Study of the anti-tumorigenic activity of recombinant Amblyomin-X protein in pediatric ependymoma stem cells: development of possible target therapy

• Grant number: 19/27624-0
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2020
• End date: October 31, 2023
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Sergio Cavalheiro
• Grantee: Sergio Cavalheiro
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Ana Marisa Chudzinski-Tavassi ; Lorena Favaro Pavon Porfirio

Abstract

Ependymomas are a group of glial tumors derived from the ependymal cells lining the ventricular surface. They arise most often from the walls of the fourth ventricle in the posterior fossa. Such tumors represent about 6 to 12% of all brain tumors, 25% of marrow tumors and 8% of pediatric brain tumors and represent third childhood malignant tumor. Ependymomas are usually slow-growing tumors, most common in children and young adults. They are classified as myxopapillary ependymoma (grade I), classic ependymoma (grade II) and anaplastic ependymoma (grade III). The main treatment of patients with a diagnosis of ependymoma is maximal surgical resection, usually followed by adjuvant radiotherapy, which in most cases is not therapeutic successful, as well as chemotherapy, which has not played an important role in controlling these tumors. Thus, it is extremely relevant, therefore, the search for new methodological studies in understanding the genesis of childhood ependymoma, as well as its mechanisms of resistance to available therapies, aiming at reducing the mortality of these patients. The difficult control of these tumors could be justified, among other hypotheses, by the competence of tumor cells to stem cell molds. The tumor stem cell hypothesis describes that tumors are maintained by a fraction of rare cells that have stem cell properties, their nature being defined by the formation of tumor neurospheres, which contain a subpopulation of CD133 + cells that initiate gliomas. Adult ependymal cells were previously described as derived from a subset of radial glial progenitor cells (CD133 +/Nestina +/RC2 +/BLBP) during embryogenesis. These cells describe a molecular profile, where the coexpression of these markers could establish a correlation between the undifferentiated state of these cells and ependymoma tumorigenesis. The hypothesis of the tumor stem cell, thus, could justify the high aggressiveness as well as the great resistance of the ependymoma to the commonly used therapeutic processes. Recent findings in the literature describe that tumor neurospheres (clonogenic CD133 + cell set) are chemo/radio resistant, and the recurrence of this tumor is characterized by dormant-like cells and thus hypothesizes that the quiescent nature of cells CD133 + resists treatment of conventional therapies. Recently, it has been shown that Amblyomin-X recombinant protein, identified in the Amblyomma cajennense transcriptome, when tested on different neoplastic cell lines, showed in vitro apoptotic activity and in vivo anti-tumor activity, as well as anti-metastatic and anti-tumor activity angiogenic; having no activity in normal cells such as fibroblasts and human humbilical cord endothelial cells (HUVECs). In vitro experiments have shown that Amblyomin-X is capable of inhibiting the proteasome of tumor cells, as well as causing changes in the cell cycle of these cells.From previous knowledge, well supported by our research group, not only in the process of tumor stem cell selection and neurosphere formation, but in the establishment of the primary ependymoma culture and the making of its experimental model (Pavon et al., 2018), the present proposal intends to study the mechanism of molecular action of Amblyomin-X in the neospheres (CD133 + stem cells) of anaplastic ependymoma (grade III), in order to establish a possible oncotherapeutic target. Thus, we will study the possible inhibition of proteasome activity and the control of gene expression through signaling pathways by transcriptome. (AU)