Research Laboratory of Pediatric Neuro-Immuno-Oncology
Research Laboratory of Pediatric Neuro-Immuno-Oncology
Head of the Laboratory — Yulia Dinikina, MD, PhD
Objective
To improve the results of treatment of CNS embryonal tumors in high-risk children by personalizing therapy based on the study of the molecular genetic profile using next-generation sequencing.
Major tasks
- To determine the frequency of pathogenic and especially druggable mutations in CNS embryonal tumors in children (retrospective and prospective studies to validate the data).
- To determine the frequency of mutations in the PIK3CA gene in patients with CNS embryonal tumors.
- To establish a database of the molecular genetic characteristics of CNS embryonal tumors.
- To identify prognostically unfavorable alterations in CNS embryonal tumors.
- To perform a comparative analysis of molecular genetic alterations in patients with CNS embryonal tumors from high and standard risk groups.
- To determine the possibilities of targeted therapy based on the molecular genetic profile in children with CNS embryonal tumors.
- To conduct a prospective study based NGS on results to evaluate the efficacy of targeted therapy for CNS embryonal tumors in children with relapsed/refractory forms.
- To evaluate the efficacy of metronomic chemotherapy combined with mTOR inhibitors in patients with relapsed and refractory forms of CNS embryonal tumors.
Project description
- Molecular genetic profiling to enable personalized combination therapy for CNS tumors.
To date, tumors of the central nervous system (CNS) are recognized as the leading burden in terms of morbidity in children and occupy the 4th place in the list of other causes of death in the pediatric population. Despite the progress made in the treatment of cancer in children and the relatively high survival rate for the total number of nosologies, which is around 70%, it should be recognized that this indicator has reached a plateau and has not changed in the last 15 years. The use of combined approaches and the introduction of high-intensity chemotherapy regimens in the treatment of malignant CNS tumors do not improve the treatment results of high-risk patients, which requires the introduction of new therapeutic technologies. Embryonal CNS tumors (the predominant histological variant in pediatric patients), especially those with a relapsed and refractory form, have an unfavorable prognosis and limited effective options for antitumor therapy. A current issue is the identification of risk factors for the aggressive course of the disease, with molecular genetic alterations being the most likely contributors.
Damaged genes/their genetic derivatives/proteins, pathways, differentiation clusters may be therapeutic targets, justifying next-generation whole exome sequencing (NGS) to personalize anti-tumor therapy with targeted drugs. The genetic heterogeneity of tumors will in some cases determine the need for their combined use to achieve the greatest efficacy. One of the most relevant approaches for the treatment of patients with relapsed and refractory forms of the disease is the method of metronomic chemotherapy combined with targeted drugs, which can be an effective option to achieve disease control with controlled toxicity and satisfactory tolerability. One example is the use of mTOR inhibitors, which have shown clinical efficacy in solid tumors in children, confirming their potential to enhance the activity of standard chemotherapeutic agents. At the same time, predicting the potential efficacy of this therapy is based on determining the frequency of mutations in the PIK3CA gene.
Specialists
- Yulia Dinikina, MD, PhD, Head of Laboratory
- Alexandra Daks, PhD in Biology, Senior Researcher
- Sergey Smirnov, Junior Researcher
- Mikhail Krapivin, Junior Researcher
- Irina Bezyazychnaya, Research Assistant
Major publications
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Daks, A. A.*, Fedorova, O. A.*, Shuvalov, O. Y., Parfenev, S. E., & Barlev, N. A. (2020). The Role of ERBB2/HER2 Tyrosine Kinase Receptor in the Regulation of Cell Death. Biochemistry (Moscow), 85(10), 1277-1287.
- Fedorova, O., Daks, A., Shuvalov, O., Kizenko, A., Petukhov, A., Gnennaya, Y., & Barlev, N. (2020). Attenuation of p53 mutant as an approach for treatment Her2-positive cancer. Cell Death Discovery, 6(1), 1-8.
- Efimova O. A., Koltsova A. S., Krapivin M. I., Tikhonov A. V., Pendina A. A. Environmental Epigenetics and Genome Flexibility: Focus on 5-Hydroxymethylcytosine. International Journal of Molecular Sciences. 2020;21(9):3223.
- Sharma N., Fonin A. V., Shpironok O. G., Silonov S. A., Turoverov K. K., Uversky V. N. Folding perspectives of an intrinsically disordered transactivation domain and its single mutation breaking the folding propensity. Int. J. Biomacromol, 2019.
Contacts
Yulia Dinikina, Head of Laboratory
E-mail: dinikinayulia@mail.ru
