Research Grants 22/06082-8 - Patologia, Carcinoma hepatocelular - BV FAPESP
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Multimodel Drug Screening Platform (MDSP): preclinical and molecular insights for Colon and Liver Cancer management

Abstract

Hepatocellular Carcinoma (HCC) and Colorectal Carcinoma (CRC) are cancers with high incidence and mortality worldwide, both displaying a poor prognosis. Many patients in advanced disease stages are submitted to low response antineoplastic therapies. Tumor microenvironment modulation is also neglected in current targeted therapies. The most prominent epidemiological studies highlight that consumption of coffee and vegetables can reduce the risk for HCC and CRC, respectively. Coffee and vegetables are reservoirs of several bioactive compounds (BCs) that have already demonstrated antiproliferative, pro-apoptotic and anti-inflammatory effects in preclinical studies, such as caffeine (CAF), chlorogenic acid (ACG), kawheol (KWL), phenethyl isothiocyanate (PEITC) and ²-cryptoxanthin (BCX). Due to the need to increase the effectiveness of current therapies, we will assess whether the administration - alone or in combination - (1) of the CAF alkaloid, the diterpene KWL and the polyphenol ACG, abundant in coffee, promotes the antitumoral effects of Sorafenib therapy or immunotherapy by Atezolizumab+Bevacizumab in in vivo, in vitro and ex vivo models of HCC; (2) of isothiocyanate PEITC, polyphenol ACG, and carotenoid BCX, abundant in vegetables, promotes the antitumoral effects of 5-fluorouracil+Bevacizumab therapy in in vivo, in vitro and ex vivo models of CRC. Co-culture models of HCC tumor cells (HepG2) and stellate cells (LX2) or CCR tumor cells (HCT-116) and fibroblasts (CCD-18Co) will be established. Co-cultures will be treated with BCs - alone or in combination - and with the respective therapies for 24 or 48 h. Cell viability (MTT), cytotoxicity (LDH), motility (scratch assay), invasion (transwell assay) and immunoexpression of Ki-67 (proliferation), caspase-3 (apoptosis) and VEGF (angiogenesis) will be evaluated. Then, the Combinatorial Index (CI) will be calculated and the combinations with additive/synergistic results will be selected for the in vivo study. BALB/c nude mice will be subjected to xenograft tumor model by the inoculation of HepG2/LX2 or HCT-116/CCD-18Co cells. The animals will be treated with the selected BCs and respective therapies, and the immunoexpression of Ki-67, caspase-3, CD31 and VEGF, and the main tumorigenic pathways and tumor microenvironment at the transcriptomic level (NanoString) will be evaluated in tumors. The main altered pathways will be validated at the protein level (immunohistochemistry and immunoblot) in human sample, using Precision Cut Slices and Patient-derived xenografts methodologies. CCR or CRC human samples of will be collected, cultured (Brazil) or implanted in immunosuppressed mice (Spain), and treated with selected therapies. The project also involves the establishment of a company involved in the execution of pharmacological tests in the in vitro, in vivo and ex vivo systems proposed, and a university extension program project focused on nutrition/scientific dissemination. (AU)

Articles published in Agência FAPESP Newsletter about the research grant:
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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)
ROMUALDO, GUILHERME RIBEIRO; HEIDOR, RENATO; BACIL, GABRIEL PRATA; MORENO, FERNANDO SALVADOR; BARBISAN, LUIS FERNANDO. Past, present, and future of chemically induced hepatocarcinogenesis rodent models: Perspectives concerning classic and new cancer hallmarks. Life Sciences, v. 330, p. 16-pg., . (23/08751-7, 22/16633-1, 22/13402-9, 22/06082-8)

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