Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 11, Issue 8, 2011

Despite advances in neurosurgical techniques, radio- and chemotherapy, the prognosis of patients with glioblastoma multiforme remains poor. Against this background, more efficacious adjuvant therapies with less toxicity are urgently needed. While molecularly targeted therapy has evolved as a highly rational and specific approach to meet this requirement, preliminary clinical results have fallen short of expectations. Among the reasons for this disappointment is the fact that glioblastoma multiforme is driven by a multitude of differentially activated or silenced signaling pathways with both parallel and converging complex interactions. As a result, the existence of a single molecular key target conferring unconditional and irreplaceable cellular “oncogene addiction” not only for the majority of tumor cells, but also in the majority of glioblastoma patients has not been confirmed in clinical settings and must be considered unlikely. To add to this complexity, lack of sometimes even moderate efficacy of targeted therapy strategies in clinical trials may not necessarily reflect an inappropriate choice of the molecular target itself, but may simply be a consequence of incomplete target inhibition. Therefore, clinical trial designs incorporating molecular in addition to “classical” endpoints will become increasingly important. At the same time, advancement of our currently deficient understanding of what “intrinsic resistance” to targeted therapy really means critically depends on exactly this type of information. It may be expected that bioinformatics research network initiatives will continue to rapidly expand our knowledge of the molecular basis of cancer by defining mutational landscapes and mapping dynamic cross-interactions of multiple signaling pathways. While this undoubtedly represents unprecedented opportunity and challenge in glioblastoma research, the cellular and molecular heterogeneity of glioblastoma is likely to remain a major obstacle to successful implementation of a truly “personalized” therapeutic approach for years and decades ahead. Engaging in this demanding subfield of glioblastoma research may be especially rewarding as some of the future lessons on the basis of “acquired resistance” to targeted therapy will have to be learned by better understanding “heterogeneity”. By merging outstanding contributions of well-recognized experts in their fields, this Special Issue aims at highlighting hopes and disappointments, changes in paradigms and future perspectives of targeted therapy for glioblastoma multiforme. While the dilemma and limitations of monotargeting are comprehensively analyzed by Karpel et al., Sathornsumetee provides valuable insights into the potential of multitargeting. These intracellular approaches are thematically complemented by extracellular strategies involving targeted toxins as described in a state-of-the-art review by Candolfi et al. An impressively broad overview regarding nucleic acidbased therapeutics afforded by Shir and coauthors is extended and specifically elaborated by Rainov and Heidecke in their insightful work on the clinical development of experimental virus-mediated gene therapy. Angiogenesis is of eminent importance to the development, maintenance and progression of glioblastoma, and targeted interference with this complex process has produced sometimes puzzling results. In the maze of targeting angiogenesis, indispensable navigation and guidance is provided by Linkous and Yazlovitskaya.....

Nucleic acid based therapeutics offer the possibility of tailor-made treatment of malignant diseases. For recurrent glioblastoma multiforme (GBM), the most aggressive type of brain tumor, no accepted treatment exists, making therapeutically active nucleic acids a viable option. In this review, current preclinical and clinical studies harnessing the potential of antitumoral nucleic acids for GBM treatment will be considered. These include gene therapy to over-express antitumoral gene products, RNA interference to knock down components that promote tumor progression, and the tumor-targeted delivery of antitumoral double stranded RNA. Vectors applied in GBM for the delivery of nucleic acids will be discussed. These include non-replicating and replicating (oncolytic) viruses, as well as non-viral delivery vectors based on polycations or cationic lipids.

Glioblastoma (GBM), the most common primary brain tumor in adults, is one of the most aggressive human cancers associated with high mortality. Standard treatments following diagnosis include surgical resection, radiotherapy and adjunctive chemotherapy. However, almost all patients develop disease progression following this multimodal therapy. Recent understanding in genomic and molecular abnormalities in GBM has shifted the treatment paradigm towards using molecularly targeted agents. One of the most prominent targets in cancer treatment is kinases, which can be commonly targeted by small molecule inhibitors or monoclonal antibodies. Despite the initial enthusiasm in exploring kinase inhibitors for GBM, first-generation kinase inhibitors that selectively disrupt single kinases have failed to demonstrate clinical benefit in most patients with GBM. Mechanisms of resistance may include genetic heterogeneity with cross-talk and coactivation of multiple signaling pathways, upregulation of alternative signaling cascades, limited drug delivery and existence of highly-resistant cellular subpopulations such as cancer stem cells. One strategy to circumvent this challenge is to target multiple kinases by multitargeted kinase inhibitors or combinations of single targeted kinase inhibitors, both of which have been evaluated in clinical trials for GBM.

