oa Editorial [Hot Topic: Designing New Drugs For High Grade Gliomas (Executive Guest Editor: Guido Frosina)]

Fighting against cancer has variable results, depending on the tumour type. Major improvements have been achieved during the past three decades for breast, prostate and colorectal cancer. In many cases, patients with those diagnoses can actually be cured, or at second best, live in hopes that their cancer may have become a manageable disease, accompanied by a decent quality of life. The story is different with high grade gliomas. Notwithstanding the virtual absence of metastases, these tumours still represent a formidable challenge to oncologists. High grade gliomas widely infiltrate normal brain, so as complete surgical removal is almost impossible and residual malignant tissues are refractory to eradication by conventional therapies. Even with today's best tripartite treatment approach (surgery + radiation + chemotherapy), survival benefit for patients with GBM is limited. After initial shrinkage, tumour relapse is a nearly inevitable re-appearing specter that takes away patients' lives within a few months. Why are residual glioma tissues so prone to drive tumour recurrence and progression? Importantly, recent findings indicate that resistant cell populations escaping radio- and chemotherapy often exhibit stem cell features. In particular, these glioma stem cells (GSC) express a number of proteins that are typical of stemness and are able to differentiate towards astrocyte, neuron or oligodendrocyte phenotypes. Whether GSC derive from transformation of normal neural stem cells (NSC) or de-differentiation of tumoral cells still is an open question that yet does not prevent us from exploiting their peculiarities for specific targeting. Recent work has shown that at least six resistance mechanisms are active in glioma. Hence, we have to simultaneously target most, if not all of them if we want to eradicate the tumour, a staggering task!. This issue of Current Pharmaceuticals Design deals with current novel approaches to overcome resistance to therapies in high grade gliomas. GSC share with normal NSC common developmental signaling pathways involving a number of pluripotency transcription factors and microRNAs. Hence, overcoming GSC resistance may likely increase neurotoxicity due to damage on normal stem and progenitor cells. David Hsieh [1] discusses how the stem phenotype is maintained in GSC in comparison to NSC as well as the pathogenic mechanisms linked to stem factors in the tumour-driving cells, two important issues for development of GSC-specific and relatively non-toxic drugs. John M. Heddleston and coworkers [2] address the role of the microenvironment in maintenance of GSC phenotype. GSC are often detected in vascularized and hypoxic niches and several factors produced by the perivascular environment, including nitric oxide and some surface molecules or matrix components such as integrins and laminins may feed the GSC tumourigenic phenotype. Hypoxic conditions favour GSC maintenance through promotion of Wnt/β-catenin signaling and acidic conditions have been proposed as well to contribute to GSC-driven malignant progression. The tumour microenvironment is a possible target of therapies aimed to eradicate glioma-driving cells. Ghazaleh Tabatabai and coworkers [3] review preclinical and clinical data on integrins inhibition as a possible therapeutic approach in malignant gliomas. Integrins are a large family of cell surface receptors that mediate the interaction of glioma cells with their microenvironment thus modulating the invasive properties of the tumour. Integrin inhibition by Cilengitide, a cyclic inhibitor binding to the arginine-glycine-aspartic acid (RGD) ligand-binding motif on alphaVbeta3 and alphaVbeta5 integrin receptors is in advanced clinical development and a phase III randomized clinical trial of Cilengitide plus conventional radio- and chemotherapy in GBM patients is ongoing (CENTRIC trial, EORTC26071-22072). The Akt protein is a nodal downstream effector of the RTK/PTEN/PI3K pathway whose deregulation contributes to uncontrolled glioma cell proliferation. Akt is often activated by phosphorylation in GBM tumours where it participates in amplification of growth signals, suppression of apoptosis and tumour progression. Kelli McDowell and coworkers [4] discuss AKT as a possible target for development of novel drugs against glioma progression. A number of AKT inhibitors have been developed and have shown therapeutic properties in animal studies, although none of them has so far advanced to the clinical setting.....