Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 10, Issue 6, 2010

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.

Induction of caspase-dependent apoptosis (type I cell death) is a major mechanism by which most chemotherapeutic drugs and radiation kill tumor cells. However, conventional cancer therapies fail to mediate their effects in a target-specific fashion. The extremely unfavorable prognosis for patients suffering from glioblastomas (GBMs) is strongly correlated to the intrinsic apoptosis resistance of GBM cells which especially occurs in diffusely migrating tumor cells. The ultimate goal for molecular, apoptosis-based therapies is to target specific components of the two major apoptotic pathways, i.e. the extrinsic and the intrinsic pathway to trigger tumor-selective apoptosis, while at the same time limiting toxicity in normal tissues. Induction of autophagic cell death (type II cell death) by proautophagic drugs is an alternative and emerging concept to trigger glioma cell death and to exploit caspase-independent programmed cell death pathways for the development of novel glioma therapies. This review provides an up to date and comprehensive report on the relevant pre-clinical and clinical drugs interfering with the major apoptosis and autophagy pathways, their therapeutic potential in glioma and adresses potential future perspectives in this exciting field of research.

Cyclooxygenase 2 (COX-2) is frequently found up-regulated during pathological conditions and in cancer, where it is thought to support carcinogenesis and tumor angiogenesis. The development of newer-generation non-steroidal anti-inflammatory drugs (NSAIDs) able to more selectively inhibit cyclooxygenase 2 (COX-2) raised expectations that these agents might be beneficial for cancer prevention and therapy. However, while chemopreventive effects of some selective COX-2 inhibitors have been established, it has remained unpersuasive whether these new NSAIDs, such as celecoxib, rofecoxib or etoricoxib, are able to exert cancer therapeutic effects, i.e., whether they would be beneficial for the treatment of advanced cancers that are already grown and established. This issue was further complicated by findings that celecoxib was able to exert pronounced pro-apoptotic effects in vitro and in vivo in the absence of any apparent involvement of COX-2. In fact, newly synthesized close structural analogs of the celecoxib molecule revealed that it was possible to separate COX-2 inhibitory function from the ability to trigger apoptosis; for example, the analog 2,5-dimethyl-celecoxib (DMC) has lost COX-2 inhibitory function, yet exerts increased cytotoxic potency. This review will summarize pertinent results from the exploratory therapeutic use of NSAIDs, in particular celecoxib, in preclinical and clinical studies of malignant glioma. Several COX-2 independent targets will be presented, and it will be discussed how DMC has helped to delineate their relevance for the surmised COX-2 independent tumoricidal effects of celecoxib.

Immunotherapy of brain tumors is rapidly emerging as a potential clinical option [1-3]. The quality and magnitude of immune responses evoked by the new generation anti-tumor vaccines is in general highly dependent on the source or choice of peptide antigens, and as well, a suitable immunopotentiator. Poorly immunogenic antigens, such as those present in tumor cell lysates, may not reliably provide stimulation like recombinant or DNA-encoded protein antigens might be expected to. In addition, the efficacy of the vaccine may depend on inherent counteracting measures of the tumor which dampen immune surveillance and immune effector activity triggered by immunization [4]. Our body has many means of limiting an immune response to our own (self) proteins. In particular, patients with gliomas exhibit a broad suppression of cell-mediated immunity [5-8]. Unfortunately, for most tumor vaccines the induction of local or systemic immune effector cells does not necessarily translate into objective clinical responses or increased survival [9]. Here we review immunotherapeutic approaches against gliomas and recent pre-clinical and clinical initiatives based on cellular or active immunization of the patient's immune system using autologous and allogeneic tissues or cultured cells. Available evidence shows that single modality cancer therapies likely remain suboptimal. Combination regimens targeting the immune system at multiple coordinated levels must be developed, and possibly combined with strategies to inhibit immune suppressive factors if significant clinical benefit is to be achieved.

