A large role in the development of malignant tumors is played by a genetic predisposition. Risk factors for cancer include the presence of mutations in oncogenes‑genes that cause the development of tumors. They were first found in the genome of viruses, and their analogs, called proto‑oncogenes, were found in humans. The study of the work of oncogenes is a promising direction in the development of new methods for the diagnosis and treatment of oncological diseases. The discovery and research of oncogenes of all classes are necessary not only to understand the mechanisms of neoplasm development but also to develop new methods of cancer treatment. Oncogenes are responsible for the synthesis of growth factors, and also control the course of the cell cycle. With an excess or violation of the functions of gene products, the processes of cell growth and division are disrupted, which leads to cell degeneration, their uncontrolled division, and, as a result, to the formation of a tumor. Based on the above, we can say that by studying the mechanisms of oncogenes at the molecular level, the functions of their products, and their influence on the vital processes of cells and the whole organism, it is possible to develop ways to treat cancer by inhibiting or correcting the work of a particular oncogene or its product. The process of oncogene activation is multifaceted and can be caused by the persistence of oncogenic viruses, the integration of retroviruses into the cell genome, the presence of point mutations or deletions in genomic DNA, chromosome translocation, or protein‑protein interaction. That is why the total number of oncogenes and possible ways of their activation at different stages of tumor progression are not fully known. In this regard, we decided in this review to analyze the available information about the relatively new and poorly studied oncogenes INHA, DLL4, and MMP2, which control important functions, including metastasis and tumor growth. 

The PI3K/Akt/mTOR is a key signaling system that binds oncogenes and various receptors to many cell functions, promotes estrogen resistance, and is the most frequently activated signaling pathway in malignant neoplasm, including breast cancer (BC). About 70 % of BC is hormone‑receptor positive and the endocrine therapy is the main component of treatment for hormone‑receptor positive BC patients. Tamoxifen remains one of the basic drugs for adjuvant endocrine therapy in estrogen‑positive BC patients. However, due to acquired resistance to this drug, 25–30 % of patients develop a relapse or disease progression. Resistance to tamoxifen is one of the key clinical problems in the treatment of estrogen‑positive BC. The potential mechanisms of tamoxifen resistance may be associated with crosstalk between estrogen receptors and PI3K/Akt/mTOR signaling. This review summarizes the current literature data on the role of the PI3K/Akt/mTOR signaling pathway in the mechanisms of hormonal resistance, including a complete characterization of its main components and the features of PI3K/Akt/mTOR interaction with estrogen receptors. The results of studies of the main components of the cascade as molecular markers of response to tamoxifen therapy in estrogen‑positive BC patients are presented. Further study of the PI3K/Akt/mTOR crosstalk with various signaling pathways will contribute to both the understanding of carcino‑ genesis and the development of new molecular‑targeted anticancer drugs for the treatment of tamoxifen‑ resistant breast tumors.

The review was compiled from a PubMed, Web of Science, Scopus and Google search, which showed a lack  of information on clinical studies of melatonin (M) in oncology, despite numerous and promising experimental results. In preliminary clinical studies carried out by P. Lissony and his co‑authors, the therapeutic potential  of M as an adjuvant in chemotherapy, radiation therapy and immunotherapy at different tumor localizations  is noted. M alleviates the toxic effect of standard therapy and, according to the authors’ observations, increases its effectiveness. Exogenous M can be in demand as a circadian rhythm synchronizer for rehabilitation and im‑ provement of the quality of life of patients, because reduces distress and improves sleep, and in supportive and palliative therapy. Oncostatic activity of M is associated with the effect on: a) homeostasis and circadian rhythms, b) inflammation, cooperation of immunocytes and cytokine production in the tumor microenvironment, c) gene expression and signalling pathways associated with angiogenesis, proliferation and metastasis, d) metabolism, hypoxia and oxidative stress, e) apoptosis and resistance to chemotherapy and radiation therapy. The review contains the following sections:  physiological and pharmacological studies, epidemiological studies, clinical studies, the immunoregulatory role of melatonin, experimental studies. Currently, randomized  and long‑term clinical studies of homogeneous groups of patients with tumor stages II−III are in demand  for statistical processing of information of the M influence on the side effects of standard therapy, on the dy‑ namics of the disease, clinical parameters, as well as on the quality and duration of life after the main treatment.

