Current Cancer Drug Targets - Volume 8, Issue 8, 2008

Research into mTOR, mammalian Target Of Rapamycin as an important drug target continues to be extremely interesting, both in terms of the increased molecular knowledge being acquired at the basis of various human diseases, and also for possible applications in drug cancer therapy. The mTOR signaling system plays a key role in several transduction pathways that are necessary for cell cycle progression and cellular proliferation. Drugs known as mTOR inhibitors have been included in ongoing and in recently completed cancer trials. New insights into the mTOR signaling system are helping to clarify the functionality of key mTOR components, and especially their possible role in apoptosis, angiogenesis and tumor progression. Three other molecules, already approved for therapeutic use and being commercialized (Everolimius, Temsirolimus and Zotarolimus) are added to Rapamycin (also known as Sirolimus), the parent drug of the mTOR inhibitors. Of these, only Temsirolimus is currently approved in the treatment of renal cell carcinoma, while the others are approved for organ transplant rejection and coronary artery restenosis. There are at least 10 other molecules currently under development for clinical and preclinical studies. This review offers an updated synopsis of the mTOR signaling system, in particular as regards relevant aspects of cancer research, looks at the known mTOR inhibitors and gives a systematic vision of current trials for each individual molecule subject to clinical investigation.

Induction of immune responses against cancer-associated antigens is possible, but the optimal use of this strategy remains to be established and especially the combination of T cell therapy and the use of new targeted therapeutic agents should be investigated. The design of future clinical studies then has to consider several issues. Firstly, induction of anticancer T cell reactivity seems most effective in patients with low disease burden. Initial disease-reducing therapy including surgery, irradiation and conventional or new targeted chemotherapy should therefore be used, preferably through induction of immunogenic cancer cell death. Secondly, after the induction phase effector T cells will induce cancer cell apoptosis mainly through the intrinsic apoptosis-regulating pathway. The effect of this anticancer immune reactivity should be strengthened by the administration of chemotherapy that mediates additional proapoptotic signalling through the external apoptosis-initiating pathway, blocking of anti-apoptotic signalling or inhibition of survival signalling. Thirdly, conventional chemotherapy and new targeted therapy have direct immunosuppressive effects on the T cell system, but even patients with severe chemotherapy-induced lymphopenia have an operative T cell system and immunotherapy may therefore be initiated immediately or early after disease-reducing therapy when the cancer cell burden is expected to be lowest. Finally, chemotherapy toxicity on human T cells is not a random process, and one should especially focus on the possibility to strengthen anticancer immune reactivity through chemotherapy-induced elimination or inhibition of immunosuppressive regulatory T cells. All these issues need to be considered in the design of future clinical studies combining chemotherapy and immunotherapy.

Drugs that target the vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) pathways have revolutionized the treatment of patients with metastatic renal cell cancer (RCC). Patients with clear cell RCC often have mutations or silencing of the von Hippel Lindau gene leading to an accumulation of HIF 1 alpha. This allows growth factors such as VEGF and PDGF to be upregulated to promote angiogenesis and endothelial stabilization. Both sunitinib and sorafenib target VEGF and PDGF receptor tyrosine kinases while bevacizumab is a monoclonal antibody to VEGF. These three agents have demonstrated superior progression free survival in patients with metastatic RCC when compared to interferon or placebo. Newer anti-VEGF agents such as axitinib, pazopanib and cediranib are currently under investigation to elucidate future treatment options. The mammalian target of rapamycin (mTOR) is downstream of the VEGF pathway and has been targeted with drugs including temsirolimus and everolimus. This review will detail the pharmacologic and molecular activity of these agents and how they translate into clinical efficacy.

Osteosarcoma (OS) is a disease that afflicts teenagers and adolescents in the prime of their lives. In spite of surgery and therapies currently used, there is a 1/3 chance of relapse. As for other cancers, current research is largely devoted to elucidating the molecular basis of the disease, with the anticipation that such research will lead to discovery and development of biological therapies. The major advantage of utilising such therapy is the relative lack of toxicity to normal tissues. One such enterprising candidate molecule, pigment epithelium-derived factor (PEDF), has recently been implicated to be involved in control of OS in orthotopic spontaneously metastasising models of the disease, whether administered as recombinant protein, overexpressed or administered as short peptides derived from the parent molecule. Expression of PEDF is inversely proportional to expression of vascular endothelial growth factor (VEGF) at the growth plate cartilage layer of growing bone in both mice and man. PEDF, originally discovered for its potent antiangiogenic activity, is now established as an anticancer factor with multiple mechanisms at its disposal for tumour inhibition. Current efforts are devoted to develop drug delivery systems, such as controlled release nanoparticles, that can be used to progress this potential drug candidate closer towards clinical trials for OS.

