Antitumor activity evaluation of Ingenol C (IngC) compound in the treatment of GBM through a preclinical trial with xenografts derived from patients

• Grant number: 21/07957-5
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): September 01, 2022
• Effective date (End): August 31, 2024
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Rui Manuel Vieira Reis
• Grantee: Mirella Baroni Milan
• Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil

Abstract

Glioblastoma (GBM) is the most common primary intracranial malignant tumor in adults. GBM is extremely invasive and aggressive, accounting for the majority of the 200,000 Central Nervous System (CNS) tumor-related deaths worldwide each year. GBM in children is relatively rare, with distinct molecular characteristics and response to treatment, when compared to adults. The current standard therapy for GBM patients is maximal surgical resection followed by radiotherapy and chemotherapy with temozolomide (TMZ). However, even with this treatment, overall survival is about 10-16 months, with less than 10% of patients surviving for 5 years or more from the time of diagnosis. Pediatric GBM also has high morbidity and mortality, with a 5-year survival of less than 20%. The ineffectiveness of the GBM treatment is due to several factors, such as a highly invasive and diffuse growth pattern, extremely heterogeneous which prevents the effective action of targeted therapies, and the presence of tumor stem cells, chemo and radioresistant cells, which they end up causing a recurrence of the tumor in many cases. There is, therefore, a critical need for more effective treatment strategies to improve the prognosis of patients facing this devastating diagnosis. An interesting approach is the use of natural substances and their derivatives, as they are relatively less toxic and have fewer side effects. Recently, our group reported the cytotoxic potential of semi-synthetic ingenol from Euphorbia tirucalli, the diterpene Ingenol-3-dodecanoate (Ingenol C - IngC) in a panel with 70 cell lines of different tumor types. The compound IngC, which the Barretos Cancer Hospital is currently the patent holder, showed evident antitumor action on GBM cell lines, reducing considerably the number of colonies, and promoting autophagy of these cells through the inhibition of the PKC molecular pathway. Therefore, due to these important in vitro results of IngC in GBM, this project aims to evaluate the effect of this compound in the treatment of adult and pediatric GBM through a pre-clinical in vivo assay, a model called Patient-Derived Orthotopic Xenograft (PDOX). The development of PDOX models is extremely relevant as it has been shown to retain the biological, histopathological, molecular, and genetic characteristics of its original tumors, making it an excellent model to test new therapeutic approaches. (AU)