Targeted strategies for inhibition of oral cancer progression dependent on the C-terminal region of agrin

• Grant number: 24/06599-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2024
• End date: February 29, 2028
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Adriana Franco Paes Leme
• Grantee: Laura Luciana de Melo Moreira Silva
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil

Abstract

Agrin is a proteoglycan composed of multidomains, containing cleavage sites mainly in the N- and C-terminal portions, which leads to the formation of several potentially active fragments, the C-terminal of Agrin (C-22kDa) being the best studied in the context of cancer. Studies by our group such as Kawahara et al. (2014) and Rivera et al. (2018) have shown an association between agrin abundance and oral cancer progression. In addition, a recent unpublished study by our group identified the formation of a complex between C-22kDa and two other secreted proteins through proteomic analysis of the secretome of an oral squamous cell carcinoma (OSCC) cell line. Considering the importance of the C-terminus of agrin and the proteins involved in this complex in SCC, the aim of this project will be to use a strategy to modulate the interaction interface between the proteins, and thus the progression of SCC.To this end, monoclonal antibodies against C-22kDa epitopes located at the interaction interface will be used in models of different complexities in three subsequent phases: (i) primary culture of oral keratinocytes isolated from oral SCC patients and (ii) organoid models using primary SCC cells will be treated with the monoclonal antibodies and subjected to functional experiments after proof of concept of the modulation of tumorigenesis, (iii) and finally, in xenograft murine models of oral SCC, the mAbs will be injected into the tumors to analyze their regression. In addition, in order to assess the off-target effect of the mAbs, the Thermal proteome Profile technique will be carried out on the different models. It is hoped that this project will advance knowledge of the mechanisms of agrin regulation as well as the development of new treatments for oral SCC.