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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, 2026, 2027, 2028.
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]
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]
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.
Long non-coding RNAs in myelodysplastic syndromes: clinical relevance and implication in the pathogenesis
AZV 17-31398A [2017 – 2020]
Ing. Michaela Dostálová Merkerová, Ph.D.
Doc. Ing. Jiří Kléma, Ph.D., FEL ČVUT Praha
Long non-coding RNAs (lncRNAs) regulate hematopoietic lineage differentiation at almost every stage and their abnormal expression may contribute to various hematopoietic disorders. They may become useful diagnostic and prognostic markers contributing to detection of the MDS progression and increase of the patients' survival, and even potential therapeutic targets in future. In the proposed project, genome-wide screening of lncRNA levels in MDS patients will be employed to compare expression profiles between various risk groups of patients with the aim to find lncRNAs with significantly different levels and relevance to MDS diagnostics. Because the knowledge about individual lncRNAs is often limited to the simple transcript annotation, the causes, roles and consequences of deregulated lncRNAs in the pathogenesis of MDS will be studied by experimental and computational approaches.
Phenotype and function of head and neck squamous cell carcinoma immune cells as predictive markers of clinical response
AZV 17-28055A [2017 – 2020]
RNDr. Ruth Tachezy, Ph.D., PřF UK Praha
RNDr. Eva Hamšíková
The aim is to identify the prognostic factors in patients with head and neck squamous cell carcinoma ( HNSCC) to improve the predictivity of the clinical response to the available therapeutic options. A comprehensive comparative analysis of infiltrating and circulating cells of the immune system will be done in patients with HPV-associated and non-associated tumors. A specific aim of this study is to consider the role of the immunosuppressive regulatory CD4+ T cells and PD-1+CD8+ T cells and their newly identified subtypes, and the importance of the expression of the pro-angiogenic VEGF. The predictive potential of the level of expression of specific molecules in epithelial tumor cells and tumor-associated plasmacytoid dendritic cells (pDCs) will be studied. One hundred retrospective paraffin-embedded biopsy specimens and cca 150 prospective fresh biopsy tissue specimens and blood samples from HNSCC patients will be investigated by multicolor immunohistochemistry, PCR, mass cytometry, and function tests. Peripheral blood parameters of immunity will also be monitored after therapy.
Identification and monitoring of prognostic and predictive molecular markers in patients with low risk myelodysplastic syndrome
AZV NV18-03-00227 [2018 – 2021]
Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal diseases with ineffective hematopoiesis and a higher risk of transformation to acute myeloid leukemia. The early stages of MDS can be considered a premalignant condition with relatively good prognosis. Despite this, some patients experience disease progression and shorten the overall survival time. In this project, we will focus on the identification of specific mutations at the time of diagnosis in patients with low risk MDS that would predict the disease progression. We will perform a mutational screening in retrospective paired samples of progressing patients and those without progression. We will carry out a prospective mutational study in patients with detected unfavorable mutations and monitor the dynamics of mutational burden using sensitive droplet digital PCR. To complete background of the progression process, we will perform a comparative analysis of mRNA expression profiles of patients' serial samples. Introduced methods will refine the patient's prognosis, allow progression prediction and optimize treatment
Epigenetic, genetic and molecular factors required for mutagenesis of oncogene BCR-ABL1 during Ph+ cells treatment with tyrosine kinase inhibitor
18-18407S [2018 – 2020]
doc. Mgr. Kateřina Machová Poláková, Ph.D.
