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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
Principal Investigator: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 maximumsurgical resection, followed by local and craniospinalirradiation, 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 farnesyltransferase enzyme activity. The intranasal form of administration of the POH is consideredan 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 strategymay 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 medulloblastomacell 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.