Liposomal targeted drug delivery makes it possible to achieve effective concentration in the target cell under various pathological conditions. The main advantage of liposomal particles is their biodegradability and immunological neutrality, which improves the safety profile of drugs. The review provides information on the composition of liposomes: the main component of the liposomal membrane is phospholipids, which provide its strength and protect from mechanical impacts. Liposomal particles are distinguished by the size and number of bilayer membranes, also secreted liposomes with a non‑lamellar organization. The composition and size of liposomes are selected depending on the purpose, including excipients in the membrane that affect the properties and functions of liposomes, including the rate of release of the components, the affinity of liposomes for the target tissue, etc. The review considers the main methods for obtaining liposomes and the features of their use, advantages and disadvantages. The creation of liposomes that are sensitive to various external or internal physicochemical factors makes it possible to realize drugs effects, localize the site of its action and reduce the number and severity of side effects. Currently, liposome‑based drugs are successfully used in various fields of medicine – dermatology, cardiology, oncology, neurology, etc. The most active condact preclinical and clinical studies of liposomal drugs for the treatment of malignant neoplasms. Particular attention is paid to the work of Russian researchers in the field of targeted drug delivery. It is shown that today liposomes are an open for study and improvement system for targeted drug delivery.

Background. Diffuse leptomeningeal glioneuronal tumor (DLGNT) is an extremely rare entity first officially recognized in 2016 WHO classification of tumors of the central nervous system. Magnetic resonance imaging (MRI) of this tumor usually visualizes diffuse meningeal infiltration with contrast enhancement, with the presence of multiple small contrast‑negative cysts, visible mainly in the T2 images. The main molecular markers of DLGNTs include the KIAA1549-BRAF fusion gene, BRAF V600E substitution is less common.

The aim of this work is to describe the manifestation of DLGNT, its neuroimaging and molecular genetic characteristics, the experience of using anti‑BRAF and anti‑MEK therapy.

Materials and methods. In this article are described four cases of DLGNT. The first patient with the presence of the KIAA1549-BRAF fusion in the tumor tissue received a full course of SIOP‑LGG / 2004 chemotherapy (carbo‑ platin and vincristine), the stabilization of the disease on the MRI remains for 4 years after completion of treatment. Second patient with KIAA1549-BRAF fusion gene in tumour tissue received MEK inhibitor trametinib as first line of treatment with the stabilization of the disease on control MRI which last for 2 years. A third patient with a mutation in the BRAF V600E gene. After disease progression on standard chemotherapy (carboplatin and vincristine) according to the SIOP‑LGG / 2004 protocol, anti‑BRAF therapy with vemurafenib was prescribed. After 10 months on MRI a complete response was recorded, which persists during the drug intake for 2.5 years. In the fourth patient, no molecular genetic aberrations were detected; a refractory / progressive course of the dis‑ ease was noted. To date, the stabilization of the disease is recorded on the fourth line of chemotherapy (everoli‑ mus and temozolomide).

Conclusion. Given the rarity of this tumor and the lack of consensus about therapy, despite the limited number of observations, our experience allows us to recommend molecular testing of DLGNT to detect activating events in the BRAF gene, as well as consideration of anti‑BRAF / MEK therapy if either the BRAF V600E mutation is de‑ tected or KIAA1549-BRAF fusion.

Introduction. The actual task of modern adoptive cancer immunotherapy is the selection of the optimal composition of cytokines for ex vivo stimulation of immunocompetent cells for subsequent administration to oncological patients.

The purpose of the study was to compare the effect of interleukin (IL) 2, 7, 15 and their combinations on the proliferation of natural killer cells in breast cancer (BC) patients in vitro.

Materials and methods. The research was conducted on natural killer cells isolated by magnetic separation from mononuclear cells of peripheral blood of ten patients with locally advanced BC (stage II). After separation, the cells were cultured at a concentration of 2.5 × 105 cells / ml for 10 days in RPMI 1640 medium supplemented with cytokines at a concentration of 40 ng / ml each in five experimental variants: IL‑2; IL‑7; IL‑15; IL‑7 / IL‑15; IL‑2 / IL‑7 / IL‑15. On the 10th day of cultivation, the phenotype of cells and the cell cycle were studied by flow cytometry. For immunophenotyping of cells, we used monoclonal antibodies to antigens: CD3, CD16 / 56, CD45, CD4, CD19, and CD8. For cell cycle study cells were stained with propidium iodide.

