Explorando a interação dinâmica da esfingosina quinase 2 e p53 em organoides de carcinoma de cabeça e pescoço

• Processo: 23/15046-8
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Data de Início da vigência: 01 de julho de 2024
• Data de Término da vigência: 30 de junho de 2025
• Área de conhecimento: Ciências da Saúde - Odontologia
• Pesquisador responsável: Andréia Machado Leopoldino
• Beneficiário: Thaís Moré Milan
• Supervisor: Alice Soragni
• Instituição Sede: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brasil
• Instituição Anfitriã: University of California, Los Angeles (UCLA), Estados Unidos
• Vinculado à bolsa: 22/10740-0 - Estudo do potencial mecanismo de regulação de microRNAs pela esfingosina quinase 2, BP.DR
• Assunto(s): Bioimpressão Neoplasias bucais p53 Oncologia molecular
• Palavra(s)-Chave do Pesquisador: Bioprinting | oral cancer | Organoids | Precision Medicine | p53 | Sphinogosine kinase 2 | Oncologia Molecular

Resumo

Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide, being responsible for many deaths due to failures of therapies and recurrences. Alterations in sphingolipids metabolism caused by deregulation of sphingosine kinase 2 (SK2) and p53 aggregation are related to tumor progression. Our hypothesis is that p53 conformation/aggregation could be regulated by SK2. Recently, our research group observed that SK2 and sphingolipids alterations were capable of accelerating tumoral growth in vivo and induced cancer stem cell characteristics in an oral keratinocyte cell line. The use of organoids provides a translation approach, due to their accurate representation of patient tumors. Then, the present project aims to investigate the interplay between sphingosine kinase 2 and p53 in HNSCC cell lines and patient samples using organoids by 3D culture and bioprinting focusing on precision medicine. Different methods will be used: bioprinting to establish tumor organoids; performing a patient-derived organoid screening to evaluate conventional therapies, and inhibiting p53 aggregation through ReACp53 peptide; evaluating p53 mutation and protein conformation in HNSCC samples and knocking down SK2 in HNSCC cell lines; testing radiation sensitivity in HNSCC organoids and perform a Caspase 3/7 and Hoechst assay to investigate DNA damage and p53 activity; analyze image-based testing chemoradiation of HNSCC organoids using 40 FDA approved drugs and drug combinations, for a total of 160 total regimens to be tested and testing drug sensitivity in organoids through imaged-based assay and ATP assay. The expected outcomes stand to bring advancement in the cancer field by focusing on HNSCC patient organoids.