Differentiation therapy as a new multidisciplinary approach to the treatment of human brain glioma
- Authors: Pavlova G.V.1,2,3, Kolesnikova V.A.1, Usachev D.Y.2, Kopylov A.M.4
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Affiliations:
- Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences
- Burdenko Neurosurgical Institute of the Ministry of Health of the Russian Federation
- Sechenov First Moscow State Medical University
- Lomonosov Moscow State University
- Issue: Vol 18, No 4 (2023)
- Pages: 524-527
- Section: Conference proceedings
- URL: https://journals.rcsi.science/2313-1829/article/view/256261
- DOI: https://doi.org/10.17816/gc623249
- ID: 256261
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Abstract
Glioblastoma is among the most severe forms of neoplastic disease in the human body, with a highly unfavorable prognosis. The annual incidence of this pathology in the population is 3.5 cases per 100,000. Currently, there are no truly effective treatments for this malignant variety of brain tumor. All known treatment methods, including surgery, radiation therapy, and chemotherapy, provide only a modest extension of the patient‘s lifespan. The heterogeneous structure of glioblastoma, characterized by abnormal regulation of cell proliferation, enables the tumor to withstand diverse therapeutic interventions. Most tumor cells die with radiation therapy or chemotherapy, but a small number of cells are resistant, leading to tumor relapse. Therefore, tumors are able to resist different types of therapy and continue to grow. The discovery of therapy failures highlights the need to search for new approaches in the treatment of glioblastoma. Glioma is comprised of tumor stem cells along with their immature progenitor cells, known as “daughter tumor cells”. All therapeutic approaches that induce cell death to treat this disease may contribute to necrosis in both cancer cells and healthy, actively dividing cells, which may explain treatment failure. Simultaneously, stem cells in poorly dividing tumors resist these effects and survive, ultimately leading to the emergence of a recurrent tumor. In contrast to utilizing cytotoxic effects which is a strategy employed, the alternative approach is to stimulate the „maturation“ of tumor cells, with the goal of losing their ability to proliferate. We propose a new treatment approach for glioma, called “differentiation therapy”. This therapy has a cytostatic effect on tumor cells by using the aptamer biG3T, which blocks their proliferation. Inducer molecules such as SB431542, LDN-193189, Purmorphamine, and BDNF are added subsequently to control neurogenesis pathways. The aptamer bi(AID-1-T) exhibits a cytostatic effect, halting the division of tumor cells without inducing cell death or necrosis. This temporary pause in proliferation sensitizes tumor cells to external influences, promoting their differentiation or maturation. Inductor molecules such as SB431542, LDN-193189, Purmorphamine, and BDNF are commonly used to influence cascades of induced pluripotent cells (iPSCs) for their differentiation into neurons. In cases of differentiation therapy featuring a temporary decrease in tumor cell proliferation levels post-aptamer exposure, inducer molecules possess the ability to steer tumor cells towards maturation. Differentiation therapy was found to be effective in targeting tumor stem cells that are resistant to chemotherapy and radiation therapy, specifically the Nestin and PROM1 (CD133)-positive cells. Studies conducted on cell cultures of gliomas demonstrated the efficacy of this approach in vitro, particularly in patients with high-grade malignancies. In order to achieve an optimal and effective combination of aptamer and factors, we conducted a series of in vivo studies using a rat model implanted with tissue glioblastoma 101/8. When using a combination of differentiation therapy factors in vivo, it‘s imperative to adjust the introduction of such factors to achieve optimal results. The introduction sequence of catheter administration of these therapy factors was found to significantly impact the size of tumors, with either complete tumor disappearance or insignificant size observed. Promising results were shown in animal model pilot studies involving glioblastoma treated with this method.
