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Evaluation of the effect of MMP9 silencing by CRISPR-Cas9 system concomitant with the use of BCG and anti-PDL1 in the treatment of bladder cancer: in vitro and in vivo study

Grant number: 22/08864-3
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): August 01, 2023
Effective date (End): July 31, 2025
Field of knowledge:Health Sciences - Medicine - Surgery
Principal Investigator:Sabrina Thalita dos Reis Faria
Grantee:Juliana Alves de Camargo
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Bladder Cancer (BCC) is the tenth most common type of cancer among both sexes, accounting for about 5% of all new cancer cases. It is a disease of significant morbidity and mortality, and the prognosis is directly related to tumor staging. In the more advanced cases of the disease, treatment is carried out with the aim of bladder preservation, thus reducing the impact on the patient's quality of life. In high-risk cases, the rates of local recurrence and progression to muscle-invasive disease are significant, corresponding to almost 50% of cases. Several factors are related to the tumor invasion capacity, including the increased expression of matrix metalloproteinases, such as MMP-9. In addition, these tumors have high expression of PD-L1 receptors that block the immune system. Consequently, the tumors show resistance to treatment with BCG, which is applied in clinical practice in patients with low-grade tumors. One of the most widely used methodologies to silence specific markers is ASO and RNAi. However, they have limitations, requiring constant treatment and even then they are not as effective. Recently, the CRISPR-Cas9 methodology was described, already standardized in our laboratory, presenting high specificity for gene editing of the target of interest. Thus, our goal is to block MMP-9 with the CRISPR-Cas9 methodology, to possibly inhibit the metastatic mechanism of cells, and at the same time, block PD-L1 stimulating tumor response to BCG therapy in a synergistic treatment with CRISPR-Cas9 for MMP-9 and intravesical BCG and systemic anti-PD-L1 in mice, using the murine orthotopic model of bladder cancer, the MB-49 cell line.

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