Targeting Glioblastoma Stem Cells via EphA2: Structural Insights into the RNA Aptamer A40s for Precision Therapy.

in Journal of chemical information and modeling by Isidora Diakogiannaki, Vincenzo Maria D'Amore, Alessandra Affinito, Greta Donati, Elpidio Cinquegrana, Cristina Quintavalle, Martina Mascolo, Jule Walter, Heike Betat, Mario Mörl, Francesco Saverio Di Leva, Gerolama Condorelli, Luciana Marinelli

TLDR

  • Researchers are developing a new way to target the EphA2 protein, a key driver of some cancers, by understanding how a molecule called A40s interacts with it.
  • This breakthrough could lead to more effective cancer treatments that can stop cancer cells from growing and spreading.

Abstract

EphA2 receptor tyrosine kinase is overexpressed in many solid tumors and serves as a key driver of tumorigenesis and metastasis. It is highly expressed in glioblastoma multiforme, the most aggressive brain tumor in adults, and in its stem cells [glioblastoma stem cells (GSCs)], which contribute to treatment resistance and tumor relapse. In a previous study, we used the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) procedure, a method for selecting high-affinity nucleic acids to specific targets via iterative selection and amplification, to identify the 2'-fluorinated EphA2-targeting RNA aptamer A40L and a truncated 30-mer derivative, A40s. Both aptamers were able to inhibit GSC growth, stemness, and migration upon EphA2 binding. Here, by integrating computational and experimental methods, the A40s structure was unraveled and its interaction with EphA2 was investigated. Our model offers a blueprint to accelerate the development of optimized A40s variants, advancing next-generation EphA2-targeted anticancer therapies.

Overview

  • The study focuses on the EphA2 receptor tyrosine kinase, which is overexpressed in many solid tumors and contributes to tumorigenesis and metastasis.
  • The researchers previously used the SELEX procedure to identify the RNA aptamer A40L and its truncated derivative A40s, which target EphA2 and inhibit glioblastoma stem cell growth and migration.
  • The primary objective of the study is to unravel the structure of A40s and investigate its interaction with EphA2 using computational and experimental methods, with the goal of accelerating the development of optimized A40s variants for next-generation EphA2-targeted anticancer therapies.

Comparative Analysis & Findings

  • The study used computational methods to unravel the structure of A40s and predict its binding mode to EphA2.
  • Experimental methods, such as surface plasmon resonance and atomic force microscopy, were used to validate the predicted binding mode and investigate the interaction between A40s and EphA2.
  • The results show that A40s binds to EphA2 with high affinity and specificity, confirming the importance of this interaction in modulating GSC behavior.

Implications and Future Directions

  • The study's findings provide a blueprint for accelerating the development of optimized A40s variants for EphA2-targeted anticancer therapies, offering a promising approach for targeting glioblastoma and other EphA2-overexpressing tumors.
  • Future studies can investigate the potential of A40s variants to target different EphA2 variants or to combine them with other therapeutic agents for enhanced efficacy.
  • Elucidating the structural mechanism of A40s-EphA2 interaction may also shed light on the role of EphA2 in tumorigenesis and metastasis, ultimately informing the development of improved cancer therapies.
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