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Full Text
Glioblastoma is among the most severe forms of neoplastic disease in the human body, with a highly unfavorable prognosis. The annual incidence of this pathology in the population is 3.5 cases per 100,000. Currently, there are no truly effective treatments for this malignant variety of brain tumor. All known treatment methods, including surgery, radiation therapy, and chemotherapy, provide only a modest extension of the patient‘s lifespan. The heterogeneous structure of glioblastoma, characterized by abnormal regulation of cell proliferation, enables the tumor to withstand diverse therapeutic interventions. Most tumor cells die with radiation therapy or chemotherapy, but a small number of cells are resistant, leading to tumor relapse. Therefore, tumors are able to resist different types of therapy and continue to grow. The discovery of therapy failures highlights the need to search for new approaches in the treatment of glioblastoma. Glioma is comprised of tumor stem cells along with their immature progenitor cells, known as “daughter tumor cells”. All therapeutic approaches that induce cell death to treat this disease may contribute to necrosis in both cancer cells and healthy, actively dividing cells, which may explain treatment failure. Simultaneously, stem cells in poorly dividing tumors resist these effects and survive, ultimately leading to the emergence of a recurrent tumor. In contrast to utilizing cytotoxic effects which is a strategy employed, the alternative approach is to stimulate the „maturation“ of tumor cells, with the goal of losing their ability to proliferate. We propose a new treatment approach for glioma, called “differentiation therapy”. This therapy has a cytostatic effect on tumor cells by using the aptamer biG3T, which blocks their proliferation. Inducer molecules such as SB431542, LDN-193189, Purmorphamine, and BDNF are added subsequently to control neurogenesis pathways. The aptamer bi(AID-1-T) exhibits a cytostatic effect, halting the division of tumor cells without inducing cell death or necrosis. This temporary pause in proliferation sensitizes tumor cells to external influences, promoting their differentiation or maturation. Inductor molecules such as SB431542, LDN-193189, Purmorphamine, and BDNF are commonly used to influence cascades of induced pluripotent cells (iPSCs) for their differentiation into neurons. In cases of differentiation therapy featuring a temporary decrease in tumor cell proliferation levels post-aptamer exposure, inducer molecules possess the ability to steer tumor cells towards maturation. Differentiation therapy was found to be effective in targeting tumor stem cells that are resistant to chemotherapy and radiation therapy, specifically the Nestin and PROM1 (CD133)-positive cells. Studies conducted on cell cultures of gliomas demonstrated the efficacy of this approach in vitro, particularly in patients with high-grade malignancies. In order to achieve an optimal and effective combination of aptamer and factors, we conducted a series of in vivo studies using a rat model implanted with tissue glioblastoma 101/8. When using a combination of differentiation therapy factors in vivo, it‘s imperative to adjust the introduction of such factors to achieve optimal results. The introduction sequence of catheter administration of these therapy factors was found to significantly impact the size of tumors, with either complete tumor disappearance or insignificant size observed. Promising results were shown in animal model pilot studies involving glioblastoma treated with this method.
ADDITIONAL INFORMATION
Funding sources. The study was conducted with the financial support of the Ministry of Education and Science of Russia (grant No. 075152020809 (13.1902.21.0030)).
Authors' contribution. All authors made a substantial contribution to the conception of the work, acquisition, analysis, interpretation of data for the work, drafting and revising the work, and final approval of the version to be published and agree to be accountable for all aspects of the work.
Competing interests. The authors declare that they have no competing interests.
About the authors
G. V. Pavlova
Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences; Burdenko Neurosurgical Institute of the Ministry of Health of the Russian Federation; Sechenov First Moscow State Medical University
Author for correspondence.
Email: lkorochkin@mail.ru
Russian Federation, Moscow; Moscow; Moscow
V. A. Kolesnikova
Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences
Email: lkorochkin@mail.ru
Russian Federation, Moscow
D. Yu. Usachev
Burdenko Neurosurgical Institute of the Ministry of Health of the Russian Federation
Email: lkorochkin@mail.ru
Russian Federation, Moscow
A. M. Kopylov
Lomonosov Moscow State University
Email: lkorochkin@mail.ru
Russian Federation, Moscow
References
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