Conjugados de aptameros para alvejar o oncogene B-MyB: uma estratégia promissora para tratamento do cancro do pulmão

LC is one of the most challenging human tumors. Tobacco smoking is associated with an increased risk and the mortality related to LC continues to increase. Current projections estimate that this tumor will be the main cause of cancer death in the next decades unless substantial progress is made. Altogether, there is a dramatic need to improve molecularly-based therapy which can significantly impact tumor treatment and patient survival. B-MYB, which acts as a transcription factor, is typically expressed in dividing cells and plays a crucial role in cell proliferation and control of cellular differentiation. It has a vital role in guiding the regulation of apoptosis and tumor progression in LC. A study found that B-MYB overexpression was related to shorter overall survival in LC patients. Due to the undruggable profile of the B-MYB transcription factor, it is necessary to develop new and efficient therapeutic approaches. The main questions tackled by HOPE consortium are: 1) Can G4s in the B-MYB promoter regulate LC development? 2) Can these G4s be recognized in real human samples? 3) Does the aptamer-peptide conjugate target G4 B-MYB and contribute to LC growth inhibition? 5) What are the predictors of response to the aptamer-peptide conjugate? 6) Can the aptamer-peptide conjugate regulate the main oncogenic mechanisms associated with the B-MYB gene? 7) How does the activity of the aptamer-conjugate interact with the activity of standard immunotherapy? 8) How can the pathway be exploited for improved in vivo pharmacology? 9) Can the target B-MYB G4s be identified through the strategies described above? The main objectives of HOPE are to validate B-MYB as a target through G4 motifs in LC human biopsies and demonstrate that the target therapeutic proposed, termed aptamer-peptide conjugate, will respond to therapy, LC progression. This research will demonstrate novel approaches that are: 1) G4-SELEX-Seq to produce L-RNA aptamers for B-MYB G4 target; 2) G4 access to isolate and sequence G4s in B-MYB gene associated to LC; 3) establishing tools and methods for standardized collection of tumor and normal tissue samples, clinical information, and strategies for sharing these data across laboratories and research groups; 4) identifying B-MYB gene expression signatures characteristic of different tumor subgroups that could be employed for objective patient stratification; 5) establishing patient cohorts for the analysis of genetic factors (variation) associated with LC risk, patient outcome, and response to therapy; 6) establishing biobanks available for future studies of LC with clinical characterization; 7) smart nano-conjugate synthesis (L-RNA aptamer-peptide conjugate); 8) monitoring functional and biological behaviors in LC cells treated with aptamer-peptide conjugate; 9) 3D bioprinted LC spheroids to a more accurate prediction of in vivo response; 10) safety and regulatory tests of the aptamer-conjugate by HPRD company; 11) demonstrate in the relevant environment all results obtained during the experimental part of the project and its dissemination. These findings underline the concept of targeted therapeutics for gene inhibition based on G4 modulation, focusing on opportunities and challenges for translation to clinical studies. The purpose of the HOPE is the implementation of a novel therapeutic approach making use of aptamer conjugates and studying if these can precisely modulate the activity of B-MYB G4-mediated gene networks.