Melatonin exerts oncostatic effects on different kinds of tumors, especially on hormone-dependent breast cancer. The general conclusion is that melatonin, in vivo, reduces the incidence and growth of chemically-induced mammary tumors in rodents, and, in vitro, inhibits the proliferation and invasiveness of human breast cancer cells. Both studies support the hypothesis that melatonin inhibits the growth of breast cancer by interacting with estrogen-signaling pathways through three different mechanisms: (a) the indirect neuroendocrine mechanism which includes the melatonin downregulation of the hypothalamic-pituitary-reproductive axis and the consequent reduction of circulating levels of gonadal estrogens, (b) direct melatonin actions at tumor cell level by interacting with the activation of the estrogen receptor, thus behaving as a selective estrogen receptor modulator (SERM), and (c) the regulation of the enzymes involved in the biosynthesis of estrogens in peripheral tissues, thus behaving as a selective estrogen enzyme modulator (SEEM). As melatonin reduces the activity and expression of aromatase, sulfatase and 17β-hydroxysteroid dehydrogenase and increases the activity and expression of estrogen sulfotransferase, it may protect mammary tissue from excessive estrogenic effects. Thus, a single molecule has both SERM and SEEM properties, one of the main objectives desired for the breast antitumoral drugs. Since the inhibition of enzymes involved in the biosynthesis of estrogens is currently one of the first therapeutic strategies used against the growth of breast cancer, melatonin modulation of different enzymes involved in the synthesis of steroid hormones makes, collectively, this indolamine an interesting anticancer drug in the prevention and treatment of estrogen-dependent mammary tumors.

Chemoprevention by dietary and pharmacological means provides a strategy for attenuating the health risks resulting from cigarette smoking and in particular from passive exposure to environmental cigarette smoke (ECS). We evaluated the ability of the glucocorticoid budesonide and of the natural agent phenethyl isothiocyanate (PEITC) to affect DNA damage in bronchoalveolar lavage (BAL) cells of CD-1 mice exposed to ECS, starting within 12 h after birth and continuing until the end of the experiment. After weanling, based on a preliminary subchronic toxicity study, groups of mice received daily either budesonide (24 mg/kg diet) or PEITC (1,000 mg/kg diet). After 2 weeks of treatment, all mice were sacrificed and subjected to BAL, mainly recovering pulmonary alveolar macrophages. Evaluation of single-cell DNA strand breaks was made by using the alkaline-halo test, a modification of the comet assay. The analysis of 481 BAL cells yielded the following results (expressed as nuclear spread factor): (a) Sham-exposed mice: mean 0.84 (lower-upper 95% confidence intervals 0.74-0.94); (b) ECS-exposed mice: 2.77 (2.46-3.09); (c) ECS-exposed mice treated with PEITC: 1.15 (1.05-1.26); (d) ECS-exposed mice treated with budesonide: 1.37 (1.25-1.49). Thus, exposure to ECS resulted in a significant increase of DNA damage as compared with sham, and both PEITC and budesonide significantly attenuated this damage. In conclusion, the analysis of sentinel cells collected by BAL, a semi-invasive technique that is commonly used in humans for diagnostic purposes, showed that the investigated chemopreventive agents are able to revert the DNA damage produced by passive exposure to cigarette smoke.

Choline Kinase (ChoK) comprises a family of cytosolic enzymes involved in the synthesis of phosphatidylcholine (PC), the most abundant phospholipid in eukaryotic cell membranes. One of the ChoK isoforms, Choline Kinase α (ChoKα), is found over expressed in human tumours. Chemical inhibitors able to interfere with ChoK activity have proven to be effective antitumoral drugs in vitro and in vivo. To validate the use of selective ChoKα inhibitors in cancer therapy, we have developed a genetic strategy to interfere specifically with ChoKα activity based on the generation of a shRNA against the alpha isoform of ChoK. Here we demonstrate that specific inhibition of ChoKα by shRNA has antitumor activity. The specific depletion of ChoKα induces apoptosis in several tumor-derived cell lines from breast, bladder, lung and cervix carcinoma tumors, while the viability of normal primary cells is not affected. Furthermore, this selective antiproliferative effect is achieved both under in vitro and in vivo conditions, as demonstrated by an inducible ChoKα suppression system in human tumour xenografts. These results demonstrate that ChoKα inhibition is a useful antitumoral strategy per se, and provides definitive and non-ambiguous evidence that ChoKα can be used as an efficient and selective drug target for cancer therapy.

