A modern approach to disease modeling for the development of oncology drugs

MNIOI named after P.A. Herzen – a branch of the Federal State Budgetary Institution “National Medical Research Center of Radiology” of the Ministry of Health of Russia, Moscow, Russia

Introduction. Oncological diseases are characterized by the complexity of pathogenesis and demonstrate a number of specific signs, such as uncontrolled proliferation, stimulation of angiogenesis, activation of invasion and metastasis. Molecular genetic testing to examine genetic abnormalities in tumor cells has been increasingly using in oncology. With an accumulation of the data on the repertoire of mutations

Issue 29. November 2023 | Cardiometry | 19

or other events in the patient’s tumors, new goals for the development of more targeted and specific antitumor therapies appear. For example, membrane proteins EGFR, HER-2, PSMA and C-met are identified as such targets. Despite the large volume of research conducted, no more than 11% of the total drug candidates are approved by regulatory authorities for clinical use. This is often due to their lack of effectiveness and the incomparability of the results obtained in pre-clinical trials in animal models with actual results in patients. Therefore, the development of experimental approaches for modeling tumor processes in laboratory animals is an urgent problem.

The aim of our research work is to develop some relevant in-vivo models for studying and assessing the effectiveness of targeted drugs.

Materials and methods . Tumor cells from breast cancer lines BT-474 (ATCC®) were used in the present research work; 22Rv1, LnCap and PC-3 prostate cancer cells (ATCC®); bladder cancer cells EJ (D.I. Ivanovsky Research Institute of Virology®) and 5637 (ATCC®); human colorectal cancer cells HT29 (D.I. Ivanovsky Research Institute of Virology®) and HCT116 (ECACC®). Immunodeficient Balb/c nude mice were used as test systems. Tumor cells were inoculated into animals subcutaneously or orthotopically (BT-474 cells were transplanted into the area of fat deposits near the mammary glands, 22Rv1, LnCap and PC-3 were inoculated into the inguinal fold area, and EJ and 5637 were transplanted intravesically).

Immunocytochemical and immunohistochemical tests were carried out using polyclonal antibodies to the HER-2 receptor (pAb Neu C-18), polyclonal antibodies to the prostate-specific membrane antigen receptor PSMA, monoclonal antibodies to the epidermal growth factor receptor EGFR (mAb D38B1) and monoclonal antibodies to the C-receptor Met (mAb CM4610).

Results . It was shown in-vitro and in-vivo, by immunocytochemical and immunohistochemical methods, respectively, that the BT-474 breast cancer tumor cells have a pronounced ability to express the membrane receptor of the epidermal growth factor receptor family (EGFR/ErB) - HER-2; prostate cancer cells 22Rv1 and LnCap – the receptor for prostate-specific membrane antigen PSMA; bladder cancer cells EJ and 5637 – epithelial growth factor receptor EGFR; colorectal cancer cells HT29 and HCT116 – C-Met receptor associated with the epithelial-mesenchymal transition gene Met. The PC-3 prostate cancer cells are characterized by weak, conditionally “negative”, expression of the PSMA receptor.

Conclusion . Thus, the models (the ectopic and the orthotopic ones) of human tumors of various histogenesis have been developed, produced by inoculation of tumor cells with high expression of target proteins, that can be effectively used for preclinical study of targeted drugs with targeted drug delivery to tumor cells.