Current Cancer Drug Targets - Volume 6, Issue 7, 2006

The importance of perturbation in transforming growth factor beta (TGFβ) signaling for the onset and progression of cancer is well established. Many tumors over express TGFβ, and high circulating levels of TGFβ1 in cancer patients are frequently associated with poor prognosis. TGFβ has context-dependent biphasic action during tumorigenesis. Because of this, it is essential to take due care about the selection of patients most likely to benefit from anti-TGFβ therapy. Anti-TGFβ therapy aims to target both the tumor cell and the tumor microenvironment and may well have systemic effects of relevance to tumorigenesis. Extra-tumoral targets include stromal fibroblasts, endothelial and pericyte cells during angiogenesis, and the local and systemic immune systems, all of which can contribute to the pro-oncogenic effects of TGFβ. Many different approaches have been considered, such as interference with ligand synthesis using oligonucleotides, sequestration of extracellular ligand using naturally-occurring TGFβ binding proteins, recombinant proteins or antibodies, targeting activation of latent TGFβ at the cell surface, or signal transduction within the cell. Consideration of which patients might benefit most from anti-TGFβ therapy should include not only tumor responses to TGFβ (which depend on activation of other oncogenic pathways in the cancer cell), but also germline genetic variation between individuals. Ultimately, a deep understanding of the interacting networks of signal pathways that regulate TGFβ outcome in tumor and host cells should allow judicial choice of drugs. This review discusses the progress made in the pre-clinical and clinical testing of TGFβ inhibitors, and discusses considerations of target populations and potential drug regimens.

The HER-2 (also known as ERBB2/ErbB2/c-erbB2/HER-2/neu) oncogene is the most frequently amplified oncogene in breast cancer and is also amplified in other forms of cancer. Beside its important role in tumor induction, growth and progression, HER-2 is also a target for new therapeutic approaches such as Herceptin (trastuzumab), a recombinant antibody designed to block signaling through the HER-2 receptor. In addition to Herceptin, which is in a wide clinical use for HER-2 amplified breast cancer, a number of various HER-2 directed immunological and genetic strategies, either targeting the HER-2 receptor, its signaling pathways or both HER-2 and epidermal growth factor receptor (EGFR) simultaneously, have demonstrated promising pre-clinical activity in HER-2 amplified carcinomas. Moreover, the HER-2 amplicon is known to contain more than 30 genes with altered copy numbers that could be therapeutic targets for chemotherapy. The topoisomerase IIα gene, TOP2A, is located adjacent to the HER-2 oncogene at the chromosome location 17q12- q21 and is either amplified or deleted (with equal frequency) in a great majority of HER-2 amplified primary breast tumors and also in tumors without HER-2 amplification. Recent experimental as well as numerous, large, multi-center trials suggest that amplification (and/or deletion) of TOP2A may account for both sensitivity or resistance to commonly used cytotoxic drugs, i.e. topoII-inhibitors (anthracyclines etc.), depending on the specific genetic defect at the TOP2A locus. The understanding of HER-2 amplification and its role in the pathogenesis of cancer is expanding, and a number of therapeutic strategies targeting either the HER-2 or its signaling pathways in cancer therapy are being investigated. Combining HER-2 targeting therapies with conventional forms of cytotoxic chemotherapy, where additional diagnostic tests such as those ascertaining TOP2A status, may be helpful for the ideal selection of patients for the combination therapy of an HER-2 targeting drug together with a cytotoxic drug such as topoII-inhibitor especially in the case of TOP2A amplification.

