Current Cancer Drug Targets - Volume 9, Issue 1, 2009

The very early intuition of Paget about the molecular feature of metastasis has come in the field of therapeutic opportunities only in the last few years with the development of targeted therapy. However, to date the diagnosis of metastases is associated in the majority of cases with the loss of any therapeutic hope. According to present knowledge, metastatic spreading is considered as part of a long process in which tumor cells gain new properties in their cellular function, including invasion and adaptive survival. This gain of function is based on the expression of new molecular markers that may be potential therapeutic targets in blocking tumor dissemination. The epidermal growth factor receptor family comprises four members (ERBB) that are frequently upregulated in advanced tumor stages and have been associated with the metastatic potential of several tumors. ERBB receptor inhibitors are very effective against specific primary tumors and their use is frequently accompanied by toxicity problems, drug resistance and molecular desensitization. However, new studies indicate that ERBB inhibitors may provide a much-needed therapeutic option mainly for patients with metastases. In order to illustrate the potential of ERBB family members as therapeutic targets in blocking metastases we summarize the new molecular evidence and the observations from clinical trials.

Acute lymphoblastic leukemia (ALL) is a clonal proliferation of early B- and T-lymphocyte progenitors and results in the accumulation of leukemic blasts in the bone marrow and various extramedullary sites. It affects both children and adults, with peak prevalence between the ages of 2 to 5 years. Despite current treatment protocols achieving rapid cytoreduction in the vast majority of patients, serious acute and late complications are frequent and resistance to chemotherapy often develops. In contrast to the successes obtained with pediatric patients, treatment outcomes for adults remain poor with only 40% of patients being long-term survivors. Extensive research in the field of ALL has helped understand the mechanisms that control leukemic cells, facilitating the design of new drugs that specifically interfere with leukemic pathways and overcome chemo-resistance induced by common treatment regimens. Herein, we review the current status of the development of novel anti-leukemic agents, with emphasis on small molecular inhibitors that have already translated into clinical trials and are in the advanced stages of preclinical development. Challenges to successful development of each strategy are discussed.

The urokinase plasminogen activator (uPA) system (uPAS) consists of the uPA, its cognate receptor (uPAR) and two specific inhibitors, the plasminogen activator inhibitor 1 (PAI-1) and 2 (PAI-2). The uPA converts the proenzyme plasminogen in the serine protease plasmin, involved in a number of physiopathological processes requiring basement membrane (BM) and/or extracellular matrix (ECM) remodelling, including tumor progression and metastasis. Data accumulated over the past years have made increasingly clear that the uPAS has a multifunctional task in the neoplastic evolution, affecting tumor angiogenesis, malignant cell proliferation, adhesion and migration, intravasation and growth at the metastatic site. In agreement with their role in cancer progression and metastasis, an increased expression of uPA, uPAR, and PAI-1 has been documented in several malignant tumors, and a positive correlation between the levels of one or more uPAS members and a poor prognosis has been frequently reported. This is particularly evident in breast cancer, for which uPA has been demonstrated to be the most potent independent prognostic factor described to date. The involvement of the uPAS in cancer progression identifies its components as suitable targets for anti-cancer therapy. Several therapeutical approaches aimed at inhibiting the uPA/uPAR functions have been shown to possess anti-tumor effects in xenograft models, including selective inhibitors of uPA activity, antagonist peptides, monoclonal antibodies able to prevent uPA binding to uPAR and gene therapy techniques silencing uPA/uPAR expression. All these strategies, however, although promising, need definitive confirmation in humans as, up to now, only few uPA inhibitors entered clinical trial.

