Background. The search and use of new molecular prognostic and predictive markers of efficacy detected by liquid biopsy are aimed at understanding the biology of Carcinomas of Unknown Primary (CUP) and improving results of patient treatment. The review is devoted to advances in scientific and clinical research on this issue.

Materials and methods. In order to assess the current state of the problem, a search and analysis of relevant data of the scientific databases PubMed, Medline, RISC was carried out.

Results. The scientific rationale for the use of liquid biopsy in clinical practice to improve the treatment of cancer patients with CUP is presented. The results of the use of modern approaches to the analysis of fluid biopsy samples in CUP are presented. In particular, the features of using circulating free DNA, circulating tumor DNA, circulating tumor cells in the analysis are considered. The modern possibilities of determining tissue specificity using liquid biopsy in CUP are discussed. The prospects for the development of liquid biopsy for improving diagnostics, determining the prognosis of the disease, and choosing a strategy for treating CUP and the treatment monitoring have been determined.

Conclusion. A review of the literature confirms that modern methods of molecular profiling of tumor cells obtained both as a result of liquid biopsy and tissue biopsies will make a significant contribution to the determination of tissue specificity, molecular characteristics of CUP for a personalized approach in order to improve strategies and treatment outcomes for patients with CUP.

Imatinib mesilate is a well-known antitumor target inhibitor of protein tyrosine kinase, which is effective in different cancer types expressing Bcr / Abl and, in particular, in hemoblastosis. A higher interest to imatinib during the COVID-19 epidemic is explained by the fact that cancer patients are one of the COVID-19 risk groups. Moreover, imatinib target mechanism of action, which is effective in cancer, can have a high potential against the most severe COVID-19 complication such as the disease associated pulmonary fibrosis. COVID-19 associated interstitial pulmonary fibrosis develops as an autoimmune process caused by systemic inflammation with atypical (idiopathic) pneumonia resulting from acute respiratory distress syndrome with the tyrosine kinase mechanism of signaling pathway activation and cellular response. Experi-mental and clinical results showing antifibrotic and dose-related antithrombotic imatinib effect demonstrate perspective use of this antitumor agent to correct COVID-19 associated pneumonia causing a high death rate of patients with COVID-19.
The review presents literature data of 2001–2020 discussing pathologic genetic and clinical characteristics of the fibrosis which exacerbates COVID-19 pneumonia in adults. The sequence of the disease processes demonstrates that disease progression with the decreasing oxygen saturation in the peripheral blood intensifies local thrombosis in the lungs. As a result, hypoxia is developing, which is difficult to control and can cause lethal outcome in severe cases. Yet, the conventional antifibrotic and thrombolytic agents can only partially control the process of pneumofibrosis including that of cancer patients. The approximate antifibrotic dose of imatinib 400 mg / day is therapeutic for oncopatho-logy. The antitumor drug registered in many countries and well described side effects and contraindications needs no long-term registration studies for a new indication, therefore, it may be easily prepared for clinical testing.

Background. According to the literature, BRCA1-associated breast cancer (BC) most often belongs to the triple negative (TNBC) molecular subtype. The data on the contribution of other molecular subtypes to this group of patients differ among different studies.

The study objective is to evaluate the frequency of different tumor molecular subtypes in BC patients with BRCA1 gene mutation treated in N. N. Blokhin National Medical Research Center of Oncology in the period from 2017 to 2020.

Materials and methods. The study included BC patients with a mutation in the BRCA1 gene (n = 209) identified as a result BRCA1 mutation screening of patients with BC. DNA diagnostics was carried out on blood samples of patients using the real-time polymerase chain reaction method. After analyzing the patients primary documentation clinical and morphological data were taken into account: the age of diagnosis, the stage of the disease, the results of immunohistochemical studies (estrogen receptor status, progesterone receptor status, HER2 expression, Ki-67 proliferation index). The assignment to the particular molecular tumour subtypes was performed according to estrogen receptor status, progesterone receptor status, HER2 status and Ki67 value.

