunotherapy and randomly assigned them in a 1:1 ratio (central block randomisation in the electronic case report form system) to either intravenous rituximab 375 mg/m2 every 3 months, or observation alone, for 2 years. Stratification was by country, line of treatment, type of chemotherapy added to the rituximab backbone, and degree of remission following induction. The primary endpoint was progression-free survival. Efficacy analysis was done in the intention-to-treat population. This is the final, event-triggered analysis. Final analysis was triggered by the occurrence of 92 events. This trial is registered with, number NCT01118234. Findings Between April 1, 2010, and Dec 23, 2013, 134 patients were randomised to rituximab and 129 to observation alone. Median observation times were 33·4 months (IQR 25·7–42·8) for the rituximab group and 34·0 months (25·4–41·9) for the observation group. Progression-free survival was significantly longer in the rituximab maintenance group (47·0 months, IQR 28·5–incalculable) than with observation alone (35·5 months, 95% CI 25·7–46·3; hazard ratio [HR] 0·50, 95% CI 0·33–0·75, p=0·00077). The incidence of grade 3–4 haematological toxicities other than neutropenia was similar in the two treatment groups. Grade 3–4 neutropenia occurred in 28 (21%) patients in the rituximab group and 14 (11%) patients in the observation group. Apart from neutropenia, the most common grade 3–4 adverse events were upper (five vs one [1%] patient in the observation group) and lower (three [2%] vs one [1%]) respiratory tract infection, pneumonia (nine [7%] vs two [2%]), thrombopenia (four [3%] vs four [3%]), neoplasms (five [4%] vs four [3%]), and eye disorders (four [3%] vs two [2%]). The overall incidence of infections of all grades was higher among rituximab recipients (88 [66%] vs 65 [50%]). Interpretation Rituximab maintenance therapy prolongs progression-free survival in patients achieving at least a PR to induction with rituximab plus chemotherapy, and the treatment is well tolerated overall. Although it is associated with an increase in infections, there is no excess in infection mortality, suggesting that remission maintenance with rituximab is an effective and safe option in the management of chronic lymphocytic leukaemia in early treatment phases. Funding Arbeitsgemeinschaft Medikamentöse Tumortherapie gemeinnützige GmbH (AGMT), Roche. © 2016 Elsevier Ltd

Melchardt T.,Paracelsus Medical University | Melchardt T.,Salzburg Cancer Research Institute SCRI | Hufnagl C.,Paracelsus Medical University | Hufnagl C.,Salzburg Cancer Research Institute SCRI | And 17 more authors.
Oncotarget | Year: 2016

Little information is available about the role of certain mutations for clonal evolution and the clinical outcome during relapse in diffuse large B-cell lymphoma (DLBCL). Therefore, we analyzed formalin-fixed-paraffin-embedded tumor samples from first diagnosis, relapsed or refractory disease from 28 patients using nextgeneration sequencing of the exons of 104 coding genes. Non-synonymous mutations were present in 74 of the 104 genes tested. Primary tumor samples showed a median of 8 non-synonymous mutations (range: 0-24) with the used gene set. Lower numbers of non-synonymous mutations in the primary tumor were associated with a better median OS compared with higher numbers (28 versus 15 months, p=0.031). We observed three patterns of clonal evolution during relapse of disease: large global change, subclonal selection and no or minimal change possibly suggesting preprogrammed resistance. We conclude that targeted re-sequencing is a feasible and informative approach to characterize the molecular pattern of relapse and it creates novel insights into the role of dynamics of individual genes.

Weiss L.,Salzburg Cancer Research Institute SCRI | Huemer F.,Salzburg Cancer Research Institute SCRI | Mlineritsch B.,Salzburg Cancer Research Institute SCRI | Greil R.,Salzburg Cancer Research Institute SCRI
Memo - Magazine of European Medical Oncology | Year: 2016

Increased numbers of tumour infiltrating T‑cells have long been associated with a better prognosis in ovarian cancer, which has led to the general assumption of a relevant impact of T‑cellular anti-tumour immunity in this disease. As a consequence of this knowledge, a multitude of immunologic therapies has emerged over the past years. Although some reports could evidence a successful induction of anti-tumour T‑cells, in general, these attempts did not translate into clinically significant activity. As has already been shown in other tumour entities, immune checkpoint blockade – mainly antibodies directed against PD-1 and PD-L1 – could possibly become a real “game changer” in ovarian cancer in the future. © 2016, The Author(s).

Melchardt T.,Paracelsus Medical University | Melchardt T.,Salzburg Cancer Research Institute SCRI | Hufnagl C.,Paracelsus Medical University | Hufnagl C.,Salzburg Cancer Research Institute SCRI | And 14 more authors.
BMC Cancer | Year: 2015

Background: Induction chemotherapy incorporating docetaxel, cisplatin and 5- fluorouracil before radiotherapy may improve the outcome of patients with advanced head and neck cancer. Nevertheless, the addition of docetaxel increases hematological toxicity and infectious complications. Therefore, genetic markers predicting toxicity and efficacy of this treatment regimen may help to identify patients, who would have the most benefit from this intensive treatment. Methods: A cohort of 78 patients with advanced head and neck cancer treated with induction chemotherapy was assessed for clinical outcome and toxicity during treatment with curative intention. Genetic polymorphisms primary associated with treatment efficacy (ERCC2-rs13181, rs1799793, ERCC1-rs3212986, rs11615, XRCC1-rs25487) or with docetaxel caused toxicity (CYP39A1-rs7761731, SLCO1B3-rs11045585) were evaluated in all patients. The results of these analyses were correlated with the clinical outcome of the patients (loco regional control, progression free survival, overall survival) and treatment related toxicity during induction chemotherapy. Results: Median progression free survival and overall survival was 20 and 31 months in an intention to treat analysis, respectively. Overall response rate to induction chemotherapy was high with 78.1 % of all patients. None of the polymorphisms tested was associated with the clinical outcome of the patients. Genotype A of the CYP39A1 rs7761731 polymorphism was associated with a higher incidence of leucopenia and infections or death during induction chemotherapy. Conclusions: Intensive induction chemotherapy results in a high response rate in the majority of patients. None of the polymorphisms tested was associated with the clinical outcome of the patients. The CYP39A1 polymorphism rs7761731 may help to identify patients at high risk for treatment related toxicity. © 2015 Melchardt et al.

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