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

Glioblastoma multiforme (GBM), the most common and deadliest brain cancer in adults, is among the least responsive human cancers to therapy. This dismal prognosis has not been significantly improved in the past decades, despite considerable advance made in the biological understanding of GBM. To address this clinical problem, much effort has been invested in identifying and targeting novel molecular targets and pathways that are critical for GBM biology. Many new therapeutic approaches have been exploited to improve clinical outcome of GBM. The objective 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. Specifically, the Part II of this special issue includes four excellent comprehensive review articles with each covering a unique area of GBM research and therapeutics. The review article by Liu and Lin is focused on signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor that is constitutively activated in many human cancers. In recent years, activated STAT3 has been shown to be detected in the majority of GBM tumors and cell lines, playing an essential role in the growth, progression and therapeutic response of GBM cells. STAT3 is also implicated in GBM stem cell biology, as reported by several recent studies. Concurrent with these biological analyses, various preclinical studies have been conducted to examine anti-STAT3 treatments for their ability to suppress GBM growth and to sensitize GBM to chemotherapy. Consequently, much enthusiasm has been generated in this very active field of GBM research. The article by Liu and Lin, therefore, provides an in-depth, timely overview of the nature of the STAT3 pathway, including its upstream regulators and downstream target genes, the pathological impact of STAT3 activation on GBM, and the outcome of various pharmacological approaches that have been developed to target STAT3. Radiation therapy and DNA-damaging chemotherapeutic agents are among the leading treatments for GBM patients. Unfortunately, tumor resistance to these therapies is not uncommon and this is largely attributed to the intrinsic ability of GBM cells to repair therapyinduced DNA damage. The article by Anthony Chalmers summarizes the molecular pathways that mediate tumor response to DNA damage with a major focus on the DNA repair enzyme poly(ADP-ribose) polymerase (PARP). PARP-1 is abundantly expressed in cells, binds to both single and double stranded DNA breaks, and is associated with tumor resistance to DNA-damaging therapies. To overcome this resistance, a number of PARP inhibitors have been developed with several of them being tested in early phase clinical trials. Therefore, Chalmers has assembled a comprehensive review that covers recent promising results showing that combining the PARP inhibitors with chemotherapy and radiotherapy could be an effective strategy that targets GBM. Natural products have been extensively exploited for their preventative and therapeutic effects on various human cancers. Tetrandrine, a bis-benzylisoquinoline alkaloid derived from the Chinese medicinal herb Stephania tetrandra S, has attracted much attention because of its ability to block calcium channel, promote apoptosis and cell-cycle arrest, and to induce oxidative stress. Tetrandrine appears to also affect a number of other physiological processes, such as, immune response and angiogenesis. Importantly, tetrandrine has been recently investigated for its anti-GBM activity and the results were encouraging. In this special tissue, Chen and Tseng provide a timely review on the role and mechanisms of tetrandrine as a sensitizing agent for radiotherapy and chemotherapy in GBM. High degrees of invasiveness and motility are major characteristics of GBM that prevent the tumor from complete resection and this allows for recurrence. Gaining a greater understanding of the molecular pathways that drive GBM invasion and migration will help develop therapeutic strategies that minimize GBM infiltration and thereby, will enable successful surgical removal of the tumor mass. As the final article of this special issue, Adamson and colleagues provide an excellent update on some of the molecular pathways that have been shown to promote GBM cell migration, such as, those mediated by integrins, EGFR, c-Met, PI-3K, PDGFR, VEGF and MMPs. In this review, the authors also summarize the outcome of various preclinical and clinical studies that were designed to target these migration-associated pathways. The four papers summarized above represent the Part II of the thematic issue and also conclude this special tissue of “Anti-Cancer Agents in Medicinal Chemistry”. The eight articles included in this issue, together, have covered an array of different fields of cancer research and treatments. Collectively, more than one thousand studies have been cited which indeed represents the tremendous effort that the contributors have invested in their articles. For this, I would like to express my gratitude to all the contributing authors for their time and outstanding effort. As to the readers, it is my sincere hope that our literature reviews and personal perspectives will introduce you to an exciting area of cancer research and also inspires you to join us in filling the knowledge gaps of one of the deadliest human malignancies and in developing more effective treatments for this devastating disease.