The successful therapy of chronic myeloid leukemia (CML) is based on targeted inhibition of BCR-ABL1 kinase activity by specific inhibitors (TKI), preferentially by imatinib in the first line treatment. Mutations in the BCR-ABL1 kinase domain represent a quite frequent mechanism of acquired resistance to the TKI therapy. We hypothesize, that development of TKI resistance by acquisition of BCR-ABL1 mutations during imatinib treatment is not just passive process of selection of preexisting mutated clones. BCR-ABL1 mutations may be acquired de novo, requiring a sublethal concentration of imatinib in concert with intrinsic epigenetic, genetic and molecular factors enabling to escape of subclones in early apoptosis from cell cycle control and DNA reparation process. We expect that identified molecules and connected nodes of the networks required for resistant phenotype may be potentially druggable and useful for early prediction of predisposition of CML cells to acquire BCR-ABL1 mutations.
Očkování proti HPV u pacientů s rekurentní laryngální papillomatózou – je možné zlepšit kvalitu jejich života?
Merck & Dohme s.r.o. IIS ID 37651 [2011 – 2021]
RNDr. Ruth Tachezy, Ph.D.
MUDr. Jitka Vydrová – Medical Healthcom., s.r.o.,, Hlasové centrum, Praha
Klinická studie fáze III b. Hlavním cílem studie bude ověřit vliv očkování tetravalentní HPV vakcínou na vznik rekurentních papillomatozních lézi a interval remisí u pacientů s RRP. Vedlejšími cíli bude zjištění typu HPV v lézi RRP, sledování hladin protilátek proti HPV antigenům obsaženým ve vakcíně, případně složkám imunitního systému v odebraném s
Analysis of T cells specific for BK polyomavirus and Adenovirus in haploidentical transplant recipients with hemorrhagic cystitis
AZV 17-31593A [2017 – 2021]
The aim of the proposed project is to analyse risk factors contributing to recently recorded elevation in number of cases of haemorrhagic cystitis (HC) in oncohematological patients after allogeneic hematopoietic stem cell transplantation (HSCT) what could help to find subjects at high risk of this type of morbidity. The main analysed factor will include the type of used posttransplant immunosuppressive prevention of GvHD, connection with haploidentical HSCT and association with BKV and AdV infection and the state of antiviral cellular immune response. Analysis of anti-viral effector T cells in HC patients with BK or AdV infection will result in determination of protective levels of anti-viral effector T cells and in characterisation of phenotype, functional activity and antigenic specificity of T cells responsible for virological and clinical response. The results of the study are essential for adoption and optimization of protocols for expansion of T cells for immunotherapy of opportunistic viral infections that endanger adult and children HSCT patients.
Phenotype and function of head and neck squamous cell carcinoma immune cells as predictive markers of clinical response
AZV 17-28055A [2017 – 2021]
RNDr. Ruth Tachezy Ph.D., PřF UK Praha
RNDr. Eva Hamšíková
The aim is to identify the prognostic factors in patients with head and neck squamous cell carcinoma ( HNSCC) to improve the predictivity of the clinical response to the available therapeutic options. A comprehensive comparative analysis of infiltrating and circulating cells of the immune system will be done in patients with HPV-associated and non-associated tumors. A specific aim of this study is to consider the role of the immunosuppressive regulatory CD4+ T cells and PD-1+CD8+ T cells and their newly identified subtypes, and the importance of the expression of the pro-angiogenic VEGF. The predictive potential of the level of expression of specific molecules in epithelial tumor cells and tumor-associated plasmacytoid dendritic cells (pDCs) will be studied. One hundred retrospective paraffin-embedded biopsy specimens and cca 150 prospective fresh biopsy tissue specimens and blood samples from HNSCC patients will be investigated by multicolor immunohistochemistry, PCR, mass cytometry, and function tests. Peripheral blood parameters of immunity will also be monitored after therapy.
