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In vitro models for pre clinical studies of melanoma Chemoresistant


Human melanoma presents extreme chemoresistance and poor prognosis with a high risk of metastasis. The overexpression of MAPK/ERK pathway proteins is closely related to uncontrolled melanoma cells survival, and this route has been studied for the development of targeted therapies. Thus, the recent chemotherapeutics Vemurafenib (BRAF V600E inhibitor) and Trametinib (MEK inhibitor) have been considered a hope for patients with melanoma, who have presented very high rates responses few weeks after treatment. Despite the clinical success of the advanced melanoma treatment, most of the observed responses is transient, with relapse and resistance in the majority of cases, about after 7 months of treatment. The current treatment is therefore still based on the same used in the past decades, even in spite of the evolution therapeutic technology. Understanding the resistance mechanism can provide clues both for developing improved versions of a drug and for guiding the selection of appropriate drug combinations for therapy. Recent data from our laboratory has shown that the novel compounds 4-NC as well as DM-1 induce cell death for melanoma cells in a specific manner. The 4-NC is a potent proteasome inhibitor, and DM-1, a caspase 3-dependent apoptosis inductor. Here, we aim to evaluate and overcome the melanoma chemoresistance to BRAF and MEK inhibitors, by use of combinatorial therapies using 4-NC or DM-1 with BRAF/MEK inhibitors on melanoma resistant cells resistant to such therapeutics currently established. For this, Vemurafenib and Trametinib resistant from established melanoma cultures cells will be generate in our lab. In addition, we will also isolate primary cells from chemoresistant tumors samples of patients at the Cancer Hospital of Barretos. Their resistance profile will be confirmed by cell viability, DNA fragmentation, cell migration and invasion mechanisms, gene expression, and protein expression focusing on ERK reactivation, proteasome activity, autophagy and senescence profiles. Furthermore, we will compare organotypical models of human reconstructed skin in vitro with melanoma cells to monolayer cultures for characterization the importance of the tumor microenvironment in chemoresistance overcoming. Thus, drugs combinations with 4-NC and DM-1 will be determinated according to the results obtained, and collaborate on improving of current melanoma therapeutics. (AU)

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Scientific publications (8)
(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)
FAIAO-FLORES, F.; ALVES-FERNANDES, D. K.; PENNACCHI, P. C.; SANDRI, S.; VICENTE, A. L. S. A.; SCAPULATEMPO-NETO, C.; VAZQUEZ, V. L.; REIS, R. M.; CHAUHAN, J.; GODING, C. R.; et al. Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells. Oncogene, v. 36, n. 13, p. 1849-1861, . (14/24400-0, 13/05172-4, 15/10821-7, 12/04194-1)
DE OLIVEIRA, ERICA APARECIDA; DE LIMA, DIOGENES SAULO; CARDOZO, LUCAS ESTEVES; DE SOUZA, GARCIA FERREIRA; DE SOUZA, NAYANE; ALVES-FERNANDES, DEBORA KRISTINA; FAIAO-FLORES, FERNANDA; PABLO QUINCOCES, JOSE AGUSTIN; DE MORAES BARROS, SILVIA BERLANGA; NAKAYA, HELDER I.; et al. Toxicogenomic and bioinformatics platforms to identify key molecular mechanisms of a curcumin-analogue DM-1 toxicity in melanoma cells. PHARMACOLOGICAL RESEARCH, v. 125, n. B, p. 178-187, . (14/24400-0)
SANDRI, SILVANA; FAIAO-FLORES, FERNANDA; TIAGO, MANOELA; PENNACCHI, PAULA COMUNE; MASSARO, RENATO RAMOS; ALVES-FERNANDES, DEBORA KRISTINA; BERARDINELLI, GUSTAVO NORIZ; EVANGELISTA, ADRIANE FEIJO; VAZQUEZ, VINICIUS DE LIMA; REIS, RUI MANUEL; et al. Vemurafenib resistance increases melanoma invasiveness and modulates the tumor microenvironment by MMP-2 upregulation. PHARMACOLOGICAL RESEARCH, v. 111, p. 523-533, . (14/24400-0, 13/05172-4)
MASSARO, R. R.; FAIAO-FLORES, F.; REBECCA, V. W.; SANDRI, S.; ALVES-FERNANDES, D. K.; PENNACCHI, P. C.; SMALLEY, K. S. M.; MARIA-ENGLER, S. S.. Inhibition of proliferation and invasion in 2D and 3D models by 2-methoxyestradiol in human melanoma cells. PHARMACOLOGICAL RESEARCH, v. 119, p. 242-250, . (12/05732-7, 14/24400-0, 13/05172-4, 15/10821-7)
ALVES-FERNANDES, DEBORA KRISTINA; DE OLIVEIRA, ERICA APARECIDA; HASTREITER, ARACELI APARECIDA; FAIAO-FLORES, FERNANDA; FELIPE-SILVA, ALOISIO SOUZA; TURATO, WALTER; FOCK, RICARDO AMBROSIO; MARIA-ENGLER, SILVYA STUCHI; DE MORAES BARROS, SILVIA BERLANGA. In vivo antitumoral effect of 4-nerolidylcatechol (4-NC) in NRAS-mutant human melanoma. Food and Chemical Toxicology, v. 141, . (17/07010-2, 14/24400-0, 14/06959-0, 17/04926-6)
ALVES-FERNANDES, DEBORA KRISTINA; DE OLIVEIR, ERICA APARECIDA; FAIAO-FLORES, FERNANDA; ALICEA-REBECCA, GRETCHEN; WEERARATNA, ASHANI T.; SMALLEY, KEIRAN S. M.; DE MORAES BARROS, SILVIA BERLANGA; MARIA-ENGLER, SILVYA STUCHI. ER stress promotes antitumor effects in BRAFi/MEKi resistant human melanoma induced by natural compound 4-nerolidylcathecol (4-NC). PHARMACOLOGICAL RESEARCH, v. 141, p. 63-72, . (17/07010-2, 14/24400-0, 14/06959-0, 17/04926-6)
CARVALHO, VANESSA F. M.; MIGOTTO, AMANDA; GIACONE, DANIELA V.; DE LEMOS, DEBORA P.; ZANONI, THALITA B.; MARIA-ENGLER, SILVYA S.; COSTA-LOTUFO, LETICIA V.; LOPES, LUCIANA B.. Co-encapsulation of paclitaxel and C6 ceramide in tributyrin-containing nanocarriers improve co-localization in the skin and potentiate cytotoxic effects in 2D and 3D models. European Journal of Pharmaceutical Sciences, v. 109, p. 131-143, . (14/24400-0, 15/23976-9, 16/04913-9, 13/16617-7)
PEDROSA, TATIANA DO NASCIMENTO; CATARINO, CAROLINA MOTTER; PENNACCHI, PAULA COMUNE; DE ASSIS, SILVIA ROMANO; GIMENES, FABRICIA; LOPES CONSOLARO, MARCIA EDILAINE; DE MORAES BARROS, SILVIA BERLANGA; MARIA-ENGLER, SILVYA STUCHI. A new reconstructed human epidermis for in vitro skin irritation testing. TOXICOLOGY IN VITRO, v. 42, p. 31-37, . (11/07441-7, 11/22812-1, 14/24400-0, 13/00735-0, 11/14327-6, 13/12682-9)

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