Results. Clinical and pathomorphological data of 209 patients with BRCA1-associated BC were analyzed. The age at diagnosis ranged from 23 to 72 years, the median age was 40 years, the mean age was 41.46 ± 9.82 years. BC associated with BRCA1 was found to be TNBC in 71.3 % and luminal B, HER2 negative (LumB–) in 19.1 % of the cases. Other tumour subtypes were much less common: luminal B, HER2 positive (LumB+) in 7.2 %, luminal A (LumA) in 1 % and HER2-positive (HER2+) in 1.4 % of the cases. The frequency of subtypes was estimated in different age groups (1st – patients 23–34 (n = 53), 2nd – 35–49 (n = 111), and 3rd – 50–72 (n = 45) years old). TNBC frequency was 81.1 % in the 1st group, 73.9 % in the 2nd and 53.4 % in the 3rd group; LumB– frequency was 15.1, 15.3 and 33.3 % respectively. Using the Fisher test it was shown that the differences in frequencies were statistically significant between groups 1st and 3 rd, as well as between groups 2 nd and 3 rd (p <0.05).

Conclusion. TNBC was the main molecular subtype in all age groups of BC patients with BRCA1 germinal mutation, TNBC frequency was lower in the older age group. LumB– subtype was also common in BRCA1-associated tumors especially in older women.

Background. Application of mathematical modeling for search for biologically active molecules is currently a promising scientific approach. Application of numerical algorithms for optimization of peptide sequences and molecular dynamics allowed to obtain modified peptide sequences that are functional analogs of the sequence of natural inhibitor of cyclin-dependent kinase 4/6 p16INK4a.

The study objective is to establish biological characteristics of peptide sequences of CDK 4/6 inhibitors obtained using mathematical modeling.

Materials and methods. The studies were performed in vitro using tumor cell lines (MCF-7, А549, SKOV-3, НСТ116). Apoptosis level, cell distribution per cell cycle stages, changes in Bcl-2 expression, changes in the level of phosphorylated pRb under the effect of the studied molecules were investigated using flow cytometry. Proliferation dynamics of cell populations were studied using RTCA iCELLIgence biosensor technology.

Results. Peptide sequences obtained using mathematical modeling decrease the level of phosphorylated pRb, Bcl-2 expression when applied to actively proliferating cells. These proteins serve as molecular targets for the cyclin-dependent kinase 4/6–cyclin D complex, and changes in pRb and Bcl-2 levels might indicate inhibition of complex formation. Consequently, decreased proliferative activity and increased apoptosis were observed. Effectiveness of the peptide sequences depended on their molecular structure and type of the used cell line. Two (2) of the studied modified peptide sequences have higher antiproliferative and proapoptotic effect on tumor cells than native p16INK4a (90-97) sequence.

Conclusion. Application of mathematical modeling for search and development of functionally active molecules allowed to create peptide sequences with stronger cyclin-dependent kinase inhibitor effect than p16INK4a, the native inhibitor CDK4/6.

Background. Retinoic acid (RA), by modulation of the transcription of a number of retinoid-responsive genes, is involved in the regulation of cell differentiation and proliferation. The mechanisms by which the RA-binding proteins, molecular chaperones CRABP1 and CRABP2 (Cellular Retinoic Acid Proteins-1 and -2), participate in the realization of RA activity, as well as their precise role in tumor progression are still not fully understood. Recent data indicate that functional differences of CRABP proteins with respect to malignization of breast cancer cells could be determined by different sensitivity of tumor cells to RA and with the receptor status of the tumor.

Materials and methods. The CRABP1 coding sequence was overexpressed in breast cancer cells without endogenous expression of this protein, with different levels of RA sensitivity and receptor status – SKBR3 (RA-sensitive, ER(–) / HER2(+) cells) and MDA-MB-231 (RA-resistant, triple negative status). The growth of CRABP1(+) derivatives and control cells was evaluated under standard culture conditions and in the presence of various concentrations of RA.

Results. The effect of CRABP1 expression in RA-sensitive and RA-resistant breast cancer cells with different receptor status on the growth rate and sensitivity of cells to RA was studied. The expression of CRABP1 in RA-sensitive SKBR3 cells enhances proliferation in the absence of RA and decreases the antiproliferative effect of RA, while in RA-resistant triple-negative MDA-MB-231 cells, the expression of CRABP1 does not affect the studied characteristics.

Conclusion. CRABP1 stimulates growth and suppresses the RA-sensitivity of HER2(+) RA-sensitive cells, but does not have a similar effect on highly aggressive triple-negative RA-resistant cells.