Renal cell carcinoma patient-derived organoids as a tool in precision medicine and roles of BAP1 mutations in the tumor biology

• Grant number: 21/05037-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2022
• End date: April 30, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Vilma Regina Martins
• Grantee: Stefano Piatto Clerici
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
• Associated research grant: 14/50943-1 - INCT 2014: on Oncogenomics and Therapeutic Inovations, AP.TEM

Abstract

Renal cell carcinoma (RCC) is one of the ten most common types of tumors globally and has several histological subtypes with unique molecular signatures. Treatment of RCC is performed with partial or total nephrectomy for localized disease. However, part of the diagnoses occurs when the disease is in an advanced stage or when metastasis is present, resulting in resistance to systemic treatments. There is no consensus on which therapy offers a greater efficacy for patients with advanced and/or metastatic RCC. Patient-derived organoids (PDOs) have become an alternative for functional analysis in precision medicine and have advantages over in vivo models (xenografts) and in vitro monolayer cultures. This project proposes to establish a platform based on mimetic organoids derived from patients with different subtypes and staging of RCC for the screening of drugs that promote better therapies. To validate the experimental platform, we intend to correlate the ex vivo results with the patient's temporal therapeutic response, indeed expanding the precision medicine in the context of RCC. It is well known that 10 and 20% of RCC tumors present mutations in the BRCA-associated protein 1 (BAP1), a tumor suppressor gene, causing aggressive tumors with high metastatic capacity, resulting in low survival of the affected patient. Organoids from BAP1 mutated tumors will be used to elucidating the mechanisms associated to synthetic lethality (PARP inhibition), histone deacetylase (HDA) and enhancer of zeste homolog 2 (EZH2) in the treatment of RCC.