Materials of the 6th All-Russian Conference on Molecular Oncology

Materials of the 6th All-Russian Conference on Molecular Oncology.Moscow, 21–23 December 2021

Markers of Epstein–Barr virus in clinical assessment of Russian patients with nasopharyngeal cancer

Introduction. Epstein–Barr virus (EBV) is equally widespread in the endemic and non-endemic world regions for nasopharyngeal cancer (NPC). High incidence of NPC in endemic countries and low in non-endemic countries suggest there are different mechanisms and conditions for tumor occurrence and, possibly, different clinical significance of EBV-associated markers. However, significance of these markers for determining NPC in non-endemic regions is still poorly understood. Objective – to determine clinical significance of titers of IgG/IgA antibodies to EBV capsid antigen and concentrations of the viral DNA in patients’ blood plasma as diagnostic and monitoring markers for NPC in a non-endemic region of Russia. Materials and methods. Titers of EB-specific antibodies were determined by indirect immunofluorescence, and concentration of the viral DNA in plasma was measured using a quantitative polymerase chain reaction in real time. Study group included patients with NPC (n = 96), and control group – blood donors (n = 171) and patients with other head and neck tumors (n = 33).Results. Titers of IgG/IgA antibodies to EBV capsid antigen, being an important diagnostic marker of nasopharyngeal cancer, did not always correlate with patients’ clinical condition. Humoral response to emerging events often delayed due to inertia of the immune system. Concentration of EBV DNA in patients’ blood plasma clearly reflected the dynamics of the pathological process: it decreased to background values in remission and increased while the disease progressed. In contrast to endemic regions, we did not find any correlation between the studied EBV markers and clinical manifestations of the disease, evaluated in accordance with the TNM classification (Tumor, Nodus and Metastasis).Conclusion. In non-endemic countries, such as Russia, serological and molecular markers of EBV can be successfully used for the primary diagnosis of NPC. However, for the disease monitoring, it is preferable to use the value of the concentrations of circulating EBV DNA, which, in contrast to the values of IgG/IgA antibody titers to VCA EBV, more accurately reflect the patient’s clinical condition.

Glioblastoma: a molecular genetic portrait and modern therapeutic strategies for drug treatment

Glioblastoma multiforme is the most common and malignant primary tumor of the central nervous system. Despite the existing modern complex therapy and advances in the study of molecular genetic changes in this tumor, the prognosis for patients with glioblastoma is one of the most unfavorable in oncology. This overview reviews existing therapeutic agents and clinical studies of potential drugs for the treatment of patients with glioblastoma multiforme.Next-generation sequencing has become firmly established in the clinical practice of oncologists and allows detecting gene mutations in tumor cells, some of which can serve as targets for therapy. Glioblastoma is characterized by a large number of potentially targeted molecular genetic disorders. As in the case of other solid tumors, targeted and immunotherapy for glioblastomas is being actively studied, including the combination of drugs with physical methods of exposure. To date, new treatment methods of glioblastoma, including antiangiogenic therapy, immunotherapy, oncolytic viral therapy and gene therapy still have uncertain or very modest clinical results. There are many reasons for the lack of progress in the treatment of glioblastoma – from the banal inability of most molecules to overcome the blood-brain barrier to the wide genetic heterogeneity of these tumors. The most promising direction of studies is immunotherapy. But at this stage, we cannot say that there is an effective monotherapy for glioblastoma. The combination treatment with radiation therapy and chemotherapy increases the mutational load, the expression of stress and other factors, therefore, the researchers pin great hopes on the combined methods of treatment.

Circulating predictive markers of immune checkpoint inhibitors in non-small cell lung cancer

Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy have become one of the key approaches in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Evaluation of level of PD-L1 (ligand of the programmed cell death receptor 1) expression on tumor cells using immunohistochemistry is the only approved option for determining the indications of ICIs in this group of patients. However, despite high level of PD-L1 expression, up to 80 % of patients do not respond to therapy due to the presence of primary or acquired resistance, which determines the limited effectiveness of ICI. In addition, 8–17 % of PD-L1-negative patients with NSCLC are also able to respond to ICIs. The limitation of this marker is that it does not allow assessing both intratumoral and systemic immune status. It is necessary to search for additional predictive markers to improve the accuracy of the selection of candidates for immunotherapy, which will avoid costs, wasted time, and a high risk of immune-related adverse events in potentially unresponsive patients. The attention of researchers is devoted to circulating markers in peripheral blood, as a non-invasive alternative to biopsy for predicting and monitoring the response. This review focuses on the most promising immunological markers in peripheral blood as potential predictors of response to ICIs in patients with advanced NSCLC.