Epidermal growth factor (EGF) and its receptor (EGFR) as well as the EGFR-coupled Ras>Raf>MEK>ERK pathway are known to affect the survival of cancer cells upon chemotherapeutic treatment. In the present investigation, we analyzed the role of EGFR signaling pathways for the activity of artesunate towards cancer cells. The microarray-based mRNA expression of genes involved in EGFR signaling pathway was correlated with the 50% inhibition concentrations (IC50) of 55 tumor cell lines for artesunate. The log10IC50 values were in a range of -6.609 to -4.0M. Candidate genes identified by this approach were then experimentally validated by transfecting cell lines with corresponding cDNA vectors and treating them with artesunate. Indeed, we observed that the Ras>Raf>MEK>ERK pathway is an important signaling route for the response of tumor cells to artesunate. As exemplarily shown for artesunate, the application of such a combined approach to identify signal transduction pathways involved in the response of tumor cells to cytotoxic compounds might foster the development of novel molecular targeted therapies for cancer treatment.

The chronic lung inflammatory activity and carcinogenicity of nickel compounds have been well documented by previous studies from epidemiology both in vitro and in vivo. However, the molecular mechanism involved in nickelinduced chronic lung inflammation is much less understood. The current study demonstrates that exposure of human bronchial epithelial cells (Beas-2B) to nickel compounds results in the induction of the inflammatory cytokine tumor necrosis factor-α (TNF-α) and transactivation of nuclear factor of activated T cells (NFAT), nuclear factor-κB (NF-κB), and activator protein-1 (AP-1). Further studies show that neither overexpression of IKKβ-KM, a kinase inactive mutant of IKKβ, nor the ectopic expression of a dominant negative mutant of NFAT could inhibit the TNF-α induction by nickel exposure. Overexpression of TAM67, a dominant-negative mutant of c-Jun, dramatically reduced the TNF-α induction, suggesting that AP-1 is a mediator of TNF-α induction in nickel responses. Our results show that ERKs are AP-1 upstream kinases responsible for TNF-α induction by nickel exposure; although JNKs, ERKs, and p38K were all activated in the Beas-2B cells exposed to nickel compounds. Our results demonstrate that inflammatory TNF-α could be induced by nickel exposure in Beas-2B cells specifically through an ERKs/AP-1-dependent pathway.

Histone deacetylase (HDAC) inhibitors are currently used in the study of epigenetics and have potential in clinical cancer therapy. A novel and potent HDAC inhibitor, depsipeptide, also known as FK228 or FR901228, is highly efficient in inhibiting the activity of HDACs even at nanomolar concentrations. Depsipeptide has a unique structure that is distinct from most of the other HDACs, and it thus exhibits diverse pharmacologic functions. In addition, depsipeptide has a metabolic activation pathway, which affects many intracellular processes. However, the specific features of this pathway are as yet not completely worked out. In this article, we will focus on the uniqueness of this molecule's specific structure, the relationship of this structure to its putative metabolic activation pathway, and specifically review its newly discovered biological functions and clinical applications.

DNA interstrand crosslinkers, a chemically diverse group of compounds which also induce alkylation of bases and DNA intrastrand crosslinks, are extensively utilized for cancer therapy. Understanding the cellular response to DNA damage induced by these agents is critical for more effective utilization of these compounds and for the identification of novel therapeutic targets. Importantly, the repair of DNA interstrand crosslinks (ICLs) involves many distinct DNA repair pathways, including nucleotide excision repair, translesion synthesis (TLS), and homologous recombination (HR). Additionally, proteins implicated in the pathophysiology of the multigenic disease Fanconi anemia (FA) have a role in the repair of ICLs that is not well understood. Cells from FA patients are hypersensitive to agents that induce ICLs, therefore FA proteins are potentially novel therapeutic targets. Here we will review current research directed at identifying FA genes and understanding the function of FA proteins in DNA damage responses. We will also examine interactions of FA proteins with other repair proteins and pathways, including signaling networks, which are potentially involved in ICL repair. Potential approaches to the modulation of FA protein function to enhance therapeutic outcome will be discussed. Also, mutation of many genes that encode proteins involved in ICL repair, including FA genes, increases susceptibility to cancer. A better understanding of these pathways is therefore critical for the design of individualized therapies tailored to the genetic profile of a particular malignancy. For this purpose, we will also review evidence for the association of mutation of FA genes with cancer in non-FA patients.