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project info
Start date: 9 January 2019
End date: 6 January 2023
funding
Fund: European Regional Development Fund (ERDF)
Total budget: 12 773 810,99 €
EU contribution: 2 950 645,02 € (23,1%)
programme
Programming period: 2014-2021
Managing authority: Ministerstvo dopravy a výstavby SR

Integrated strategy in the development of personalised medicine of selected malignant cancers and its impact on quality of life

Innovative treatments for patients with malignant cancers require the identification of subgroups of patients who can benefit from precision medicine from targeted (personalised) treatment (PL), recognised at European and national regulatory level, in a set of patients treated with existing standard procedures; the proportion of these subgroups varies from 20-95 % depending on the histologically determined type of cancer of the various organs. “Precision medicine” makes it possible to guide the patient’s entire therapeutic management, starting with diagnosis according to progress in understanding the genetic nature of his cancer, which is referred to as “genome-driven oncology”. The essence of this treatment is the inhibition of tumour growth by intervening in various signaling pathways of canrogenesis, e.g. by blocking action driver-mutations or other genetic activating tumour cell alterations by interrupting oncogenic signalling at the level of extracellular (e.g. growth) signaling receptors, or intracellular signaling domains (e.g. tyrosine kinases), thereby achieving a halt in the growth and division of tumour cells, their transition to apoptosis, etc. Identification of “driver” alterations in the tumor is a predictive factor of a targeted “tailor-made” treatment.  A part of innovative therapies is today re-defined immunotherapy, so-called immuno-oncology (hereinafter I-O), aimed at activating anti-cancer immunity. A key predictive factor of I-O is the identification of the interaction of the tumor – the immune system in the field of microenvironment bioptically investigated tumor by analysing the state of the so-called immune checkpoints and their ligands, required for treatment with so-called immune guardpoint inhibitors. The importance of other predictive factors of I-O is now increasing, in particular the ‘tumor mutation burden’ and the state of microsatellite stability (‘MSS’) or instability (‘MSI’).  The determination of predictive factors for each patient requires a comprehensive bioptic analysis of tumour tissue and by tumour type oriented molecular-genetic analysis of tumour DNA – either in situ, i.e. directly in tissue, e.g. immunohistochemistry (IHC) by detecting predictive relevant proteins (“products” of genetic alternation) or by detection of genetic alterations by in situ-hybridisation techniques (FISH/CISH/dDISH), or by gout analyses or RNA isolated from tumour tissue. The genetic analysis of ‘tumour products’ released into the patient’s blood, such as cell-free tumour DNA (ctDNA), RNA, exosomes and blood circulating tumour cells (CTCs) through a liquid biopsy, is also part of innovative techniques. According to the level of knowledge to date, the analysis of ctDNA isolated from plasma and CTCs is particularly useful for clinical practice, the analyses of other products are experimental. However, the area of CTC analysis is also gradually expanded, with more accurate cytometric analysis becoming key, including the differentiation of some clinically relevant subpopulations of CTCs, such as circulating stem cells (CSCs), with the expected tumour initiation potential. CtDNA testing is possible in the “baseline” disease in the absence of DNA isolated from tumour tissue, but especially when identifying progression or development of resistance to the targeted treatment used, as it prevents the clinical or radiological manifestation of progression. A liquid biopsy cannot yet fully replace the DNA analysis from a tissue biopsy, but is complementary to it. Its advantage is that within the tumor heterogeneity it represents comprehensive genetic information from all tumour sites, especially for metastatic (MTS) so-called “systemic tumor burden”, that it minimises the patient’s burden and as a non-intervention method is also cost-effective. An important step in the processing of samples is isolation of ctDNA and CTC from liquid biopsy. Innovative procedures for tumor DNA analyses of tissue and liquid biopsy allow detecting predictive factors of targeted treatment, although the problem of this detection is the biological complexity of the tumor, its variability during the onset, progression and treatment. In addition to intertumor heterogeneity, intra-tumor heterogeneity also plays a role, while the genomes of cancer cells are not stable and new changes and clones appear. Due to selective pressure from targeted treatment and (sub-)clonal tumour evolution, new either activating genetic alterations or alterations that make resistance to the treatment used arise. These should also be identified for consideration of the next line of targeted therapy or for the indication of immunotherapy. Implementation of suitable methods of tumor cell analysis (including procedures for their isolation from liquid biopsy) of tumor microenvironment, miRNA, incRNA, cftDNA and construction of appropriate algorithms of procedures of analysis is today a major global problem due to the insufficiency of the respective gui

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