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Understanding the biology of the minimal residual disease after targeted therapy of BRAF mutant melanoma

 

 

Project Title: „ Understanding the biology of the minimal residual disease after targeted therapy of BRAF mutant melanoma”

Funding: European Regional Development Fund (ERDF), Measure 1.1.1.1 “Support for applied research” 

Project Nr.: 1.1.1.1/18/A/099

Period: 1 March 2019 – 28 February 2022

Project costs: 648 648,00 EUR

Principle Investigator: Dr. biol. Dace Pjanova

 

Project summary:

Metastatic melanoma, which arises after initially successful targeted therapy, represents a painful problem for medicine and society due to its high mortality. This project will explore the role of the meiotic component imposed by the melanoma-specific driver mutation of the BRAF kinase onto proliferative cycle in the mechanism of resistance to targeted therapy. The project hypothesis presumes that meiotic and CTA (CTCFL-MAGE A group) proteins ectopically activated by the mutant BRAF modulate the RAS-RAF-MEK-ERK proliferation pathway adapting the BRAF-inhibitor-induced G1/S checkpoint and causing metaphase arrest that enables “mitotic slippage” (also involving down-regulation of the Hippo tumour suppressing pathway) resulting in illicit tetraploidy coupled to reprogramming  and drug escape of a small proportion of resistant and finally de-polyploidised clonogenic cells. This modulated cell cycle, termed the ‘meiomitosis’, is little explored and may open a new avenue in melanoma pathogenesis studies and therapy perspectives. The hypothesis will be tested on melanoma cell cultures and also melanoma patient material. The aim of this project designed as a fundamental research is to address this mechanism as a proof of concept looking for possible new therapeutic targeting, attracting new people to science and increasing the capacity of scientific excellence in the BMC.

Information published 01.03.2019.

 

1 March 2019 – 31 May 2019

During the initial phase of the project, the origin of cancer triploidity was studied using 15 malignant and five benign tumour types from male patients (altogether 2928 karyotypes) available in the Mitelman database. The in silico meta-analysis showed that the heterogeneity of the karyotype with a pronounced triploid fraction was observed in all types of malignancies. In contrast, chromosome X disomy (most commonly seen as XXY karyotype) positively correlated with triploidity, negatively correlated with diploidity and did not correlate with tetraploidity. An additional in silico analysis based on exome sequencing data is underway. In parallel, a collection of primary melanoma tissues and primary melanoma cell lines obtained from these tissues was tested for the presence of the BRAF V600 mutation using conventional Sanger sequencing. The mutation was found in five out of 17 primary melanoma tissues and one primary melanoma cell line, which was also triple positive for specific melanoma markers. This culture will be further used to test the hypothesis in clinical material.

Information published 31.05.2019.




Mājas lapas izstrādi finansēja ERAF 2.1.1.2. aktivitātes projekts Nr. 2010/0196/2DP/2.1.1.2.0/10/APIA/VIAA/004 "Latvijas biomedicīnas pētījumu integrācija Eiropas zinātnes telpā".