Blood vessel formation is a fundamental process that occurs during both normal and pathologic periods of tissue growth. In aggressive malignancies such as glioblastoma multiforme (GBM), vascularization is often excessive and facilitates tumor progression. In an attempt to maintain tumors in a state of quiescence, multiple anti-angiogenic agents have been developed. Although several angiogenesis inhibitors have produced enhanced clinical benefits in GBM, many of these pharmacologic agents result in transitory initial response phases followed by evasive tumor resistance. Thus, a significant need exists for the discovery of novel and effective anti-angiogenic therapies. The development of new molecular-targeted therapeutic strategies is often complicated by the complexity of angiogenic signal transduction. Due to the labyrinthine nature of these signaling pathways, increased production of other angiogenic factors may compensate for the inhibition of key vascular targets like vascular endothelial growth factor (VEGF). Such compensatory mechanisms facilitate vascularization and allow tumor growth to proceed even in the presence of anti-angiogenic agents. This review presents the challenges of targeting the intricate vascular network of GBM and discusses the clinical implications for recent advancements in targeted anti-angiogenic drug therapy.

Glioblastoma multiforme (GBM) is the most common, aggressive, and chemorefractory brain tumor in human adults. Notwithstanding significant discoveries in the elucidation of pathways of molecular signaling and genetics of GBM during the past 20 years there has been no breakthrough in the pharmacological treatment of this high-grade malignancy. We, and others, have previously demonstrated increased expression of βIII-tubulin in GBM asserting a link between aberrant expression of this β-tubulin isotype and a disruption of microtubule dynamics associated either with malignant tumor development de novo, or with progression and malignant transformation of a low-grade glioma into GBM. This article reviews βIII-tubulin as a promising target in the experimental treatment of GBM and examines the potential use of epothilones, a new family of anticancer agents shown to be active in βIII-tubulin-expressing tumor cells, as well as the “double hit” therapeutic concept of tumor cell sensitization to tubulin binding agents (TBAs) by βIII-tubulin silencing. The latest progress regarding the function and potential role of βIII-tubulin in aggressive tumor behavior, cancer stem cells, tumor cell hypoxia, and resistance to taxane-related compounds, is also critically appraised.

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. GBM is very aggressive due to its poor cellular differentiation and invasiveness, which makes complete surgical resection virtually impossible. Therefore, GBM's invasive nature as well as its intrinsic resistance to current treatment modalities makes it a unique therapeutic challenge. Extensive examination of human GBM specimens has uncovered that these tumors overexpress a variety of receptors that are virtually absent in the surrounding non-neoplastic brain. Human GBMs overexpress receptors for cytokines, growth factors, ephrins, urokinase-type plasminogen activator (uPA), and transferrin, which can be targeted with high specificity by linking their ligands with highly cytotoxic molecules, such as Diptheria toxin and Pseudomonas exotoxin A. We review the preclinical development and clinical translation of targeted toxins for GBM. In view of the clinical experience, we conclude that although these are very promising therapeutic modalities for GBM patients, efforts should be focused on improving the delivery systems utilized in order to achieve better distribution of the immuno-toxins in the tumor/resection cavity. Delivery of targeted toxins using viral vectors would also benefit enormously from improved strategies for local delivery.

Advances in medical and surgical treatments in the last decades have resulted in quantum leaps in the overall survival of patients with many types of malignant disease, while survival of patients with malignant gliomas (WHO histological grades 3 and 4) has been only moderately improved. Maximum surgical resection, external fractionated radiotherapy, and oral chemotherapy during and after irradiation currently represent the pillars of malignant glioma therapy. Novel and experimental modalities aimed at a more selective and more effective treatment are however being increasingly developed and tested in clinical studies. Improved understanding of the fundamental mechanisms of glioma growth, resistance, and recurrence has resulted in the introduction of biologically and molecularly targeted therapies such as virus-mediated gene therapy, often in combination with spatially defined delivery methods specifically designed to be used in the local environment of the brain, such as convection-enhanced delivery. This review summarizes the key findings of the most important phase I and II clinical studies employing gene therapy with naturally occurring or genetically modified non-replicating or conditionally replicating (oncolytic) viruses, such as retrovirus, adenovirus, herpes-simplex-virus, Newcastle disease virus, or reovirus, in patients with primary or recurrent malignant gliomas. In addition, the two phase III gene therapy studies carried out to date in glioma patients and employing retrovirus or adenovirus vectors are presented in detail and critically discussed. Areas of necessary improvements and possible future developments of viruses and delivery methods are outlined.