Genetic variability of BKV in the Czech Republic and its influence on pathogenesis of infection in kidney transplant recipients
AZV 17-29992A [2017 – 2021]
RNDr. Martina Saláková Ph.D., PřF UK Praha
MUDr. Mariana Wohlfahrtová Ph.D., IKEM Praha, RNDr. Viera Ludvíková, MUDr. Miroslav Fajtr, FN Hradec Králové
Eighty percent of adult population is infected with BK polyomavirus (BKV). After primary infection which usually occurs in childhood, virus establish lifelong persistency in kidney with occasional reactivation. While in immunocompetent subject the infection or reactivation is clinically inapparent, in immunocompromised patients may cause severe complications. Reactivation BKV is observed in about 30% kidney transplant recipients, uncontrolled infection may lead to polyomavirus nephropathy (PVAN) and loss of graft. The factors affecting progression of infection are not yet well understood. The aim of this study is evaluate the genetic variation of BKV, as well as prevalence of various BKV genotypes and the type-specific antibodies in kidney donors and recipients and clarify risk factors for the progression of BKV infection and for the development of PVAN.
A promotor methylation of TSGs associated with HPV-driven carcinogenesis as a screening tool for anal carcinoma at risk population - validation study
AZV 17-31777A [2017 – 2021]
RNDr Jana Kašpírková PhD., LF Plzeň, UK Praha
1. Spoluřešitel: RNDr. Jana Šmahelová, 2. Spoluřešitel: Prof. MUDr. Jana Hercogová, CSc., Nemocnice Na Bulovce, Praha
Anal cancer is one of the malignancies with the rising incidence, especially at specific populations of men who have sex with men (MSM) and HIV positive patients. In these groups incidence reaches up 131 cases per 100 thousand inhabitants. Due to steeply increasing number of HIV positive patients in the Czech Republic (CR), whose vast majority belongs to MSM, early diagnosis of precancerous lesions is an essential prerequisite in the fight against this disease. Anal cancer is in its etiology and biological behavior very similar to cervical cancer, therefore the investigative and screening procedures are virtually identical. Currently used cytology in the anal area is not among the highly sensitive nor specific methods of investigation. DNA methylation appears to be a new method having already confirmed efficiency in screening of cervical cancer. This research should therefore validate DNA methylation as a potential new diagnostic and screening method for anal cancer and compare its sensitivity and specificity with established screening methods in immunocompetent and immunosuppress...
Critical evaluation of the lipidome in acute coronary syndrome and acute stroke patients in correlation with the level of oxidative stress
AZV 18-08-00149 [2018 – 2021]
Do. MUDr. Martin Malý, Ph.D.. ÚVN Praha
prof. Ing. Jana Hajšlová, CSc., VŠCHT Praha, Ing. Jiří Suttnar, CSc.
Atherosclerosis and thrombosis are underlying causes of acute coronary syndrome and stroke. In clinical practice, several markers (such as LDL, HDL cholesterol, glycaemia, C-reactive protein etc.) of elevated risk are available, however, translation of the population risk to personal risk is rather questionable. For this reason, additional information to explain such condition is of a great interest. Advanced instrumental technique represented by high performance liquid chromatography coupled to high-resolution tandem mass spectrometry will enable, based on chemometric assessment fingerprints of metabolome components, to identify the differences between patients´ groups that are not evident when employing conventionally measured parameters. Blood samples will be obtained from patients with acute and subacute phase of acute coronary syndrome and stroke. The relationship between the generated data and the degree of oxidative stress will be searched. The possibly detected changes may represent the interface between the atherosclerosis and thrombosis.
Pre-clinical validation of cGMP production of CAR T-cells for solid tumorstherapy
AZV 19-08-00147 [2019 – 2022]
Doc. RNDr. Irena Krontorád Koutná, Ph..D., FNUSA Brno
doc.MUDr. Pavel Otáhal, Ph.D., Mgr. Pavel Šimara, Ph.D., MU Brno
Chimeric antigen receptor (CAR) T-cell is a cutting edge technology for targeted cell therapy of oncologic diseases. Promising clinical results were reported for hematological malignancies, but the results in solid tumors are not that encouranging yet. Here we propose to validate protocols for the production of CAR T-cells against solid tumor antigens under cGMP rules. We will focus mainly on target antigens GD2, PSMA, and PSCA. Standard operation protocols and analytical certificates will be presented to the State Institute for Drug Control for their approval. The consortium of three prominent research facilities will participate on this project: (i) International Clinical Research Center of St. Anne's University Hospital Brno (FNUSA-ICRC), (ii) Centre for Biomedical Image Analysis at Masaryk University Brno (MU-CBIA), and (iii) Institute of Hematology and Blood Transfusion in Prague (UHKT). Our main aim is to establish production of CAR T-cells for anti-solid tumor therapy which can be translated into clinical applications.
