Current Cancer Therapy Reviews - Volume 5, Issue 3, 2009

Casein Kinase I η (CKIη) and Casein Kinase I δ (CKIδ) are Serine/Threonine Kinases that have been implicated in several human conditions and have been receiving increasing attention as potential therapeutic targets. Recent findings in gastrointestinal cancers strengthen this notion and suggest that they may also play important roles in both colon cancer and pancreatic cancer, which are among the most common and deadly cancers affecting both men and women. In this short review, we summarize up to date what is known about these two kinases and their involvement in carcinogenesis and other pathological conditions. Our emphasis is on their implications in gastrointestinal cancers and their potential for screening and cancer therapy.

The second law of thermodynamics does not allow us to make entropy barriers, but it does not exclude changing the direction of some particular components of entropy flow from a tumour to the normal tissues. The reversal of entropy flow in co-existing normal and tumour tissues may halt tumour development due to reversed signal transmission in the tumour-host entity. This thermodynamic approach may help in the design of cancer therapy. Different pathways are involved in the de-regulation of cell proliferation leading to cancer. Although many signalling and genomic approaches have been successfully identified, a variety of other processes are associated with carcinogenesis, some of which have been established for the therapy of solid cancers. The topic of survival of individual patients is related to some thermodynamic and other features of the cancer. For example, therapeutic prospects can be improved when based on the needs and opportunities of traditional therapies and thermodynamic interventions by considering the irregular or discontinuous growth of tumours. To explain basic differences between metabolism of normal and cancer cells the first and second laws of thermodynamics are applied together with changes in the electrical properties of the cell membrane and cell interior. Thermodynamic features of tumour organisation are maintained by entropy production and exchange. The differences in basic factors of entropy production between normal and cancer cells determine the direction of fluxes and consequently can be targets of specific interventions in cancer therapy. The basic routes of entropy production are: availability of mobile electrons, electrical polarization and depolarization, membrane potentials, ion fluxes, pH, temperature, chemical and electric potential, Gibbs energy, nutrition, chemotactic constraints, growth kinetics, mobilization of nutrients (proteins, fatty acids), dielectric differences, conductivity and response rate to external forces. Any one or a combination of these may be considered as possible new targets for selective modification of tumour growth. Differences in electro physiological, thermodynamic and metabolic activities of normal and cancer cells are compared and discussed in this review including some current research. New therapeutic strategies are now receiving support from many biomedical fields which we hope will contribute to successful therapy of solid cancers.

Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic tumor, which is universally associated with Epstein-Barr virus (EBV). Clinically, radiotherapy, but not surgery, is usually performed for the treatment of NPC because of the deep and complex location of the tumor. Previous randomized trials did not demonstrate that either neoadjuvant or adjuvant chemotherapy offered survival advantages over radiotherapy alone. Therefore, concurrent chemoradiotherapy consisting of three courses of CDDP administration during radiotherapy followed by three courses of adjuvant chemotherapy with 5-FU and CDDP is the widely accepted treatment modality at present. Further efforts have been attempted to establish less intensive but more or equally effective treatment, including an alternating chemoradiotherapy consisting of three courses of chemotherapy with 5-FU and CDDP accompanied by radiotherapy during their intervals. Furthermore, the association of NPC with EBV can be applied to treatment with antiviral drugs. The phosphonated nucleoside analog, cidofovir, inhibits and prevents NPC xenografts in nude mice. However, the highly metastatic capability of NPC has been linked to the EBV oncoprotein, latent membrane protein 1 (LMP1). LMP1 promotes metastasis through induction of matrix metalloproteinase-9, vascular endothelial growth factor, fibroblast growth factor-2, MUC1 as well as an epithelial-mesenchymal transition through various signaling pathways such as nuclear factor kappa-B and others. The article will review currently developing clinical treatment methods as well as therapeutic possibilities from the perspective of an EBV-associated treatment of NPC.

Gastric cancer is the fourth most common cancer and the second most common cause of cancer deaths worldwide. The 90% of gastric cancers are adenocarcinomas and two main types can be distinguished: diffuse and intestinal. The process preceding the diffuse-type carcinomas is not well known whereas the precursor stages of the intestinal-type are histologically well identified. The colonization of the gastric mucosa by Helicobacter pylori and the associated inflammatory response, induced by the presence of inflammatory cytokines, have been postulated as initiators of the neoplastic transformation. TNF-α, IL-1β, IL-6, and IFN-γ cytokines have been detected in H. pylori-infected stomachs, and can activate specific transcription factors that would regulate the expression of genes implicated in the transformation of the gastric mucosa. In vivo mouse models of gastric cancer have been recently developed to analyse the implication of the inflammatory cytokines in the regulation of specific genes involved in the gastric neoplastic transformation. The signalling pathways activated by proinflammatory cytokines represent new valid approaches for antitumor therapies, and the specific transcription factors activated are potential targets for inhibition. STAT3 and NF-kappaB that are hyperactivated in many human tumors, are implicated in the transcription of genes that promote oncogenesis and metastasis by the participation in cell proliferation, apoptosis, migration, angiogenesis and immune evasion processes. Different approaches such as peptidomimetics and small molecule inhibitors have been synthesised. Their potential antitumoral effects are being analysed in different tumor models and some data from pre-clinical assays are available. The association between inflammation and gastric cancer development makes this human tumor type a potential target for the use of these therapeutic approaches.

