Current Pharmaceutical Design - Volume 13, Issue 5, 2007

The current issue of CPD focuses on novel targets for cancer therapy as well as the development of therapies that take advantage of newly emerging information on carcinogenesis and tumor survival mechanisms. Such treatments may hold the key to successful cancer treatment and long-term survival of patients with otherwise poor prognosis. T. Okamoto et al. [1] review the regulatory function of NF-κ B for various genes involved in cell cycle progression, inhibition of apoptosis and other cellular processes. This makes NF-κ B a crucial factor in the promotion of carcinogenesis and tumor progression. Moreover, NF-κ B is involved in inflammatory responses reminding us of the link between chronic inflammation and carcinogenesis. The authors discuss the feasibility of targeted cancer therapy using NF-κ B and its signaling cascade as a molecular target. C. Leonetti and G. Zupi [2] summarize the studies on antisense oligonucleotides targeting various pathways involved in the regulation of proliferation, apoptosis and angiogenesis. The authors focus in their review on the use of antisense oligonucleotides targeting oncogenes and the combination of such treatment with chemotherapeutic drugs or signaling inhibitors. The provided information is then discussed in respect to the feasibility of such treatments in clinical settings. I. Zavrski et al. [3] give a comprehensive overview of the crucial role proteasomes play in destabilizing cell growth and survival by selectively degrading cellular proteins that are involved in the regulation of cell proliferation, growth and apoptosis. This feature makes the proteasome a potential target for anticancer treatments. The authors report on various proteasome inhibitors and their clinical efficacies. P. Tassone et al. [4] report on a very exciting new approach that is based on cell biological studies and involves the identification of survival factors. Understanding the micromilieu of the tumor and the cellular response of cancer cells to stress situations caused by the expansion of the tumor and the changes in the micromilieu is the key to comprehending the adaptations that the tumor constantly performs in order to survive. The authors report on the establishment of in vivo models that simulate these conditions and the utilization of such models for the development of novel anticancer therapies. R. Longo et al. [5] comprehensively convey the latest progress in targeted therapies for breast cancers; these therapies encompass humanized antibodies directed against growth factor receptors as well as anti-angiogenic compounds. The authors add to the review of achieved milestones an essential discussion on the remaining challenges in the development of efficacious treatments especially for patients with poor prognosis. C. Oehler et al. [6] summarize the efforts made in combining radio- and chemotherapy in order to sensitize inherently radio-resistant tumors to radiotherapy. Such radio-sensitizing drugs target various aspects of the intercellular communication network and can affect either individual cells or the entire tumor tissue. Based on recently obtained insights into the cellular responses involved in carcinogenesis and radiation responses, various reaction patterns have been identified (i.e., Repair, Reassortement, Repopulation and Reoxygenation). The authors discuss the current approaches of sensitization in the light of these reaction patterns. S. Mocellin et al. [7] review the efforts to take advantage of a powerful immune factor, tumor necrosis factor (TNF) in cancer therapies. TNF had originally been described as a molecule that affects the neovasculature of tumor cells. Later, studies have shown that tumor cells have receptors for TNF and can undergo apoptosis upon ligation of the receptor. However resistance to TNF can occur early on in tumorigenesis and thus tumor cells of more advanced cancers may be resistant to the effects of TNF. Another disadvantage of the clinical use of TNF is its systemic toxicity. The authors concisely summarize the biological, cancer-related properties of TNF and the efforts to overcome the disadvantages of TNF in order to make it a cancer-specific toxic drug........

NF-κB is an inducible transcription factor that is controlled by the signal activation cascades. NF-κB controls a number of genes involved in immuno-inflammatory responses, cell cycle progression, inhibition of apoptosis and cell adhesion, thus promoting carcinogenesis and cancer progression. Interestingly, some proteins encoded by oncogenes and oncogenic viruses have been shown to be involved in NF-κB activation pathway. In fact, NF-κB is constitutively activated in some cancer and leukemia cells. These findings have substantiated the old concept of the link between chronic inflammation and carcinogenesis. In this review, we have attempted to overview the possible involvement of NF-κB in cancer and discuss the feasibility of anti-cancer strategy with NF-κB and its signaling cascade as novel molecular targets.

The evidence that cancer development is a complex and multistep process, characterized by alterations of genes involved in the regulation of proliferation, apoptosis and angiogenesis, has led to development of new therapeutic strategies based on the use of agents able to selectively inhibit key molecules of these pathways. In particular, antisense oligonucleotides (ASOs) have proved their efficacy as targeted therapy in preclinical studies, have been well tolerated and able to modulate target protein expression in clinical studies. Although these agents have shown considerable promise for antitumoral therapy, treatment with ASOs used as single agent does not seem particularly promising because of the multigenic alterations of tumors. Based on these considerations, approaches based on the combination of ASOs targeting oncogenes involved in different molecular pathways have been investigated. Moreover, the role of this novel strategy when integrated with conventional drugs or signaling inhibitors, has been assessed. This review addresses some advances in the ASOs combination and reports the potential application of this strategy for the treatment of human cancer.

