Current Pharmaceutical Design - Volume 17, Issue 23, 2011

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.....

The discovery of discrete functional components in cancer systems advocates a paradigm shift in therapeutic design towards the targeted destruction of critical cellular constituents that fuel tumorigenic potential. In astrocytomas, malignant growth can be propagated and sustained by glioma stem cells (GSCs) endowed with highly efficient clonogenic and tumor initiation capacities. Given their disproportionate oncogenic contribution, GSCs are often considered the optimal targets for curative treatment because their eradication may subvert the refractory nature of GBMs. However, the close affinity of GSCs and normal neural stem cells (NSCs) is a cautionary note for off-target effects of GSC-based therapies. In fact, many parallels can be drawn between GSC and NSC functions, which ostensibly rely on a communal collection of stem cell-promoting transcription factors (TFs). Only through rigorous scrutiny of nuances in the stemness program of GSCs and NSCs may we clarify the pathogenic mechanisms of stemness factors and reveal processes exploited by cancer cells to co-opt stem cell traits. Importantly, discerning the specific requirements for GSC and NSC maintenance may be an essential requisite when assessing molecular targets for discriminatory targeting of GSCs with minimal sequelae.

Glioblastomas are highly lethal cancers for which conventional therapies provide only palliation. The cellular heterogeneity of glioblastomas is manifest in genetic and epigenetic variation with both stochastic and hierarchical models informing cellular phenotypes. At the apex of the hierarchy is a self-renewing, tumorigenic, cancer stem cell (CSC). The significance of CSCs is underscored by their resistance to cytotoxic therapies, invasive potential, and promotion of angiogenesis. Thus, targeting CSCs may offer therapeutic benefit and sensitize tumors to conventional treatment, demanding elucidation of CSC regulation. Attention has been paid to intrinsic cellular systems in CSCs, but recognition of extrinsic factors is evolving. Glioma stem cells (GSCs) are enriched in functional niches-prominently the perivascular space and hypoxic regions. These niches provide instructive cues to maintain GSCs and induce cellular plasticity towards a stem-like phenotype. GSC-maintaining niches may therefore offer novel therapeutic targets but also signal additional complexity with perhaps different pools of GSCs governed by different molecular mechanisms that must be targeted for tumor control.

The tumor environment is critical for tumor maintenance and progression. Integrins are a large family of cell surface receptors mediating the interaction of tumor cells with their microenvironment and play important roles in glioma biology, including migration, invasion, angiogenesis and tumor stem cell anchorage. Here, we review preclinical and clinical data on integrin inhibition in malignant gliomas. Various pharmacological approaches to the modulation of integrin signaling have been explored including antibodies and peptide- based agents. Cilengitide, a cyclic RGD-mimetic peptide of αvβ3 and αvβ5 integrins is in advanced clinical development in glioblastoma. Cilengitide had only limited activity as a single agent in glioblastoma, but, when added to standard radiochemotherapy, appeared to prolong progression-free and overall survival in patients with newly diagnosed glioblastomas and methylation of the promoter of the O6 methylguanine methyltransferase (MGMT) gene. MGMT gene promoter methylation in turn predicts benefit from alkylating chemotherapy. A phase III randomized clinical trial in conjunction with standard radiochemotherapy in newly diagnosed glioblastoma patients with MGMT gene promoter methylation has recently completed accrual (EORTC 26071-22072). A companion trial explores a dose-escalated regimen of cilengitide added to radiotherapy plus temozolomide in patients without MGMT gene promoter methylation. Promising results in these trials would probably result in a broader interest in integrins as targets for glioma therapy and hopefully the development of a broader panel of anti-integrin agents.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. The treatment options for patients diagnosed with GBM are limited and the current median survival is 14-16 months following diagnosis. Genetic mutations have been identified that act as drivers of GBM growth and these should be considered as a basis for identifying novel therapeutic strategies. AKT is a downstream serine/threonine kinase in the RTK/PTEN/PI3K pathway and large scale genomic analysis of GBM has demonstrated that this pathway is mutated in the majority of GBMs. This RTK/PTEN/PI3K pathway leads to activated AKT and phospho-AKT levels are elevated in the majority of GBM tumor samples and cell lines, which studies show help glioma cells grow uncontrolled, evade apoptosis, and enhance tumor invasion. AKT represents a nodal point in this pathway which allows for amplification of growth signals, thereby making inhibition of AKT an attractive target for GBM therapy. Many different classes of AKT inhibitors exist, however, few have been tested sufficiently to demonstrate in vivo efficacy. This article will summarize the key components of the Akt pathway with special attention to gliomas, the genetic alterations driving this pathway in gliomas, and the studies evaluating inhibitors of this pathway. Inhibitors of the Akt pathway represent a potential treatment option against GBM and additional research efforts are required to fully explore and develop this possible treatment strategy.

