Current Cancer Drug Targets - Volume 5, Issue 8, 2005

The lymphatic vasculature is an important route of metastatic spread in cancer and recent studies have demonstrated that lymphangiogenesis (the growth of lymphatic vessels) associated with tumors promotes metastasis via the lymphatics. Therefore, the molecular mechanisms that drive lymphangiogenesis are attractive targets for development of novel therapeutics designed to restrict cancer metastasis. Such therapeutics would be of high priority as metastasis is the most lethal aspect of tumor biology. Research over the past seven years has identified protein growth factors and cell surface receptors that signal for lymphangiogenesis during embryonic development, in adult tissues and in cancer. Proteases that process and thereby activate lymphangiogenic growth factors have also been defined. Lymphangiogenic growth factors, the enzymes that activate them and the cell surface receptors signalling for growth of lymphatic vessels are prime targets for antilymphangiogenic drugs designed to restrict cancer metastasis. Agents targeting some of these proteins have already shown promise for blocking tumor lymphangiogenesis and lymphatic metastasis in animal models. This article focuses on current and emerging targets for blocking these processes that have been defined in recent studies of the molecular mechanisms controlling lymphangiogenesis. Strategies to block the actions of these proteins in cancer are also explored.

The existence of specific angiogenesis inhibitors was first postulated by Judah Folkman in 1971. The term "antiangiogenesis" was introduced to describe treatments designed to prevent the induction of new blood vessels and perhaps reduce the number of those already present. Several approaches inhibit tumor angiogenesis and more than 60 antiangiogenic compounds have been clinically evaluated. Because tumorassociated angiogenesis takes place in a physiological context, its inhibition should not induce resistance and should potentiate the oncostatic effect, because each neovessel supplies hundreds of tumor cells. Inhibitors may be synthetic or semi-synthetic agents, endogenous inhibitors, or biological antagonists of the angiogenic cascade. Several direct and indirect vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitor strategies are under clinical investigation for treatment of solid tumors and hematological malignancies. Approaches to disrupt the VEGF/VEGFR signalling pathways range from small-molecule ATP competitive VEGFR inhibitors to biological agents such as soluble receptors, anti-VEGF and anti-VEGFR antibodies, small molecule inhibitors, and VEGF transcription inhibitors. This review summarizes the literature on the use of these molecules in the treatment of hematological malignancies.

Angiogenesis is indispensable for the growth of solid tumors and angiogenic factors are also involved in the progression of hematological malignancies. Targeting the formation of blood vessels is therefore regarded as a promising strategy in cancer therapy. Interestingly, besides demonstration of some beneficial effects of novel anti-angiogenic compounds, recent data on the activity of already available drugs point to their potential application in anti-angiogenic therapy. Among these are the statins, the inhibitors of 3- hydroxy-3-methylglutaryl-coenzyme A reductase. Statins are very efficient in the treatment of hypercholesterolemia in cardiovascular disorders; however, their effects are pleiotropic and some are not directly related to the inhibition of cholesterol synthesis. Some reports particularly highlight the proangiogenic effects of statins, which are caused by low, nanomolar concentrations and are regarded as beneficial for the treatment of cardiovascular diseases. On the other hand, the anti-angiogenic activities, observed at micromolar concentrations of statins, may be of special significance for cancer therapy. Those effects are caused by the inhibition of both proliferation and migration and induction of apoptosis in endothelial cells. Moreover, the statin-mediated inhibition of vascular endothelial growth factor synthesis, the major angiogenic mediator, may contribute to the attenuation of angiogenesis. It has been suggested that the anti-cancer effect of statins can be potentially exploited for the cancer therapy. However, several clinical trials aimed at the inhibition of tumor growth by treatment with very high doses of statins did not provide conclusive data. Herein, the reasons for those outcomes are discussed and the rationale for further studies is presented.

