Current Cancer Drug Targets - Volume 7, Issue 3, 2007

Glycogen synthase kinase (GSK) was initially described as a key enzyme involved in glycogen metabolism. However, since that time it has been found to regulate a diverse range of cell functions. In addition to having a major role in the regulation of the important onco-protein β-catenin, GSK is also a critical regulator of NF-κB. NF-κB comprises a family of transcription factors which activate the expression of a wide array of genes involved in inflammation, tumourigenesis, metastasis, differentiation, embryonic development, apoptosis . Inflammation mediated by the NF-κB family has been implicated in the initiation of pancreatic cancer, resistance to chemotherapy and the development of the debilitating cancer cachexia seen with advanced disease. Hence, GSK has potential as an important new target both in the treatment of resectable pancreatic cancer as an adjuvant to surgery, and in the palliation of inoperable tumours.

S100A4 (also known as Mts1, metastasin, p9Ka, pEL98, CAPL, calvasculin, Fsp-1, placental calcium-binding protein) belongs to the family of EF-hand calcium-binding proteins, whose expression is elevated in a number of pathological conditions. Although it is well documented that S100A4 is expressed in cancer cells and contributes to tumor cell motility and metastatic progression, the exact underlying mechanisms remain elusive. An important characteristic feature of S100 proteins is their dual function, inside and outside the cell. In this review, we focus on the intracellular function of S100A4. The review contains structural analysis of S1004 in comparison with other members of S100 proteins. Possible modes of the interaction of S100 proteins with targets are described. Several examples of best-studied molecular interactions involving S100A4 with heavy chain of nonmuscle myosin IIA, LARinteracting protein liprin β1 and tumor suppressor protein p53 are provided. We suggest that the binding of S100A4 to these molecules is critical for the S100A4 function. Further studies of the implications of these interactions in different molecular pathways may shed additional light on the role of S100A4 protein in the control of tumor cell motility and migration. We discuss the approaches for down-regulation of S100A4 expression and their potential for application in the clinics.

One of the older and most validated cancer treatments is endocrine therapy. Some tumors are dependent on hormone stimulation for growth, and therefore therapeutic interventions aiming to deprive the cells of the hormone are feasible and have been successful. Tumor growth also depends in some cases on growth factors, so that the concept of hormone-dependence can be extended to growth factors deprivation. Hormone deprivation has been therapeutically achieved up to now by surgical, radiation and chemical means. However, the immune system usually can be manipulated to recognize hormones and growth factors, and in fact some autoimmune diseases exists involving autoantibodies against hormones. The idea of inducing a deprivation of hormones and growth factors by active immunizations is appealing, and initial evidence about the feasibility of this approach is starting to appear in the literature. Clinical trials have been initiated using immunization with human chorionic gonadotrophin (hCG), gastrin, luteinizing hormone releasing hormone (LHRH) / gonadotropin releasing hormone (GnRH) and epidermal growth factor (EGF). Preliminary data already show that antibody titers can be elicited, which results in a decrease in the concentration of a given hormone or growth factor. Both the antibody titers and the decrease in the hormone level are related to survival. This immunological approach for hormone and growth factor deprivation creates the possibility of chronic management of advanced cancer patients.

Non-homologous DNA end joining (NHEJ) is the major pathway for the repair of double-strand breaks (DSBs) in human cells. Proteins involved in NHEJ pathway can become molecular targets in the treatment of cancer. Inhibition of this pathway leads to radio- and chemosensitization of cancer cells. This review will focus on the new therapeutic strategies for NHEJ pathway inhibition and their application in anticancer therapy.