Cancer metabolism has gained considerable interest, since significant studies have indicated a close relationship between the activation of various oncogenes and alterations of cellular metabolism. Furthermore, several lines of evidence have shown that metabolic imaging can significantly impact malignant glioma patient management and monitoring of tumor response to therapy. In this context, mitochondria play a central role in cellular energy production, apoptosis and free radical generation. Mitochondrial malfunctions have been associated with development of many cancers, including brain tumors. Glioblastoma multiforme (GBM) is the most common primary intracranial neoplasm and its almost uniform lethality is exemplified by a median survival of 12-15 months. Current management consists of a combination of surgery, radiotherapy and chemotherapy. Despite aggressive treatment approaches, recurrence occurs in 90% of GBM patients. One cause of this poor outcome is development of a multidrug-resistance (MDR) phenotype. We and others have described in detail the bioenergetic pathways central to glioma growth and progression. One of the most striking observations is that glioma cells which rely on glycolytic metabolism readily adapt to bioenergetic stress by engaging their mitochondrial pathway in order to survive and grow. This suggests that mitochondrial function plays a critical role in the biology of gliomas. Still, the role that mitochondrial function has in development of chemoresistance in malignant brain tumors is largely unknown. Our goal in this review is to describe the current knowledge on the role of mitochondria function in the development of chemoresistance in glioma. Particular emphasis will be on ABC transporters. We will discuss the significance of these research areas in the context of development of more effective, targeted therapeutic modalities and diagnostic strategies for malignant glioma patients.

The endoplasmic reticulum (ER) stress response represents a cellular “yin-yang” process, where low to moderate activity is cell protective and supports chemoresistance (yang), but where more severe conditions will aggravate these mechanisms to the point where they abandon their protective efforts and instead turn on a cell death program (yin). Because tumor cells frequently experience chronic stress conditions (due to hypoxia, hypoglycemia, acidification, etc.), the protective yang components of their ER stress response are continuously engaged and thus less able to neutralize additional insults taxing the ER stress response. This tumor-specific situation may provide therapeutic opportunities for pharmacologic intervention, where further aggravation of ER stress would lead to the activation of pro-apoptotic yin components and result in tumor cell death. This review will describe the yin-yang principle of ER stress, and will present pharmacologic agents and combination strategies aimed at exploiting the ER stress response for improved therapeutic outcomes, particularly in the setting of difficult to treat tumor types such as glioblastoma.

Glioblastoma (GBM) is a deadly tumor, which in spite of surgery and radio/chemotherapy frequently undergoes relapses related to the infiltration of the normal parenchyma and to resistance to cytotoxic and radiation therapy. Immunotherapy may represent a promising approach, which may complement existing therapies with the aim of eliminating residual tumor cells, through their selective targeting by immune effector cells or antibodies. This goal can be achieved through different approaches, based either on the induction of an immune response of the host, or by the injection of in vitro generated effector cells or monoclonal antibodies. Recent advances in the immunobiology of GBM and of its stem cell compartment will help in the development of more effective immunotherapy protocols. To this aim, the identification of antigens and receptors involved in GBM/immune cell interactions and of GBM immune escape mechanisms will provide new targets and tools. In this review we will discuss active immunotherapy approaches, including molecular-defined, GBM cell-based and dendritic-cell based vaccines. In addition, cytokines such as interferons and several interleukins can be used to enhance the immune response, both as recombinant molecules and by gene transfer technologies. Monoclonal antibodies or other ligands specific for GBM- or neovasculature-associated targets are now available in different genetically modified formats and can be used as such or for the targeted delivery of active compounds. Finally the in vitro activation and expansion of specific or innate immunity effector cells endowed with anti-GBM properties may provide an additional weapon for adoptive imunotherapy approaches.

High-grade gliomas, including glioblastoma, are among the most malignant and treatment-refractory human neoplasms. The tumors show high levels of resistance to conventional therapies (i.e. surgery, irradiation, and chemotherapy), and despite treatment advances patient outcome remains poor. New therapeutic options are needed. An especially interesting idea is the rational development of new therapies targeting molecules in cancer specific signaling pathways, thereby ideally increasing treatment efficacy and minimizing toxicity. Clearly, rational design requires thorough understanding of the molecular pathogenesis and resistance mechanisms. One highly promising approach is the targeted inhibition of ErbB growth factor receptors, which are recognized as key signaling pathways in many types of human tumors, including high-grade glioma. The ErbB receptor family of tyrosine kinases comprises four members: epidermal growth factor receptor (EGFR/ErbB1/HER1), ErbB2 (HER2/neu), ErbB3 (HER3) and ErbB4 (HER4). Physiologically, signaling is induced by ligand initiated receptor homo- or heterodimerization, activating intracellular downstream signaling pathways and leading to increased cell proliferation, anti-apoptosis and migration. A truncated, constitutively activated mutant EGFR (EGFRvIII) is associated with poor survival in GBM. Thus, to date anti-ErbB approaches are mainly focused on EGFR. The two major classes of anti-ErbB therapeutics are monoclonal antibodies (e.g. cetuximab, panitumumab) and small molecule Tyrosine kinase inhibitors (TKI, e.g. gefitinib, erlotinib, lapatinib). Some compounds entered clinical trials already, but clinical efficacy needs to be enhanced. Here we review current therapeutic advances targeting ErbB receptors in high-grade gliomas, and give a concise overview on current understanding of ErbB biology in gliomas, paving the way to novel rational therapeutic development.