Research and development of new therapeutic methods in blood tumors

The research program consists of 3 main activities.

Main activity 1 Genomic profiling of monoclonal gammopathy – identification of molecular targets

The purpose of the activity is to broad the diagnostic possibilities for hematooncologic diseases – monoclonal gammopathy, using less invasive approaches to patients, and thereby expanding the diagnostic panel and stratification of patients with monoclonal gammopathy.

The activity will be implemented in several parts with defined goals and expected probable outputs, benefits and findings:

• Identification of molecular changes in tumor cells of patients in resistant/aggressive stages of monoclonal gammopathies
  • Sequencing of DNA nad RNA isolated from tumor and healthy tissue samples
  • Identification of changes at individual levels (mutations, gene expression) and comparison with less aggressive stages
  • Data integration from different levels of genome regulation – bioinformatic analysis
  
  
• Identification of molecular biomarkers by minimally invasive techniques – liquid biopsies (peripheral blood)
  • Circulating cells, cell-free DNA, correlation with disease aggressiveness
  • Bioinformatic evaluation and analysis
  
  
• Design of a diagnostic panel for the diagnosis and stratification of patients with monoclonal gammopathies
  • Circulating cells, cell-free DNA, correlation with disease aggressiveness
  • Bioinformatic analysis
  
  
• Design of a diagnostic panel for the diagnosis and stratification of patients with monoclonal gammopathies
  • Literature search – searching for key gene loci
  • Review of available diagnostic methods
  • Optimization of laboratory processing
  • Bioinformatic analysis
  
  
• Study of epigenetic changes in monoclonal gammopathies
  • Methylation profile study
  • Study of changes in acetylation of histones and non-histone proteins
  • Study of chromatin changes
  
  
• Study of interactions between different components of tumor microenvironment in monoclonal gammopathies
  • Flow cytometry, single-cell analysis (gene expression), proteomics – data integration
  
  
• Publishing activity, intellectual property protection

Main activity 2 Study of the molecular basis of hematological malignancies for the identification of diagnostic, predictive and stratification biomarkers and new therapeutic targets of precision medicine

The purpose of the activity is to increase the diagnostic possibilities for hemato-oncological diseases – multiple myeloma, acute myeloid leukemia and lymphomas, by specific analyses of gene and its mutational status. The research will be focused on oncogenic cell signaling to identify new therapeutic targets.

The activity will be implemented in several parts with defined goals and expected probable outputs, benefits and findings:

• Validation and functional characterization of mutations and genes in hematological malignancies to obtain diagnostic, predictive and stratification biomarkers
  • Literature and bioinformatics research of publicly available genomic databases
  • Selection of candidate genes and mutations
  • Preparation of genetic model systems
  • Introduction and optimization of phenotypic screening methods
  • Phenotypic screening
  • Functional testing of positive hits
  • Validation of mechanistic models of protein signaling
  • Generation and acquisition of in vivo models (mouse models)
  • Characterization in vivo (mouse models)
  
  
• Oncogenic cell signaling to identify new therapeutic targets in multiple myeloma, acute myeloid leukemia and lymphomas.
  • Literature and bioinformatics research of publicly available proteomic databases
  • Introduction and optimization of methods for analyses of cellular oncogenic signaling
  • Analysis of therapeutic signaling modulation
  • Selection of candidate processes and therapeutic targets
  • Design and development of new inhibitors in cooperation with commercial sphere
  • Testing of targeted treatment in vitro (cell culture models)
  • Testing of targeted treatment in vivo (mouse models)
  
  
• Study of multiple myeloma and minimal residual disease (MRD) biology in the context of the bone marrow microenvironment
  • Literature search
  • Preparation of cell culture models
  • Preparation of organoids
  • Testing of organoids
  • Obtaining in vivo models (mouse models)
  • in vivo analysis (mouse models)
  
  
• Accreditation of the new doctoral study program (in cooperation with VP1) with the working title Biomedicine (lectures in English language)
  • Preparation of the accreditation file
  • Submission of the accreditation file and settlement of objections
  
  
• Publication activity, intellectual property protection, establishment of a spin-off, preparation of a grant project

Main activity 3 Cell therapy

The purpose of the activity is the development of suitable technological approaches for cell therapy and immunotherapy, especially focused on CAR T lymphocytes and Natural Killer cells.

The activity will be implemented in several parts with defined goals and expected probable outputs, benefits and findings:

• Technological procedure for the production of universal CAR T lymphocytes
  • Identification and testing of cell types
  • Implementation of genetic manipulations
  • Optimization of cultivation conditions
  • Pre-clinical testing
  • Collaboration with the commercial sphere
  
  
• Technological procedure for the production of modified Natural Killer (NK) cells
  • Identification and testing of cell types
  • Implementation of genetic manipulations
  • Optimization of cultivation conditions
  • Pre-clinical testing
  • Collaboration with the commercial sphere
  
  
• The development of new innovative methods for improving of immunotherapy
  • Development of a tools for modulation of CAR receptors
  • Designing and testing of new CAR receptors
  • Collaboration with the commercial sphere
  
  
• Optimization and validation of new therapeutic approaches based on immunotherapy
  • Validation and implementation of new biomarkers for immunotherapies
  • Testing of new target structures for immunotherapy
  • Collaboration with the commercial sphere
  
  
• Intellectual property protection, publication of results, the preparation for technology transfer

Collaboration with other VPs and collaborating entities

Due to the very strong interdisciplinary link, the VP6 research team collaborates on some activities with other research teams:

VP1 – Shared preparation of a diagnostic panel for hematological malignancies (within VP6 HA1) and the new doctoral study program with the working title Biomedicine.

VP2 – Shared common infrastructure and use of VP2 methods for the detection of oxidative damage of biological membranes and macromolecules in the analytical phases of VP6 HA2 research.

VP3 – Cooperation in testing of the interaction biomolecules sites, validation of model structures on biological systems – in vitro, in vivo.

In order to prepare the applicability of the research into practice, at the time of the experimental research, at least 2 collaboration entities dealing with patient rehabilitation and virtual reality (without generating profits for the cooperating entities) will be ienvolved. The entities will participate in:

• The development of bioinformatics software
• The development of cell therapies