Editorial [Hot Topic: Emerging Therapeutic Targets and Agents for Glioblastoma Therapy - Part I (Guest Editor: Hui-Wen Lo)]

Glioblastoma multiforme (GBM) is the most common brain cancer in adults and one of the deadliest human malignancies. Prognosis for these patients remains dismal and has not been significantly improved in the past decades. Specifically, most GBM patients survive only one year after diagnosis and rarely live longer than two years. This poor prognosis is largely due to our insufficient understanding of the complex nature of GBM, thus making it difficult to design and develop more effective treatments for the patients. Another major factor contributing to the unfortunate clinical outcome is that GBM is highly refractory to various therapies and the mechanisms underlying this resistance are still not well understood. To address these knowledge gaps and unmet clinical needs, much effort has been invested in identifying and targeting novel molecular targets and pathways that are critical for GBM biology. Consequently, a number of new therapeutic approaches have been exploited and have yielded promising results with some of them in early phases of clinical trials. The goal of this special issue, therefore, is to summarize some of these exciting findings and to highlight emerging therapeutic targets and approaches for the treatment of GBM patients. GBM is highly resistant to various therapies that supposedly induce intrinsic (mitochondrial) apoptosis. This resistance has been shown to be attributed to the ability of GBM cells to overexpress and activate several prosurvival proteins, such as, anti-apoptotic members of the Bcl-2 family of proteins, inhibitors of apoptosis (IAPs) and mTOR, as well as, to inactivate proapoptotic genes, such as, the p53 tumor suppressor. To overcome the intrinsic ability of GBM to escape apoptosis, therapeutic activation of apoptosis and autophagy has emerged as a new class of anti-cancer approach that possesses the potential to sensitize GBM to various therapies. Within this context, in the first article in this special issue, Kogel and colleagues provide a timely and comprehensive report on the agents that activate components of the apoptotic and autophagic pathways. Kogel et al also summarize the molecular pathways that antagonize apoptosis and detail the therapeutic interventions designed to overcome this antagonism. Cyclooxygenase 2 (COX-2) is frequently overexpressed in human cancers, including, GBM. Consequently, COX-2 has been regarded as an important target of anti-cancer therapy. To this end, a new generation of non-steroidal anti-inflammatory drugs (NSAIDs) has been developed to selectively inhibit COX-2. However, increasing amount of evidence indicates that some of these NSAIDs can potentially produce life-threatening side effects because of their inhibitory effect on COX-2. To overcome this unwanted normal tissue toxicity, a number of groups have developed derivatives of NSAIDs that exert potent apoptotic and cytotoxic effects against cancer cells but lacks anti-COX-2 activity that results in unwanted side effects on normal tisssues. The results of these studies are comprehensively summarized by Dr. Schonthal in the second article in this special issue. For example, the structural analog of celecoxib, 2,5-dimethyl-celecoxib (DMC) has been shown to lose the COX-2 inhibitory function and exert increased cytotoxic activity against malignant gliomas. Indeed, these agents represent a new class of promising COX-2-independent anti-cancer agents that are with less risk but with higher potency towards cancerous cells. Immunotherapy has become an active area of GBM research and an emerging treatment option for patients with GBM. In the third article in this special tissue, Hofman and colleagues comprehensively describe the history, progression and current status of various anti-GBM immunotherapies. The review also summarizes the results of recent clinical trials, including, systemic immunotherapy using dendritic cells or peptide vaccines that have been reported to induce an immune response in malignant glioma and prolong patient survival. Like the vaccine therapy, understanding and targeting glioma stem cells research constitute an exciting area of GBM research. In the fourth article by Dr. Kondo, a timely overview is provided to cover recent advances made in the identification of new biomarkers that define glioma stem cells and in the creation of appropriate models that allow for characterization of these cells. These advances are significant in the context of GBM therapy because they could lead to therapeutic interventions that target GBM stem cells, a small subpopulation of the tumor cells that has been shown to be highly resistant to radiation therapy and chemotherapy. The four papers summarized above represent the Part I of the thematic issue that is focused on emerging new treatments for GBM that are currently under pre-clinical development and clinical evaluation. Additional four outstanding reviews will be included in the Part II of this special issue of Anti-cancer Agents in Medicinal Chemistry and they will be directed at emerging targeted therapy for GBM. Without a doubt, it is my hope as well as those of the contributors to this special issue that our literature review and personal perspectives have introduced the readers to an exciting area of cancer research and have inspired scientists and clinicians to join us in gaining a greater understanding of one of the deadliest human malignancies and in developing more effective treatments for the disease.