Hsp90 inhibition effects in therapeutic escape pathways in BRAF-mutant melanoma

• Grant number: 15/10821-7
• Support type: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): November 01, 2015
• Effective date (End): October 31, 2016
• Field of knowledge: Biological Sciences - Morphology
• Principal Investigator: Silvya Stuchi Maria-Engler
• Grantee: Fernanda Faião Flores
• Supervisor abroad: Keiran Smalley
• Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Local de pesquisa : Moffitt Cancer Center, United States
• Associated to the scholarship: 13/05172-4 - Impact of epithelial-mesenchymal transition proteins in vemurafenib chemoresistant melanoma, BP.PD

Abstract

Melanoma is the most aggressive form of skin cancer and practically all patients treated with BRAF inhibitors acquire resistance after initial treatment by multifactorial escape mechanisms. The molecular chaperone heat shock protein-90 family plays a key role in maintaining the malignant potential of cancer cells and HSP90 client proteins are critical for melanoma progression, leading to many studies that aim the pharmacological inhibition. This project aim to investigate the hypothesis that all of the pathways required for both intrinsic, acquired and microenvironment-mediated BRAF, MEK and BRAF+MEK pathway inhibitor resistance involve signaling proteins that are either clients of HSP90 or are regulated by proteins that are clients of HSP90. We will define a common set of network hubs that emerge following drug treatment, the HSP90 clients that are important for network stability and the mechanism by which these hubs interact to drive MAPK inhibitor resistance. We will use a HSP90 inhibitor called PU-H71 to pull down client proteins, and perform functional validation studies. Besides, we will analyze tumor samples from a clinical trial of a BRAF and an HSP90 inhibitor in melanoma patients to investigate the patterns of HSP client degradation that are associated with long-term therapeutic response to the combination. This project also intend to correlate the results obtained in regular postdoctoral project (FAPESP 2013/05172-4) with the patient's tumor samples to evaluate the GLI1/GLI2 expression (transcription factors of Hedgehog pathway) that showed an increase in vemurafenib-resistant melanoma cell lines in order to investigate whether HSP90 inhibitors can induce GLI1 and Gli2 decrease with consequent reduction of cell proliferation. Using HSP90 inhibition, we expect to identify novel combinations of therapeutic targets that will allow the development of new therapeutic strategies to prevent the onset of and overcome both intrinsic and acquired MAPK inhibitor resistance. (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)

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.; SMALLEY, K. S.; MARIA-ENGLER, S. S. Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells. Oncogene, v. 36, n. 13, p. 1849-1861, MAR 30 2017. Web of Science Citations: 17.

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, MAR 2017. Web of Science Citations: 3.