Exploring Novel Molecular Targets for the Treatment of High-Grade Astrocytomas Using Peptide Therapeutics: An Overview

Abstract

Diffuse astrocytomas are the most aggressive and lethal glial tumors of the central nervous system (CNS). Their high cellular heterogeneity and the presence of specific barriers, i.e., blood-brain barrier (BBB) and tumor barrier, make these cancers poorly responsive to all kinds of currently available therapies. Standard therapeutic approaches developed to prevent astrocytoma progression, such as chemotherapy and radiotherapy, do not improve the average survival of patients. However, the recent identification of key genetic alterations and molecular signatures specific for astrocytomas has allowed the advent of novel targeted therapies, potentially more efficient and characterized by fewer side effects. Among others, peptides have emerged as promising therapeutic agents, due to their numerous advantages when compared to standard chemotherapeutics. They can be employed as (i) pharmacologically active agents, which promote the reduction of tumor growth; or (ii) carriers, either to facilitate the translocation of drugs through brain, tumor, and cellular barriers, or to target tumor-specific receptors. Since several pathways are normally altered in malignant gliomas, better outcomes may result from combining multi-target strategies rather than targeting a single effector. In the last years, several preclinical studies with different types of peptides moved in this direction, providing promising results in murine models of disease and opening new perspectives for peptide applications in the treatment of high-grade brain tumors.

Keywords: astrocytomas; molecular targets; peptide-based therapy; rehabilitation.

Figure 1

Schematic drawing of high-grade astrocytoma structure, microenvironment, and molecular targets. In the last few years, many key signaling pathways for astrocytoma development and invasiveness have been identified on different components of the tumor mass, including glioma-initiating cells (GICs), glioma cells, extracellular matrix (ECM) and vasculature. Several peptide therapeutics and peptide-based drugs, addressing these targets, have been subsequently designed to maximize the therapeutic efficacy of the treatments and reduce their side effects.