The phenylaminopyrimidine-derivate Imatinib mesylate has been developed for targeted inhibition of the Abelson kinase (c-ABL), which is constitutively activated when translocated to the genetic locus of the breakpoint cluster region (leading to the BCR/ABL fusion gene), thereby forming the causative pathogenetic event for the development of chronic myeloid leukemia (CML). Of note, due to its physico-chemical properties, kinase specificity of Imatinib is limited. Despite of its well documented clinical efficacy mediated by inhibition of constitutively activated tyrosine kinases such as BCR/ABL in CML, PDGF-RA in HES and mutated c-kit in GIST patients, other tyrosine kinases such as Flt-3, Lck and mitogen-activated kinases (MAPK) are affected as well. Accordingly, it has recently been shown that therapeutic doses of Imatinib also target a variety of immune cells, e.g. by modulating the differentiation of dendritic cells (DC) as well as by impeding proper T-cell and macrophage function. In contrast, combining Imatinib with Interleukin 2 (IL-2) potently activates NK-cells and led to the description of a new subclass of DC, so-called IK-DC. The latter mediate Imatinib/IL-2-induced regression of tumors in pre-clinical animal models via production of high amounts of IFN-γ and the death receptor ligand TRAIL. Thus, Imatinib exerts potent immuno-modulatory effects in vitro and in vivo, which will be discussed together with their clinical relevance in detail throughout this review.

Prostate cancer (CaP) is one of the most common malignancies in men, and the incidence of CaP is increasing. Because of the limitations of current therapeutic approaches, many patients die of secondary disease (metastases). Mucins are used as diagnostic markers as well as therapeutic targets due to their aberrant and unique expression pattern during cancer progression. There is a growing interest in mucins as treatment targets in human malignancies, including CaP. So far, 21 mucin genes have been identified. Of these, MUC1 has been investigated most extensively. In neoplastic tissues, MUC1 is underglycosylated compared with that in normal tissues. The reduced glycosylation permits the immune system to access the peptide core of the tumor-associated underglycosylated MUC1 antigen (uMUC1) and reveal epitopes that are masked in the normal cell. This feature makes it possible to design an antibody that discriminates between normal and adenocarcinoma cells and target tumor-associated MUC1 with toxins or radionuclides, or use a vaccine targeting tumor-associated MUC1 antigen. The results from our recent study have shown that over-expression of MUC1 plays a very important role in CaP progression and MUC1 is an ideal target for targeted therapy to control micrometastases and hormone refractory disease. This review will cover our current understanding of the structure and functions of MUC1, summarize its expression on human CaP tissues and focus on the MUC1-based immunotherapy for control of metastatic CaP.

With the beginning of the 21st century, a new and exciting era for cancer therapy has begun with the appearance of molecular targeted drugs. Numerous drugs for chemotherapy have been discovered following careful screening of natural and synthetic components. After screening, candidate chemotherapy drugs are examined to determine if they have sufficiently cytotoxic to function as an anti-tumor therapeutic. However, the development of molecular targeted drugs is based on more logical methodologies. First, the target is determined then a search is conducted for molecules able to inhibit the target molecule. Some molecular targeting drugs, such as Glivec (Imatinib, STI571), have shown amazing effects when compared to currently used chemotherapy drugs, whereas few others have completely failed to inhibit tumor development in clinical trials. Thus, an efficient method for finding effective molecular targeted drugs is needed. An important question is whether the target molecule is responsible for tumor growth or metastasis. In addition, the clinical administration schedule must be suitable for the component used. The drugs will not be completely successful in clinical trials if any of the key points are overlooked. Translational studies are necessary for a complete evaluation of molecular targeted drugs and, based on the results observed in clinical applications, the testers must return to their basic laboratory if necessary and improve the drugs for more advanced therapy. In this review we discuss on the current and future status of molecular target drugs.

Replication-conditional, oncolytic adenoviruses are emerging as powerful tools in the warfare on cancer. The ability to modify cell-specific infectivity or tissue-specific replication machinery, as well as the possibility of modifying viral-cellular protein interactions with cellular checkpoint regulators are emerging as new trends in the design of safer and more effective adenoviruses. The integration of oncolytic adenoviruses with mainstream cancer therapies, such as chemotherapy and radiotherapy, continues to yield significant therapeutic benefits. Adenoviruses can be armed with prodrug-activating enzymes as well as tumor suppressor genes or anti-angiogenic factors, thus providing for enhanced anti-tumor therapy and reduced host toxicity. Thus far, encouraging results have been obtained from extensive preclinical and human clinical studies. However, there is a need to improve adenoviral vectors to overcome unresolved problems facing this promising anti-cancer agent, chief among these issues is the adenovirus-triggered immune response threatening its efficacy. The continued expansion of the knowledge base of adenovirus biology will likely lead to further improvements in the design of the ideal oncolytic adenoviruses for cancer treatment.