Both stem cells and cancer cells are thought to be capable of unlimited self-renewal. Moreover, a small number of cancer cells express stem cell markers, including CD133 and ATP-binding cassette transporters through which the cells can pump out anti-cancer drugs or specific fluorescence dyes such as Hoechst33342, suggesting that either cancer cells resemble stem cells or that cancers contain stem cell-like cancer cells, called cancer-initiating cells (CICs) or cancer stem cells. Using the common characteristics of tissue-specific stem cells, malignant tumors and cancer cell lines were shown to contain CICs, which self-renew and are tumorigenic. CICs are also resistant to both irradiation and chemotherapy. These findings suggest that CICs are critical targets for successful therapy. However, CICs have not been well characterized, due to a lack of specific markers. We recently established mouse glioma-initiating cell (GIC) lines by overexpressing oncogenic HRasL61 in p53-deficient neural cells. These cells form transplantable glioblastoma multiforme (GBM) with features of human GBM when as few as 10 cells are transplanted in vivo, suggesting that these GIC-like cells are enriched in CICs. Characterization of these GICs showed that they expressed little or no Sox11. The overexpression of exogenous Sox11 in GICs blocked their tumorigenesis by inducing their neuronal differentiation, which was accompanied by decreased levels of a novel oncogene, plagl1. These findings suggest that Sox11 and Plagl1 work as a tumor suppressor and oncogene, respectively, in GBM and are potential therapeutic targets.

Obesity has been recognized as an important risk factor for many serious medical conditions. The association of obesity with an increased risk of many cancers is of enormous economic importance to the health industry.The metabolic syndrome and visceral obesity have an increasing prevelance and incidence in the general population.The actual prevelance of the metabolic syndrome is 24% in US population and between 24.6% and 30.9% in Europe. Recent evidence from epidemiologic and basic research studies, as well as clinical and intervention studies, supports the emerging hypothesis that metabolic syndrome may be an important etiologic factor for the onset of cancer. In addition, increased body weight has recently been shown to be associated with an increased risk of cancers at multiple specific sites. The close interaction between cancer cells and adipocytes is an intriguing issue in tumor biology. In nowdays, several metabolic markers are implicated in the development and progression of several malignancies. This review describes the emerging data concerning the role of metabolic markes in tumor cell growth and relates them to their future clinical prospects.

The epidermal growth factor (EGF) receptors, one family of protein tyrosine kinases (PTK), are promising targets for the cancer therapy. Many potential inhibitors including monoclonal antibodies (mAbs), reversible inhibitors and irreversible inhibitors have been developed. Some of them have been approved by the FDA or in the stage of clinical trials. This report reviews the recent progress of the structures, functions and inhibitors of the epidermal growth factor receptor tyrosine kinases.

Arsenic trioxide (ATO) has shown great promise in the treatment of patients with relapsed or refractory acute promyelocytic leukemia (APL). However, the risk/benefit ratios of ATO in hematologic malignancies other than APL are still unclear. In this review, the author attempts to provide current experimental and clinical challenges to gain more knowledge of the effects of ATO by examining combination therapies with other agents, especially for non-APL hematologic malignancies, such as acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphoid leukemia (CLL) and multiple myeloma (MM). The drugs combined with ATO can be roughly classified into (1) signaling inhibitors (imatinib, PD184352, LY294002, 17-Allylamino- 17-demethoxygeldanamycin: 17-AAG), (2) oxidative stress pathway modulators (ascorbic acid, 2-methoxyestradiol: 2-ME, dlbuthionine-[ S,R]-sulfoximine: BSO), (3) a chemotherapeutic drug (melphalan) and (4) others (bortezomib, ATRA). Some of these combination therapies have shown promising results in MM not only at the experimental level but also at the clinical level. However, studies are still ongoing for other non-APL hematologic malignancies. Since ATO is well tolerated and its toxicities are manageable and reversible, cell type-specific and efficient combination therapies with ATO are advantageous for non-APL hematological malignancies and should be developed in the near future.