Glioblastoma represents the most common primary brain tumor in adults. Despite improvements of multimodal therapy, the prognosis of this disease remains unfavorable. Thus, great efforts have been made to identify therapeutic agents directed against those specific molecular targets whose presence was shown to be associated with worse clinical outcomes. The epidermal growth factor receptor (HER1/EGFR) has been identified as one such target, and different compounds were developed to inhibit HER1/EGFR and/ or its mutant form, EGFRvIII. However, clinical trials did not confirm the initial enthusiasm conveyed by promising results from experimental studies. Therefore, a therapeutic approach directed at inhibiting solely HER1/EGFR does not seem to translate into a clinical benefit. This review discusses the current therapeutic situation in the setting of glioblastoma while putting the spotlight on erlotinib, a HER1/EGFR-targeted small molecule tyrosine kinase inhibitor.

Data from past research is presented showing that neutrophils are active participants in new vessel formation in normal physiology, in proliferating human endometrium, in non-cancer pathologies as in the pannus of rheumatoid arthritis, and in various cancers, among them glioblastoma. These data show that interleukin-8 (IL-8) is a major chemokine attracting neutrophil infiltrates in these states. Since the old anti-Hansen's disease drug dapsone inhibits neutrophil migration along an IL-8 gradient towards increasing concentrations, and is used therapeutically for this attribute to good effect in dermatitis herpetiformis, bullous pemphigoid and rheumatoid arthritis, we suggest dapsone may deprive glioblastoma of neutrophil-mediated growth promoting effects. We review past research showing that vascular endothelial growth factor, VEGF, is carried predominantly intracellularly within neutrophils- only 2% of circulating VEGF is found free in serum. Based on the available evidence summarized by the authors, dapsone has a strong theoretical potential to become a useful anti-VEGF, anti-angiogenic agent in glioblastoma treatment.

Cancer and many chronic inflammatory diseases are associated with increased amounts of reactive oxygen species (ROS). The potential cellular and tissue damage created by ROS has significant impact on many disease and cancer states and natural therapeutics are becoming essential in regulating altered redox states. We have shown recently that iron content is a critical determinant in the antitumour activity of bovine milk lactoferrin (bLF). We found that 100% iron-saturated bLF (Fe-bLF) acts as a potent natural adjuvant and fortifying agent for augmenting cancer chemotherapy and thus has a broad utility in the treatment of cancer. Furthermore, we also studied the effects of iron saturated bLF's ability as an antioxidant in the human epithelial colon cancer cell line HT29, giving insights into the potential of bLF in its different states. Thus, metal saturated bLF could be implemented as anti-cancer neutraceutical. In this regard, we have recently been able to prepare a selenium (Se) saturated form of bLF, being up to 98% saturated. Therefore, the objectives of this study were to determine how oxidative stress induced by hydrogen peroxide (H2O2) alters antioxidant enzyme activity within HT29 epithelial colon cancer cells, and observe changes in this activity by treatments with different antioxidants ascorbic acid (AA), Apo (iron free)-bLF and selenium (Se)-bLF. The states of all antioxidant enzymes (glutathione peroxidase (GPx), glutathione reductase (GR), glutathione- s-transferase (GsT), catalase and superoxide dismutase (SOD)) demonstrated high levels within untreated HT29 cells compared to the majority of other treatments being used, even prior to H2O2 exposure. All enzymes showed significant alterations in activity when cells were treated with antioxidants AA, Apo-bLF or Se-bLF, with and/or without H2O2 exposure. Obvious indications that the Se content of the bLF potentially interacted with the glutathione (GSH)/GPx/GR/GsT associated redox system could be observed immediately, showing capability of Se-bLF being highly beneficial in helping to maintain a balance between the oxidant/antioxidant systems within cells and tissues, especially in selenium deficient systems. In conclusion, the antioxidative defence activity of Se-bLf, investigated in this study for the first time, shows dynamic adaptations that may allow for essential protection from the imbalanced oxidative conditions. Because of its lack of toxicity and the availability of both selenium and bLF in whole milk, Se-bLF offers a promise for a prospective natural dietary supplement, in addition to being an immune system enhancement, or a potential chemopreventive agent for cancers.

Although major progress has been made in surgery, radiation, and chemotherapy for the treatment of malignancy during the last 20 years, there has been little improvement in the survival of patients with recurrent or advanced head and neck cancer. Because of the ease and accessibility for surgery and their loco-regional biological behavior, head and neck cancers serve as an ideal model to test combined laser energy delivered via interstitial fiberoptics and chemotherapeutic agents activated by photo-thermal energy as an alternative, less invasive treatment for cancer. A number of investigators have shown that anthracyclines and cisplatin are likely candidates for light or heat activation in cancer cells. Maximum tolerated dose followed by photochemical and thermal activation via laser fiberoptics can improve treatment by sensitizing tumor response. The higher intratumor drug levels compared to systemic drug administration along with laser activation should also reduce systemic toxicity. In this article the authors analyze the concept of combining anti-cancer drugs and laser therapy and review the clinical application. In summary, the literature available suggests photochemotherapy with currently approved drugs and lasers may soon become an attractive alternative for cancer treatment.