Ovarian carcinoma is the leading cause of gynecological cancer-related mortality. Cytoreductive surgery followed by combination chemotherapy including paclitaxel and a platinum compound usually results in complete remission in approximately 70% of patients. Despite this, the majority of patients will eventually relapse and die. There is, therefore, a crucial need to develop new therapeutic agents and better strategies to improve the outcome of these patients. Recently, tumor microenvironment has become an attractive target in gynecological malignancies. Angiogenesis is a complex and highly regulated process consisting in the development of new vessels from pre-existing ones. This process has been shown to have a main role in cancer beginning and progression. In ovarian cancer increased angiogenesis is associated with rapid recurrence and decreased survival. Moreover, targeting of vascular endothelial growth factor (VEGF) has produced promising results in early clinical trials, suggesting that angiogenesis plays a critical role in the development and maintenance of ovarian carcinomas. However, many questions remain open related to optimal dosing, sequencing of therapies, toxicities, patient selection, and response assessment. This article reviews the mechanisms of the angiogenic process and resumes the latest clinical studies of antivascular agents in ovarian carcinoma in a “from bench to bedside” approach.

In 1971, J. Folkman started his crusade on the therapeutic targeting of tumor angiogenesis [1]. This strategy gained an increasing number of sustainers showing promising, if not sensational results in animal models. Numerous potential targets were identified on the endothelial cell, causing the sensation to have no more secrets to disclose. Times were mature for an optimistic clinical transfer. This transfer immediately appeared a disaster: most molecules showed high toxicities, without appreciable therapeutic effects. Several trials were suddenly discontinued by the pharmaceutical industry, was it the end of “antiangiogenesis”? Fortunately, among numerous endothelial targets, one survived as potentially interesting: vascular endothelial growth factor (VEGF) and its receptor. Today we know that bevacizumab, a humanized anti VEGF antibody, significantly improves patients' life expectancy, when associated to the chemotherapy of colon and other solid cancers. In addition synthetic inhibitors of tyrosine kinase receptors (TKR) - like sunitinib and sorafenib- are deeply investigated. While these molecules have “saved” the anti angiogenic theory and will be perfected, we could ask why so many promising drugs failed in clinic. Among several answers, one can resume the others: the milestones of the anti-angiogenic theory were misunderstood by its clinical application. Born for chemoprevention, angiogenesis was targeted in advanced cancers, frequently as monotherapy. This implied the study of a MTD in phase I trials causing severe side effects, while an “optimal dose for chronic scheduling” (ODCS) should be tested instead. The evaluation of rapidly evolving cancers with an already established vascularization was a clear limit to those anti-angiogenic molecules unable to affect a completed angiogenic process. In addition it was immediately clear that classic response evaluation protocols were inadequate for anti-angiogenic assessment, due to the short time of the screening, and the lack of surrogate markers. In this review we revisit the different therapeutic strategies historically developed to target tumor vessels, describe the state of the art for VEGF and TKR inhibitors, comment recent trials based on molecules with known anti angiogenic activities and finally suggest possible guidelines for improving basic research and clinic experimentation.

Elimination of solid tumors refractory to the standard approaches is a significant challenge. The hypothesis that cancer stem cells (CSC) are responsible for the resistance to treatment, require novel therapies for cancer. Although recent studies determined phenotypes associated with CSC in distinct tumors, therapeutics lags behind. It is possible that the originally described CSC contain cells in different stages of differentiation and in different phases of the cell cycle. Most CSC should be sensitive to current treatment with enzyme inhibitors (PI3K, HDAC, PARP). In some patients, tumors recur after long periods (20-24 months) of disease free life. Novel molecular therapies, with inhibitory RNA or metastasespreventive vaccine are needed for patients which develop metastases originating from small numbers of cancer cells undetectable at the time of cure. We hypothesize that a common denominator of molecular therapies against CSC is the need for two agents: one, (available) which inhibits cell-cycle progression and a second, (to be developed) which kills “resting“ CSC.

The 11q23 abnormalities are frequent cytogenetic abnormalities found in some adult and pediatric cases of primary acute leukemia (AL), and also in the majority of patients with secondary AL after previous treatment with DNA topoisomerase II inhibitors. According to the WHO classification, AL with 11q23 abnormalities involving the Mixed- Lineage-Leukemia (MLL) gene composes one category of recurring genetic abnormalities. Over 60 chromosome partners of 11q23 have been reported to date, and 33 of the presumptive gene partners of 11q23 have been cloned and analyzed at the molecular level. 11q23/MLL abnormalities have been widely recognized as an important prognosis factor in AL. Recent studies showed that the prognosis of AL with 11q23/MLL is dependent on 11q23 fusion partner, and that the prognosis of AL with 11q23/MLL according to the 11q23 fusion partner is different between adults and children. The present article summarizes the current status of prognosis and treatment of AL with 11q23/MLL according to the fusion partner especially in adult, in which prognosis analysis has not be fully established due to a small number of cases, compared with infant cases.