Advanced plasmonic biosensors: towards the next-generation biomolecular interaction analysis
GA ČR 19-02739S [2019 – 2021]
doc. Ing. Jiří Homola, CSc., DSc., Ústav fotoniky a elektroniky AV ČR
Prof. Ing. Jan Dyr, DrSc., doc. Ing. Mgr. Bc. Roman Kotlín, Ph.D. MHA, Ing. Tomáš Riedel, Ph.D., Ústav makromolekulární chemie AV ČR
Life is associated with myriad of interactions that occur among a large variety of biomolecules. Hence, the understanding of biomolecular interactions and their roles in diseases represents a research goal of paramount importance. This project aims to develop a new plasmonic biosensor-based technology that will enable investigation of biomolecular interactions in complex real-world biological environments, which will advance the field of biomolecular interaction analysis beyond the current state of the art. This multidisciplinary project encompasses research efforts in multiple areas, including plasmonic (nano)structure-based biosensors, mass transport in microfluidic systems, immobilization of biomolecules, and methodologies for investigation of biomolecular interactions. The resulting biosensor technology will provide new insights into interaction of biomolecules involved in onco-hematological diseases, such as myelodysplastic syndrome and other frequently occurring hematological malignancies.
Role of nucleophosmin interactome in acute myeloid leukemia with mutated NPM
GA ČR 19-04099S [2019 – 2021]
Prof. RNDr. Petr Heřman, CSc., MFF UK Praha
Mgr. Barbora Brodská, Ph.D.
One third of acute myeloid leukemia (AML) occurrences exhibits characteristic nucleophosmin (NPM) mutation causing its aberrant cytoplasmic localization. Subsequently, multiple NPM-interaction partners, interacting also with mutated NPM or its complexes, become mislocalized from their site-of-action with functional and regulatory consequences. By combination of spectroscopic, microscopic, biochemical and immunochemical methods (e.g. FLIM, FRET, GFP-Trap) we will evaluate unknown/neglected relations between AML-related NPM mutations, oligomerization, and ability of wild-type and mutated NPM to interact with the tumor suppressor p53. Dynamics and cellular trafficking of NPM and p53 will be assessed in vivo and the role of NPM-interacting proteins regulated by p53 in the leukemogenesis will be elucidated. We will characterize cellular response of the NPM interaction network to anticancer drug treatment in relation to the NPM mutation and the drug used. Results will contribute to understanding of the role of NPM mutation in leukemogenesis and will open new strategies for AML treatment.
Advanced Immunomonitoring and Immunotherapy of Hematological and Hemato-oncological Patients
OP VVV CZ.02.1.01/0.0/0.0/16_025/0007428 [2018 – 2022]
The development of diagnostic methods for determination of immunosuppressive escape mechanisms of leukemic cells, that should serve for the selection of a appropriate personalized immunotherapy of hemato- oncological patients, Development of procedures for the expansion of T-lymphocytes capable of recognizing antigens of leukemic cells in AML patients, Implementation of methods for monitoring the immune system reconstitution of patients after HSCT for identification of patients with insufficient immune system reconstitution. Identification of markers predicting the longterm in vivo persistence of transferred multi-virus specific T-lymphocytes and their tracking in treated patients, the construction of a new generation of CAR T-lymphocytes.
