Effects of STAT3 inhibition in combination with Ovarian Cancer therapy

• Grant number: 24/17550-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2025
• End date: October 31, 2028
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Ana Paula Lepique
• Grantee: Ana Luiza de Araújo Butarelli
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Ovarian cancer (OC) is one of the most common and lethal gynecological tumors in the global female population. The high-grade serous type is the most frequent and the major contributor to the high mortality rates of the disease. The etiology of OC is multifactorial, but about 10 to 15% of cases are related to mutations in DNA repair genes, especially BRCA1 and BRCA2. The treatment of OC includes surgical excision combined with radio or chemotherapy, or with angiogenesis inhibitors and PARP inhibitors; however, resistance and recurrence rates have been increasing. The tumor microenvironment of OC is characterized by the presence of various cell lineages, in addition to neoplastic cells. Constitutive expression of STAT3 is common in these tumors, with both oncogenic and tolerogenic functions. Our hypothesis is that the inhibition of STAT3 combined with PARP inhibition (in BRCA1/2 incompetent patients) or chemotherapy (in BRCA competent patients) can cause damage to tumor cells and potentiate immune responses. Specifically, in the case of PARP inhibition, there may be cooperation between the activation of the cGAS/STING pathway and STAT3 inhibition to enhance anti-tumor immune responses. Ovarian cancer cells obtained by paracentesis will be used to establish three-dimensional ex vivo models, where the proposed treatments will be tested. Based on previous data from our laboratory and others, increased tumor death and activation of cytotoxic immune responses are expected. (AU)