Science and research

Grant Projects (ongoing in the year 2019)

View ongoing grants in the year: 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021, 2022, 2023, 2024, 2025.

Development of methods for cellular and gene therapy of hematological malignancies

AZV 15-34498A [2015 – 2019]

MUDr. Pavel Otáhal, Ph.D., VFN Praha
RNDr. Šárka Němečková, DrSc.

Significant progress in the field of tumor immunotherapy has been recently shown to complement available treatment modalities of hematological malignancies. This novel treatment method is based on the use of adoptively tranferred T lymphocytes which were modified in vitro prior to transfer to express artificial signaling molecule designated Chimeric Antigen Receptor (CAR) which redirects the specificity of modified lymphocytes to surface antigens expressed by malignant cells. In this project we propose to develop methods for CAR-based therapy of lymphomas and leukemia. Next, we propose to develop methods for selective expansion of T cells specific for EBV, HCMV or adenovirus from donor lymphocytes for the use in patients who received allogeneic stem cell transplantation and as a result of immunosupresion developed acute viral infection. The goal of the project is the manufacture of GMP-grade cells and their pre-clinical testing.

Anti-tumor effects of chelation therapy in myelodysplastic syndrome and identification of new therapeutic biomarkers

AZV 16-31689A [2016 – 2019]

prof. MUDr. Jaroslav Čermák, CSc.
Doc. RNDr. Vladimír Divoký, Ph.D., LF UP Olomouc

Myelodysplastic syndrome (MDS) is a clonal disorder characterized by ineffective hematopoiesis and increased risk of transformation to leukemia. Low-risk MDS patients are typically transfusion dependent, and their chelation therapy not only removes surplus of toxic iron stores, but has also antiproliferative and proapoptotic effects on tumor cells. Our preliminary data revealed an activation of DNA damage response (DDR) signaling and induction of apoptosis in pluripotent stem cells exposed to iron chelator in vitro. In vivo, 6-week applications of chelator to preleukemia mice lead to a decrease of actively replicating myeloid cells and an activation of G2/M checkpoint. Correspondingly, we observed an activation of stress signaling pathways in CD34+ cells from low-risk MDS patients receiving chelation therapy. We propose: to elucidate how iron chelation reinforces DDR and cell cycle checkpoints in oncogene-positive pre-leukemia cells in vivo; to identify biomarkers in MDS useful in clinical practice, allowing the prediction of a positive effect of chelation therapy for leukemia free survival.

Application of high-throughput technologies for screening of plasma circulating microRNAs in myelodysplastic syndromes

AZV 16-33617A [2016 – 2019]

Ing. Michaela Dostálová Merkerová, Ph.D.

Circulating micorRNAs (miRNAs) are new promising semi-invasivemolecular markers of various types of cancer. However, little information is known about their deregulation in myelodysplastic syndromes (MDS). Nowadays, the diagnosis of MDS is based on morphological evidence of bone marrow dysplasia. In the proposed project, we will employ next-generation sequencing for the screening of circulating miRNAs in plasma samples from MDS patients. Comparison of plasma miRNA profiles i) in untreated MDS patients with various disease subtypes, ii) in different risk categories, and iii) in MDS patients during treatment will enable to select circulating miRNAs with altered levels associated with the course of the disease. The genome-wide analysis followed by a validation phase performed by digital PCR on the level of particular preselected miRNAs aims to identify novel semi-invasive molecular markers suitable for monitoring of MDS patients, finally contributing to the prevention of the disease progression, an increase of survival, and an improvement of patient comfort.

Integrative analysis of genomic changes in DNA repair systems in myelodysplastic syndrome and their relevance in the pathogenesis

AZV 16-33485A [2016 – 2019]

RNDr. Hana Votavová , Ph.D.

Myelodysplastic syndrome is charactererized by a high heterogeneity of clinical course and an increased risk of development of acute myeloid leukemia. We assume that the as yet unexplained mechanism of the disease, leukemia transformation and a large number of mutations detected recently may be related to a decreased function of DNA repair systems, which under physiological conditions form an effective protective barrier against malignant transformation of cells. The project will monitor changes in 84 genes involved in DNA repair mechanisms at the level of genome, transcriptome and proteome, and reparative cell activity using in vitro assays. Due to the clonal character of the disease, the changes will be observed mainly in pluripotent hematopoietic CD34+ bone marrow cells. Data obtained using modern molecular genetic techniques such as targeted next generation sequencing will be closely correlated with clinical data of the patients.The proposed project aims to identify new molecular biomarkers involved in the formation and progression of the disease and to find new potential therapeutic targets.

Mutated nucleophosmin as a potential target for immunotherapy of acute myelogenous leukemia

AZV 16-30268A [2016 – 2019]

RNDr. Kateřina Kuželová, Ph.D.

Nucleophosmin (NPM) C-terminalmutations are detected in about 30% of patients with acute myeloidleukemia (AML). Our pilot study indicated that individuals with appropriate HLA alleles (about 85% of population) are able to raise a spontaneous immune response against mutated NPM which can prevent AML development. Anti-NPM immune response is also active during therapy and essentially contributes to a better outcome of patients having NPM mutations. The objectives of the project are: (i) to confirm and to extend these findings on a larger patient cohort, (ii) to obtain experimental evidence of the existence of NPM-specific T-cells, (iii) to establish diagnostic methods for the detection of reasons for transient or complete failure of the immune response which allows for AML development. The practical aim of this applied research is to prepare conditions for the implementation of individualized immunotherapy into the treatment regimen of AML patients in order to achieve the disease eradication.

Adoptive immunotherapy of hematological malignancies in elderly patients: preclinical and clinical study

AZV ČR 16-34405A [2016 – 2019]

MUDr. Petr Lesný, Ph.D.

Innovative immunotherapy approaches, such as administration of haploidentical natural killer (NK) cells with phenotype changed by cytokine induction or with molecular genetic methods, are being extensively utilized in the therapy of hematological malignancies, such as acute myeloid leukemia (AML). Our project aims at the combination of these two methods, using the cytokine induced killer (CIK) cells genetically modified in order to express chimeric antigen receptors targeting suitable AML targets, such as CD123. We expect a cumulative effect of these two modifications, increasing the specific cytotoxic effect of the administered cells without increasing their toxicity. During the project, we plan to obtain sufficient preclinical and clinical supportive data in order to submit ambitious clinical trial of gene modified CIK cells in the therapy of AML. This approach will be useful in elderly patients, where the chemotherapy is less effective and limited by comorbidities.

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Ústav hematologie a krevní transfuze
(​Institute of Hematology and Blood Transfusion)

U Nemocnice 2094/1
128 00 Praha 2

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