Results. On the final 10th day of cultivation the number of living cells expressed as percentage of the seeding numbers were significantly different from control (45.9 %) in samples IL‑2 (86.8 %) and IL‑7 / IL‑15 (85.6 %), IL‑15 (76.4 %), IL‑2 / IL‑7 / IL‑15 (75.8 %). The proportion of natural killers (CD16+CD56+) significantly differed from the control (18.2 %) in samples IL‑2 (45.6 %), IL‑15 (39.9 %), IL‑7 / IL‑15 (36.2 %), IL‑2 / IL‑7 / IL‑15 (35.9 %). The propor‑ tion of natural killer T cells (CD3+ / CD16+CD56+) significantly differed from the control (0.4 %) in samples incu‑ bated with IL‑2 (2.06 %), IL‑15 (2.2 %), IL‑7 (0.9 %), IL‑7 / IL‑15 (1.26 %), IL‑2 / IL‑7 / IL‑15 (2.46 %). All experimental tests also showed a significant increase in the proportion of cells in the S‑phase and increase in the proliferation index (G2 / M + S).

Conclusion. The maximum stimulation of the proliferation of natural killer cells isolated from the blood of patients with BC in vitro was obtained by stimulation with IL‑15 alone and in combinations with γc‑cytokines.

Introduction. The main cause of clinical progression of tumor under the conditions of treatment is the resistance. Reactivate apoptosis in resistant to chemotherapy cells is impossible, the tumor grows into an irreversible growth phase. Recently published data on the ability of ferroptosis inducers to induce the death of resistant cells opens up new possibilities for improving the effectiveness of antitumor therapy.

The purpose of the study – assessment of the mechanism of ferroptosis induction of the synthesized analogue of erastin OVN‑002 on Mel Z melanoma cells and investigation of its antitumor activity on transplanatated B‑16 melanoma of mice.

Materials and methods. In this study 2D cultivation of metastatic Mel Z melanoma cells, phase‑contrast and fluorescence microscopy, and a model of experimental growth of B‑16 melanoma in female hybrids of immu‑ nocompetent mice F1 (C57Bl/6 × DBA / 2) were used. The antitumor effect was evaluated by measurement of tumor growth inhibition (TGI,  %) and increase of life span of the treated animals as compared to the control ones.

Results. The cytotoxic activity of OVN‑002 was equal to the activity of erastin on metastatic melanoma cells Mel Z: 744 ± 20 and 719 ± 20 a. u., respectively. OVN‑002 at a dose 50 mg / kg reduced the growth of experimental melanoma B‑16 about 81 % (TGI 81–57 %, p <0.05). The effect was stable up to 7th day, while erastin showed only a direct antitumor effect (TGI 65 %, p <0.05).

Conclusion. The data obtained suggest that OVN‑002 might be considered as a novel antitumor agent.

Introduction. One of the key tasks in freeze‑drying of drug is to choose the optimal cryoprotector that provides a high‑quality lyophilized product.

The aim of research. Selection of cryoprotectant and its concentration for the preparation of lyophilizate of the liposomal dosage form of the indolocarbazole derivative LHS‑1269.

Materials and methods. Substance LHS‑1269 ≥99 % (N. N. Blokhin National Medical Research Center of Onco logy), egg phosphatidylcholine Е РС S (Lipoid, Germany), cholesterol ≥99 % (Sigma‑Aldrich, Japan), polyethylene glycol‑2000‑distearoyl phosphatidylethanolamine (Lipoid, Germany), mannose‑d (+) 99 % (Kaden, Germany), sucrose (Himmed, Russia), trehalose dihydrate (Himmed, Russia). To obtain LHS‑1269 liposomes, the Bangham method was used in modification for hydrophobic substances with subsequent extrusion of the dispersion of multilayer phos‑ pholipid vesicles. The prepared liposomal dispersion was dosed into vials of 6 ml and lyophilized in the freeze‑dryng chamber using the «step‑by‑step» freezing mode. LHS‑1269 liposomes were analyzed before and after freeze‑drying using laser scattering spectroscopy and determination of the electrophoretic mobility of particles.

Results. To prevent the destruction of LHS‑1269 liposomes during lyophilization, substances from the carbohy‑ drates class – mannose, sucrose and trehalose – were studied in two concentrations. In the course of compara‑ tive evaluation of the obtained lyophilizates in terms of quality, appearance, rehydration, size and zeta potential of liposomes before and after sublimation, it was found that sucrose introduced into the liposomal dosage form LHS‑1269 in the molar ratio sucrose / egg phosphatidylcholine 5:1 has optimal cryoprotective properties.

Conclusion. As a result of the study, the optimal cryoprotector and its concentration were selected, which ensure the production of high‑quality lyophilizate of the liposomal composition of the indolocarbazole derivative LHS‑1269. 

The results of the intellectual activity of the researchers of the N. N. Blokhin National Medical Research Center  of Oncology of the Ministry of Health of the Russia in 2019–2020 are presented in the short message. It is high‑ lighted that the number of patents is an index of an innovative level in the organization.