Investigation of anti-proliferative and anti-invasive effects of perillyl alcohol on medulloblastoma-SHH and its influence on the modulation Ras and its effectors

• Grant number: 16/08125-5
• Support type: Scholarships in Brazil - Master
• Effective date (Start): October 01, 2016
• Effective date (End): September 30, 2018
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal researcher: María Sol Brassesco Annichini
• Grantee: Marcela de Oliveira Silva
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in childhood, with its highest peak of incidence at 8 years of age. Currently, MB is classified not only according to prognosis and histological features, but also as a result of its altered molecular pathways. In this way, MB is currently divided into 4 subgroups: WNT (wingless), Shh (sonic hedgehog), Group 3 and Group 4. The standard treatment consists of maximum surgical resection, followed by local and craniospinal irradiation, and adjuvant chemotherapy. The knowledge of the molecular changes that occur in this tumor has been important for the improvement of therapeutic strategies. Nonetheless, the Shh MB subgroup presents variants resistant to chemotherapy, due to the activation of the Ras-MAPK pathway that replaces the Shh oncogenic signal, and allows the proliferation of tumors with increased metastatic behavior. Perillyl alcohol (POH), a monoterpene found in small concentrations in many plants, has shown favorable effects for the treatment of various tumor types. However, the exact mechanisms of action of this compound remain unclear. It is known that the POH prevents post-translational modification of the Ras protein, a signaling element that belongs to the family of proteins associated with small GTPases of the membrane, by inhibiting farnesyl transferase enzyme activity. The intranasal form of administration of the POH is considered an extremely useful noninvasive option for tumors of the central nervous system because of its capacity to cross the blood-brain barrier, thus reaching more accurately the tumor. This strategy may also be effective in treating children affected with MB,being more convenient for them to inhale the drug. Previous studies by our group showed that in vitro POH reduces proliferation and colony formation, increasing cell deathin pediatric medulloblastoma cell lines. Therefore, this project aims to analyze the effects of POH relative to Ras activity and its effectors in vitro and to study its antiproliferative and anti-invasive effects in vivo in intracranial MB xenografts by intranasal administration. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SILVA, MARCELA DE OLIVEIRA; DE SOUSA, GRAZIELLA RIBEIRO; SIMOES, SARAH CAPELUPE; NICOLUCCI, PATRICIA; TAMASHIRO, EDWIN; SAGGIORO, FABIANO; DE OLIVEIRA, RICARDO SANTOS; BRASSESCO, MARIA SOL. Perillyl alcohol for pediatric TP53- and RAS-mutated SHH-medulloblastoma: an in vitro and in vivo translational pre-clinical study. CHILD'S NERVOUS SYSTEM, v. 37, n. 7, p. 2163-2175, JUL 2021. (16/08125-5, 13/23881-2)