The 26S proteasome is a multicatalytic intracellular protease expressed in eukaryotic cells. It is responsible for selective degradation of intracellular proteins that are responsible for cell proliferation, growth, regulation of apoptosis and transcription of genes involved in execution of key cellular functions. Thus proteasome inhibition is a potential treatment option for cancer and diseases due to aberrant inflammation condition. Treatment with proteasome inhibitors results in stabilization and accumulation proteasome substrates, a phenomenon that may result in confounding signals in cells, cell cycle arrest and activation of apoptotic programs. The inhibition of the transcriptional factor nuclear factor κB (NF- κB) activation was found as one of crucial mechanisms in induction of apoptosis, overcoming resistance mechanisms and inhibition of immune response and inflammation mechanisms. Bortezomib (PS-341) and PS-519 are the first proteasome inhibitors that have entered clinical trials. In multiple myeloma, both the FDA (United States Food and Drug Administration) and EMEA (European Medicine Evaluation Agency) granted an approval for the use of bortezomib (Velcade®) for the treatment of relapsed multiple myeloma. At present, several phase II and phase III trials in hematological malignancies and solid tumors are ongoing. PS-519 that focuses on inflammation, reperfusion injury and ischemia is currently under evaluation for the indication of acute stroke.

It is a current idea that carcinogenesis as well as tumor progression are dynamic processes, which involve inherited as well as somatic mutations and include a continuing adaptation to different microenvironmental conditions. There is, in fact, rising evidence that tumor cells are under a persistent stress and that autocrine as well as microenvironment- derived survival factors play a substantial role for the final outcome of the tumor development as well as for response to the anti-tumor therapy. We will review current achievements on the molecular biology of the microenvironment- derived survival signaling and therapeutical approaches, which are presently under clinical development. By the use of plasma cell disorders as an outstanding clinical model, we will discuss the development of novel in vivo preclinical models which recapitulate the human bone marrow milieu. Finally, we will discuss several topics which appear to be relevant for a successful clinical translation of preclinical research in this specific field.

Breast cancer is the most frequent tumor of women. The development of effective adjuvant therapy based on postoperative administration of short-term chemotherapy (4-6 months) or long-term hormone therapy (5 years) or both, significantly improved survival of patients. However, therapy of adjuvant/metastatic disease is still palliative with a very low probability to induce complete remission and definitive cure of disease. The relevant efforts of basic research to identify the key and selective molecular alterations, which sustain breast cancer growth and progression allowed the possibility to develop specific molecular target treatments. Trastuzumab, a humanized monoclonal antibody to HER-2, is the first molecular targeting agent approved for therapy of metastatic breast cancer, capable to significantly improve clinical outcome in combination with cytotoxic therapy. Recent preliminary data from randomized, prospective, clinical trials suggest that trastuzumab decreases the risk of early recurrence by 50% in patients with HER-2-positive disease. Other novel targeted treatments are in clinical evaluation, including antiangiogenic compounds (Bevacizumab, sunitinib, vatalanib, and others) and bi-functional drugs such as lapatinib (anti Her-2 and EGFR agent) showing promising activity. This review provides an updated overview of the status of development of targeted therapy in breast cancer, as well as the challenges related to the rational use of molecular targeting agents.

In current applied radiobiology, there exists a tremendous effort in basic and translational research to identify novel treatment modalities combining ionizing radiation with anticancer agents. This is mainly due to the highly improved molecular understanding of intrinsic radioresistance and the profiling of cellular stress responses to irradiation during recent years. Ionizing radiation not only damages DNA but also affects multiple cellular components that induce a multilayered stress response. The treatment responses can be restricted to the individual cell level but might also be part of an intercellular stress communication network. Both DNA damage-induced signaling (which results in cell cycle arrest and induction of the DNA-repair machinery) and also ionizing radiation-induced signal transduction cascades, which are generated at cellular sites distant from and independent of DNA-damage, represent interesting targets for anticancer treatment modalities to sensitize for ionizing radiation. Due to the lack of molecular knowledge classic radiobiology assembled the cellular and tissue responses into four groups (4 R's of radiotherapy) which describe biological factors influencing the treatment response to fractionated radiotherapy. These classic 4 R's are Repair, Reassortment, Repopulation and Reoxygenation. With the tremendous progress in molecular oncology we now begin to understand theses factors on the molecular level. At the same time this classification may guide modern molecular radiobiologists to identify novel pharmaceuticals and antisignaling agents which can modulate the treatment response to irradiation. In this review we describe current approaches to sensitize tumor cells with novel anticancer agents along the lines of these 4 R's.

Although TNF antitumor activity has been demonstrated in many preclinical models and in non-comparative clinical trials, no evidence exists that TNF-based treatments increase patient survival. Moreover, due to systemic toxicity, TNF can only be administered through sophisticated locoregional drug-delivery systems in patients with some types of organ-confined solid tumors; as a corollary, the impossibility to administer TNF through the systemic route does not allow to test the effectiveness of this cytokine in other clinical settings for the treatment of a broader spectrum of tumor types. A challenge many researchers are tackling is to dissect the cascade of molecular events underlying tumor sensitivity to TNF so to fully explore the anticancer potential of this molecule. The rationale for the development of strategies aimed at sensitizing malignant cells to TNF is to exploit tumor-specific molecular derangements to modulate TNF biological activities and ultimately maximize its tumor-selective cytotoxicity. This would not only enhance the anticancer activity of current TNF-based locoregional regimens, but would also open the avenue to the systemic administration of this cytokine and thus to a much wider clinical experimentation of TNF in the oncology field. In this review we first summarize the molecular biology of TNF and its cancer-related properties; then, the available findings regarding some among the most promising and best characterized TNF sensitizers are overviewed.