The A Disintegrin And Metalloprotease (ADAM) proteins belong to the metzincin-superfamily of Zndependent metalloproteinases that shed the extracellular domains of membrane-bound growth factors, cytokines and their receptors. The latter play a central role in cell signaling and contribute a potential target in cancer therapy. Of particular interest are the ErBB/HER family of growth factor receptors associated with elevated intrinsic tyrosine kinase activity. Overexpression of ADAMs and cell signaling components have also been implicated in the development and progression of a variety of tumor types. Emerging evidence has suggested that the ADAM proteins are involved in tumour cell proliferation, in angiogenesis as well as metastasis. Therefore, strategies targeting ADAMs may constitute an important target for the design of cancer drugs. The review will focus on current understanding of the role of ADAM in the physiological and pathological functions associated with cancer. It is the intention of the review to provide insights which may assist in the development of ADAM-based approaches for the treatment of human cancers.

The development of targeted therapies with true specificity for cancer relies upon exploiting differences between cancerous and normal cells. Genetic and genomic alterations including somatic mutations, translocations, and amplifications have served as recent examples of how such differences can be exploited as effective drug targets. Small molecule inhibitors and monoclonal antibodies directed against the protein products of these genetic anomalies have led to cancer therapies with high specificity and relatively low toxicity. Recently, our group and others have demonstrated that somatic mutations in the PIK3CA gene occur at high frequency in breast and other cancers. Moreover, the majority of mutations occur at three hotspots, making these ideal targets for therapeutic development. Here we review the literature on PIK3CA mutations in cancer, as well as existing data on PIK3CA inhibitors and inhibitors of downstream effectors for potential use as targeted cancer therapeutics.

Neuronal cell specific cyclin-dependent kinase 5 (Cdk5) is a known regulator of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. We report that Cdk5 also plays an important role in the proliferation of breast cancer cells MCF-7 and MDA MB-231 and is functionally involved in chemosensitivity as well as in cell death pathways induced by anti-cancer drug carboplatin (Carb). Here, we demonstrate that carboplatin induced Cdk5 activation under positive regulation of ERK, promotes cell death in MCF-7 and MDA MB-231 cells. DNA-damage stress enhanced ERK activity utilizes Cdk5 as one of its downstream targets for the execution of death signal in carboplatin induced death in MCF-7 and MDA MB-231 cells. Additionally, present data clearly indicates that activated Cdk5 modulates p53 transactivation in MCF-7 cells. However, in p53 mutant MDA MB-231 cells, Cdk5 mediated cell death is likely to be p53 independent. Collectively, our findings not only draw attention to the extra-neuronal functions of Cdk5 but also propose Cdk5 as a novel and potential therapeutic target of chemotherapeutic drugs.

Purpose: Inhibition of COX-2 enzymes is a frequently suggested mechanism for the beneficial effects of NSAIDs on carcinogenesis. The aim of this study was to explore the role of cumulative NSAID use on four common nonskin related cancers and modification by COX-2 G^-765C genotype. Patients and methods: 7621 participants of The Rotterdam Study were included. In a mean follow up period of 10 years, 720 colorectal, lung, breast or prostate cancers occurred. Cumulative NSAID use was calculated per NSAID class. Individual associations of NSAID use and COX-2 G^-765C genotype on cancer risk were explored with Cox' proportional hazard models. Next, the association of NSAIDs and cancer stratified by COX-2 genotype was studied. Finally, the effect of combinations of NSAID use and COX-2 genotype on survival times was investigated. Conclusion: Our results confirm the protective effect of NSAID use on colorectal cancer. Individuals diagnosed with colorectal cancer who carry a COX-2 C^-765 allele and are on NSAIDs have an increased survival in comparison to non-users with the wild type ^-765.

Due to an oversight on the part of the authors, Agelopoulos, K.; Buerger, H.; Brandt, B. The following acknowledgement section was unintentionally left out in the published review entitled “Allelic Imbalances of the egfr Gene as Key Events in Breast Cancer Progression - the Concept of Committed Progenitor Cells”, Current Cancer Drug Targets, August 2008, Vol. 8(5), pp. 431-445.