RAS PATHWAY ALTERATIONS AND DRUG REPOSITIONING IN EARLY-ONSET ORAL SQUAMOUS CELL CARCINOMA: DEVELOPMENT OF 3D BIOPRINTED MODELS FOR TRANSLATIONAL EVALUATION

• Grant number: 25/22460-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: March 01, 2026
• End date: February 28, 2027
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Pablo Agustin Vargas
• Grantee: Sebastião Silvério de Sousa Neto
• Supervisor: Rogerio Moraes Castilho
• Host Institution: Faculdade de Odontologia de Piracicaba (FOP). Universidade Estadual de Campinas (UNICAMP). Piracicaba , SP, Brazil
• Institution abroad: University of Michigan, United States
• Associated to the scholarship: 23/13797-6 - TARGETED CHEMOTHERAPY STRATEGIES FOR THE ELIMINATION OF TUMOR STEM CELLS IN YOUNG PATIENTS WITH ORAL SQUAMOUS CELL CARCINOMA, BP.DR

Abstract

Early-onset oral squamous cell carcinoma (OSCC) has emerged as a distinct clinical and molecular entity, with evidence of enriched alterations in RAS pathway regulators such as RASSF1, RASA1, NF1, RAP1GAP, and RASGRP2/3, in addition to occasional canonical mutations in HRAS, KRAS, and NRAS. These dysregulations may contribute to the aggressive clinical behavior and poor prognosis observed in younger patients. In this context, repositioning of FDA-approved targeted agents that modulate RAS/MAPK-related signaling, including osimertinib, ceritinib, and pacritinib, offers a promising therapeutic strategy that remains underexplored in head and neck cancers. This project aims to develop 3D bioprinted models of OSCC that reproduce the mutational landscape of young patients, enabling functional characterization of RAS-related phenotypes and preclinical drug testing. We will (i) determine the mutational status of RAS genes and regulators in selected OSCC/HNSCC cell lines; (ii) compare RAS-mutant and wild-type models in terms of viability, proliferation, invasion, and drug resistance; (iii) investigate stromal modulation through fibroblast co-culture; and (iv) evaluate the efficacy of repositioned targeted therapies, alone and in combination with cisplatin, in 3D spheroids and bioprinted constructs. The integration of molecular characterization with advanced 3D modeling will provide a robust platform for translational research, potentially leading to personalized therapeutic strategies for young OSCC patients.