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The role of extracellular vesicles in photodynamic therapy of perihilar cholangiocarcinoma

Grant number: 17/14630-7
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): December 01, 2017
Effective date (End): November 30, 2018
Field of knowledge:Health Sciences - Pharmacy - Pharmaceutical Technology
Principal Investigator:Antonio Claudio Tedesco
Grantee:Leonardo Pereira Franchi
Supervisor: Michal Heger
Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: University of Amsterdam (UvA), Netherlands  
Associated to the scholarship:14/11870-9 - Sensitizing cancer cell lines to photodynamic therapy through inhibition of protein APE1, BP.PD

Abstract

Photodynamic therapy (PDT) is a last-line curative treatment modality used for several types of cancer. PDT induces the formation of extracellular vesicles (e.g., exosomes) that regulate resistance and survival mechanisms in tumor cells through paracrine signaling. Consequently, the extracellular vesicles enable tumor cells to survive PDT while making non-treated or sublethally afflicted tumor cells resistant to therapy. Whether these mechanisms occur in perihilar cholangicarcinoma (PHCC) is currently elusive. PHCC is a very lethal form of bile duct cancer that responds better to PDT than any other treatment yet is resistant to PDT due to activation of post-PDT survival signaling. Consequently, there is a strong need to improve therapy of PHCC. We hypothesize that exosomes from PDT-treated PHCC cells are able to induce survival signaling in PHCC cells and induce PDT resistance in non-treated cells. These processes are believed to be mediated by exosomal NRF2, HIF-1, ASK1, HSF1, and NF-ºB. The aim of the project is to determine whether exosomes from PDT-subjected PHCC cells trigger survival signaling; confer resistance in sublethally afflicted tumor cells and non-treated tumor cells (representative of metastatic tumor cells); and to elucidate the molecular mechanisms. The results will provide insight into PHCC cell survival and resistance pathways following PDT, which will be instrumental in improving therapeutic efficacy.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FRANCHI, LEONARDO PEREIRA; BARBOSA DE FREITAS LIMA, JESSICA ELLEN; PIVA, HENRIQUE LUIS; TEDESCO, ANTONIO CLAUDIO. The redox function of apurinic/apyrimidinic endonuclease 1 as key modulator in photodynamic therapy. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY, v. 211, p. 13-pg., . (17/14630-7, 13/50181-1, 14/11870-9)

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