The association of Orlistat with chemotherapic agents for the treatment of oral squamous cell carcinoma: an in vitro and in vivo study in orthotopic models

• Grant number: 14/20832-3
• Support Opportunities: Regular Research Grants
• Duration: February 01, 2015 - January 31, 2017
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Edgard Graner
• Grantee: Edgard Graner
• Host Institution: Faculdade de Odontologia de Piracicaba (FOP). Universidade Estadual de Campinas (UNICAMP). Piracicaba , SP, Brazil

Abstract

Fatty acid synthase (FASN) is the anabolic enzyme responsible for the endogenous synthesis of fatty acids. Its expression and activity is abnormally high in several human malignancies, including oral squamous cell carcinomas (OSCC). It has been consistently demonstrated that the expression of FASN is associated with higher rates of recurrence, metastatic dissemination, and poor prognosis for OSCC patients. Orlistat was initially developed and clinically used as an anti-obesity drug; however, it also has important anticancer properties due to the irreversible inhibition of FASN activity. Our group has recently shown that the systemic treatment with this drug significantly reduces the size of primary tumors and the number of regional metastases by 43% in an orthotopic model of oral tongue squamous cell carcinoma (OTSCC). The treatment of choice for OSCC is surgical resection; however, advanced cases generally receive adjuvant radiotherapy and / or chemotherapy. Cisplatin (CDDP), fluorouracil (5-FU), and paclitaxel (PTX) are widely used for the treatment of several types of cancers, including OSCC. To date, there is no information in the literature regarding the application of FASN inhibitors as adjuvants for the OSCC chemotherapy. The aim of the present research project is to evaluate the effects of the association of orlistat with CDDP, 5-FU, and PTX on the proliferation and cell death of the metastatic OSCC cell line SCC-9 ZsGreen LN1, developed in our laboratory. Synergic drug combinations in vitro will be further tested in the orthotopic OTSCC with the same cell line, in which both the primary tumors and metastatic dissemination will be analyzed. Finally, we also propose to develop OTSCC patient-derived xenografts (PDX) through the transplantation of small fragments of tumor tissues from patients attending the OROCENTRO, FOP-UNICAMP. PDX may reproduce with more fidelity the patient´s disease by representing tumor cell heterogeneity and predict individual responses to chemotherapeutic agents, their associations, and new drugs. (AU)

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)

BOELCKE, WILLIAN PETER; TEIXEIRA, ISADORA FERRARI; AQUINO, IARA GONALVES; MAZZARO, AMANDA RAMOS; CUADRA-ZELAYA, FLORENCE JUANA MARIA; DE SOUZA, ANA PAULA; SALO, TUULA; DELLA COLETTA, RICARDO; GRANER, EDGARD; BASTOS, DEBORA CAMPANELLA. Pharmacological fatty acid synthase inhibitors differently affect the malignant phenotype of oral cancer cells.. ARCHIVES OF ORAL BIOLOGY, v. 135, p. 9-pg., 2022-03-01. (16/07129-7, 16/24906-7, 14/20832-3)

BASTOS, DEBORA C.; PAUPERT, JENNY; MAILLARD, CATHERINE; SEGUIN, FABIANA; CARVALHO, MARCO A.; AGOSTINI, MICHELLE; COLETTA, RICARDO D.; NOEL, AGNES; GRANER, EDGARD. Effects of fatty acid synthase inhibitors on lymphatic vessels: an in vitro and in vivo study in a melanoma model. LABORATORY INVESTIGATION, v. 97, n. 2, p. 194-206, FEB 2017. (08/57471-7, 14/20832-3, 10/51090-1)

DE AQUINO, IARA GONCALVES; BASTOS, DEBORA CAMPANELLA; MARIA CUADRA-ZELAYA, FLORENCE JUANA; TEIXEIRA, ISADORA FERRARI; SALO, TUULA; DELLA COLETTA, RICARDO; GRANER, EDGARD. Anticancer properties of the fatty acid synthase inhibitor TVB-3166 on oral squamous cell carcinoma cell lines. ARCHIVES OF ORAL BIOLOGY, v. 113, MAY 2020. (14/20832-3)