Pirfenidone alone and associated with cisplatin on oral squamous cell carcinoma (OSCC): good girl or bad girl?

• Grant number: 25/05098-6
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2025
• End date: May 31, 2027
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Carlos Rossa Junior
• Grantee: Thaina da Silva Ferreira
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated research grant: 20/00394-2 - Head and neck squamous cell carcinoma (HNSCC) invasion and distant metastasis: relevance and crosstalk between GALR2 and efferocytosis in the tumor microenvironment and hematogenic dissemination, AP.TEM

Abstract

Pirfenidone is an anti-fibrotic drug clinically used in the treatment of idiopathic pulmonary fibrosis (IPF). It's mechanism of action is still not completely known, but many of its biological effects interfere with the biology of activated fibroblasts in IPF's chronic inflammation microenvironment, and considering the phenotypical and biological similarity between these activated fibroblasts and cancer associated fibroblasts (CAFs), some studies have investigated the influence of pirfenidone on different types of carcinoma associated with a high prevalence of these activated fibroblasts (CAFs) in which these cells are associated with worse prognosis. A search on NCBI/PubMed database did not return any experimental studies investigating pirfenidone in the context of oral squamous cell carcinomas (OSCC) revealing an important gap in knowledge. Previous experiments from our research group using the zebrafish immunodeficient xenograft model indicate that in association with cytotoxic therapy pirfenidone enhanced tumor progression and promoted metastatic dissemination. This proposal includes in vitro studies to assess the influence of pirfenidone on CAFs (proliferation, survival, TGFb and Hedgehog signaling) and on OSCC cells (proliferation, survival, EMT, migration, invasion). In vivo experiment using a murine immunocompetent orthotopic model of OSCC will investigate the role of locally-applied pirfenidone on tumor growth and metastatic dissemination and on the prevalence of two subpopulations of CAFs (myofibroblastic and inflammatory) and their association with GALR2 expression. The proposed experiments involve the use of various methodologies that are already established in the laboratory and with which the research group and the candidate in this proposal have already gained expertise, such as: cell cultures and co-cultures, RT-qPCR, Western blot, immunohistochemistry, immunofluorescence, proliferation, apoptosis, migration and invasion. The central hypothesis is that in association with cytotoxic therapies pirfenidone has a paradoxal pro-tumoral effect. Knowledge derived from this proposal will inform on the therapeutic potential of pirfenidone in OSCC and on the association between subtypes of CAFs and tumor aggressiveness, outcomes and GALR2 expression. (AU)