Recent progress in cancer drug therapy has recognized that the nucleus of the eukaryotic cell is an active site for many cellular processes important to the development of cancer. Many of these processes take place in specialized compartments of the nucleus. One of such sub-nuclear compartments is the promyelocytic leukemia nuclear body (PML NB). In acute promyelocytic leukemia (APL), PML forms a fusion protein with the retinoic acid receptor (RAR) alpha as a result of chromosomal translocation. This PML-RAR alpha fusion protein is responsible for the proliferative and de-differentiated phenotype of the leukemic cells and is the target of all-trans retinoic acid (ATRA). Another example of the specialized sub-nuclear compartments important in the targeting of cancer is the nucleolus. Recently, it has been proposed that the nucleolus serves as a stress sensor for the cell, and the molecular mechanism underlying this proposal has been discovered. Moreover, many anti-cancer drugs target specific protein-protein interactions within the nucleus. We will discuss current development surrounding two such target proteins: the hypoxia-inducible factor 1 alpha (HIF- 1alpha) and FKBP25. Furthermore, chromatin structure, which is affected by modifications of core histones, has become a target of anti-cancer drugs. In this review, we will emphasize the significance of nuclear proteins as promising targets for cancer drug therapy by discussing a few key ideas, in three broad categories of specialized sub-nuclear compartments, protein-protein interactions, and the modifications of the chromatin structure.

The pursuit of active specific immunotherapy of cancer re-emerged vigorously in the 90s. More than 50 vaccines are currently under clinical testing, and more than 400 clinical trials have been conducted. This wave of enthusiasm is rooted in fundamental immunology, as new paradigms, such as the dominant tolerance through T-regulatory cells and the instructive role of the innate immune system on the adaptive immune system, opened the possibility that an efficient cancer vaccination could be achieved even without the need of cancer neoantigens, provided that antigen presentation could be increased, and that regulatory circuits could be controlled. However, recent failures in some large trials have brought disappointment and have highlighted the differences between experiments in young, healthy mice with small transplanted tumours, and clinical testing in aged, ill patients with advanced spontaneous tumours, driving the attention to issues such as tumour editing, tumourinduced immunosuppression, and immunosenescence. The molecular basis of these phenomena is only partially known. Additionally, the inherent complexity of the immune system as a network of multiple interactions and redundant control loops among a huge diversity of components sets another barrier to the translation of in vitro reductionist knowledge into rationally designed clinical trials. All this calls for a new therapeutic paradigm in cancer vaccines, moving beyond the analogy with the classic drug-target approach, and targeting the immune system regulation as a whole, and its interaction with the tumour, in all its complexity. Early mathematical modelling of cancer immunotherapy has suggested how to go about it. This reevaluation of the cancer vaccine landscape, suggests that future successful cancer immunotherapy will be combined immunotherapy, will be exquisitely schedule-dependent and will need new experimental models allowing for the exploration of the mechanisms of resistance and tumour escape, such as tumour editing and tumour induced immunosuppression, in the context of the physiology of the immune system of the elderly. These shifts will put cancer vaccines closer to pharmacology than to conventional preventive vaccinology, or at least at the midway. A change in the design and the ultimate goals of the clinical trials will also be needed, identifying long term stabilization of the disease and quality of life as main endpoints, again closer to the clinical management of most chronic noncommunicable diseases.

Focal adhesion kinase (FAK) is a tyrosine kinase whose phosphorylation state and activity is tightly linked to cell adhesion to the extracellular matrix through integrin receptors. FAK's regulation by adhesion places it in a key position to be able to influence cellular events that are either dependent on cell adhesion like cell proliferation and survival, or that require modulation of cell adhesion like cell migration. FAK's involvement in cellular pathways that regulate cell growth and cell movement suggests that it may contribute to the development of cancer or other diseases. FAK's possible involvement in these pathways makes it a potential drug target. In this review we will focus on the developing view how FAK's activity and phosphorylation are regulated within the cell. Specifically, we will address the contribution of integrins and growth factor dependent pathways to FAK's activation. The role of the tyrosine kinase Src in FAK's regulation will be discussed. The contribution of various negative regulators of FAK's phosphorylation on its regulation including phosphatases and proteases will be discussed. Lastly, the emerging role of FAK's amino terminal FERM like domain in FAK's regulation will be explored. FAK's function within a cell are tightly linked to its phosphorylation state, thus understanding its normal regulation in the cell will provide important insight into drug development by highlighting novel regulatory mechanisms within FAK that potentially may be exploited.