Identification of oncogene dependent signaling pathways controlling aggressive tumor growth has led to the emergence of a new era of oncogene-blocking therapies, including Herceptin and Gleevec. In the recent years conditional mouse tumor models have been established that allow switching-off the expression of specific oncogenes controlling tumor growth. The results may have two important implications for oncogeneblocking therapies: (i) downregulation of oncogenes, for instance HER2, MYC, RAS, RAF, BCR-ABL or WNT1, usually leads to a rapid tumor remission. However, it was observed that the initial remission was followed by recurrent tumor growth in most studies. Interestingly, different oncogenes controlled tumor growth in the recurrent than in the primary tumors. This could explain the astonishing clinical observation that inhibitors of a broader spectrum of protein kinases (so-called: “dirty inhibitors”) may be superior over highly specific substances. Due to their additional “unspecific” inhibition of a broader spectrum of kinases, they may hamper the escape mechanisms by antagonizing also the pathways controlling recurrent tumor growth. (ii) Experiments with cell systems that allow switching-on oncogene expression point to a so far possibly underestimated cancer drug target: the dormant tumor cell. Oncogene expression (for instance: NeuT or RAS) led to a phenomenon named oncogene-induced senescence or dormancy. Dormant cells are unresponsive to mitogenic stimuli. Importantly, such cells are not at all ready to die, but can remain viable for extended periods of time. Recently, dormant tumor cells have been shown to be more resistant to stresses such as hypoxia or exposure to cytostatic drugs. It still is a matter of debate if and under which conditions dormant tumor cells can be “kissed to life”. If these cells contribute to carcinogenesis, it will be important to identify substances specifically killing senescent cells. This review will focus on the possible relevance of senescence both as a pre-oncogenic condition and also for therapy.

Aberrant arachidonic acid metabolism has recently received intensive attention in the field of cancer research. Recent discoveries regarding the long-term cardiovascular side effects of cyclooxygenase 2 inhibitors have cast doubts on their use for cancer chemoprevention. Although such a problem does not undermine the importance of cyclooxygenase 2 as a cancer chemopreventive target, investigation into other AA-metabolizing pathways that are also important in inflammation and inflammation-associated carcinogenesis is necessary. Here, the important role of the 5-lipoxygenase pathway in carcinogenesis is reviewed. Inhibition of the 5-lipoxygenase pathways clearly has chemopreventive effects on various cancers, and hence further studies on its enzymes, metabolites and receptors for cancer chemoprevention and therapy are warranted.

Identification of the key roles of protein kinases in signaling pathways leading to development of cancer has caused pharmacological interest to concentrate extensively on targeted therapies as a more specific and effective way for blockade of cancer progression. This review will mainly focus on inhibitors targeting these key components of cellular signaling by employing a technology-based point of view with respect to ATP- and non-ATP-competitive small molecule inhibitors and monoclonal antibodies of selected protein kinases, particularly, mammalian target of rapamycin (mTOR), BCR-ABL, MEK, p38 MAPK, EGFR PDGFR, VEGFR, HER2 and Raf. Inhibitors of the heat shock protein Hsp90 are also included in a separate section, as this protein plays an essential role for the maturation/proper activation of cancer-related protein kinases. In the following review, the molecular details of the mode of action of these inhibitors as well as the emergence of drug resistance encountered in several cases are discussed in light of the structural, molecular and clinical studies conducted so far.

Adrenomedullin (ADM) is a 52-amino acid peptide with structural homology to calcitonin generelated peptide (CGRP) initially isolated from human pheochromocytoma. ADM is synthesized and is secreted from many mammalian tissues, including the adrenal medulla, endothelial and vascular smooth muscle cells, as well as the myocardium and central nervous system. ADM has been implicated as a mediator of several diseases such as cardiovascular and renal disorders, sepsis, inflammation, diabetes and cancer. ADM is also expressed in a variety of tumors, including breast, endometrial and prostate cancer. ADM has been shown to be a mitogenic factor capable of stimulating growth of several cancer cell types. In addition, ADM is a survival factor for certain cancer cells and an indirect suppressor of the immune response. ADM plays an important role in environments subjected to low oxygen tension, which is a typical feature of solid tumors. Under these conditions, ADM is up regulated and acts as a potent angiogenic factor promoting neovascularization. The major focus of this review will be on the role of ADM in cancer, with emphasis on its utility in diagnostic and prognostic terms, along with its relevance as a therapeutic target.