LYN kinase and estrogen receptor ERα: involvement in carcinogenesis and potential therapeutic target for tumors

Primary or secondary resistance is an important problem when treating any type of tumor. It is often associated with changes in target genes’ functioning. This raises the question of understanding functional intracellular interactions of genes and proteins in oncological processes and therapeutic resistance occurring. When searching target proteins of targeted therapy, it is necessary to identify biomolecules, participating in cell signaling life, which differ significantly in normal and oncological processes and interact with a large number of pathways. It is also important that these biomolecules are not an artifact of tumor therapy or cell line cultivation, and that it is possible to influence them directly, obtaining complex effect. In addition, it is important to study changes occurring during therapy with the biomolecules, which include proto-oncogene of SRC family kinase LYN and gene of the estrogen receptor α ESR1. All these factors may help to overcome the emerging resistance.Objective – to study the way genes of SRC kinase LYN and estrogen receptor α ESR1 influence oncological processes and occurrence of therapeutic resistance.

Modern concepts of the molecular pathogenesis of thyroid cancer

Thyroid cancer remains the most common malignancy of the endocrine system worldwide. The indicators of its morbidity and mortality rates have been increasing rapidly over the last decades. Most cases of differentiated thyroid cancer (follicular and papillary histotypes) are clinically manifested by nodular goiter frequently combined with uncertain results of cytological diagnosis (categories III and IV according to the Bethesda (Bethesda System for Reporting Thyroid Cytopathology) classification). All of that makes it difficult to choose a proper tactic for patient treatment. It is known that the development, progression, invasion, and metastasis of cancer cells are regulated by a variety of molecular mechanisms. This review describes several molecular aspects of thyroid nodules oncogenesis, as well as its most promising diagnostic tumor markers. Following molecular pathways are described in particular: gene mutations, protein tumor markers, and epigenetic effects of micro-RNA, histones, as well as DNA methylation. The study of the pathogenesis of this disease has a prognostic value and contributes to the search for effective therapeutic and diagnostic methods and their improvement. That is why we also reviewed modern test panels aimed at preoperative differential diagnosis of thyroid nodules. Summarizing the results of world research on this topic allows us not only to expand the understanding of the fundamental processes of oncogenesis, but also to outline promising areas for future experimental research projects. All of that together will contribute to developing new prognostic, diagnostic and therapeutic technologies, and as a result, will improve the quality of medical care for patients with thyroid cancer.

Prognostic and predictive significance of osteopontin in malignant neoplasms

Osteopontin is an extracellular matrix protein which is produced by different types of cells and plays an important functional role in many biological processes. This review discusses the main functions of osteopontin, its role in the progression and chemoresistance of malignant neoplasms, in the regulation of epithelial-mesenchymal transition, angiogenesis, and the body’s immune response to the tumor. The article considers the currently known mechanisms by which osteopontin affects to the survival, mobility and invasion of tumor cells, to tumor sensitivity to drug treatment, as well as the prospects for a integrated study of the predictive significance of osteopontin, markers of hypoxia, angiogenesis, epithelial- mesenchymal transition, and immunological tolerance.

Prognostic significance of CD204 and IDO1 expression in esophageal tumors

Introduction. Cancer of the esophagus ranks sixth in mortality among malignant neoplastic diseases. To understand the molecular mechanisms of its progression, it is necessary to study not only tumor cells directly, but also cells of the microenvironment. In this work, we studied tumor-associated macrophages and their different phenotypes using membrane protein, indoleamine 2,3‑dioxygenase-1 (IDO1) as a marker for type 1 macrophages and macrophage scavenger receptor (CD204) as a marker for type 2 macrophages.The objective of this work was to study the expression of IDO1 and CD204 in tumors of squamous cell carcinoma of the esophagus and to assess its prognostic value.Materials and methods. The study included tumor samples obtained from 48 patients with squamous cell carcinoma of the esophagus. The expression of CD204 and IDO1 was assessed by immunohistochemistry. Survival analysis was carried out by constructing survival curves using the Kaplan–Meier method. Comparison of the significance of differences was performed using the logarithmic rank test. Differences were considered statistically significant at p <0.05.Results. We analyzed the expression of CD204 and IDO1 in esophageal squamous cell carcinoma tumors. Expression of CD204 was detected in stromal macrophages in 100 % of cases and was not detected in tumor cells. We have shown that in esophageal cancer, IDO1 is expressed in both stromal and tumor cells. In tumor cells, the expression of IDO1 was found in 44 % of the samples, in stromal cells, IDO1 was expressed in 92 % of cases. No association with clinical and morphological characteristics was observed for CD204 in stromal cells and IDO1 in tumor cells. For IDO1 expressed in stromal cells, an association with the stage of the disease (p = 0.0450) and the presence of regional metastases (p = 0.0279) was observed. Survival analysis showed that CD204 is a marker of a favorable prognosis for esophageal cancer (hazard ratio 0.455, p = 0.0419).Conclusion. This study has shown that the expression of IDO1 in the tumor stroma is associated with more favorable clinical characteristics. It has also been shown that an increased content of CD204+ macrophages is a marker of a good prognosis for esophageal cancer.