Current Cancer Therapy Reviews - Volume 3, Issue 1, 2007

The field of cancer therapy is rapidly moving forward with the development of numerous prospective new agents designed to inhibit cellular factors involved in signal transduction, cell proliferation, and the onset of apoptosis. At the core of these biological processes are transcription factors that are the functional mediators of these effects. Transcription factors are the downstream targets of numerous signal transduction pathways that are central to the process of carcinogenesis. The Activator Protein-1 (AP-1) complex is one such factor that has a central role in multiple processes involved in tumorigenesis including proliferation, migration, invasion and metastasis. The focus of this review is, using AP- 1 as a model, to discuss transcription factors as targets for cancer therapy. The feasibility of targeted disruption of AP-1 by various agents such as dominant-negative mutants, small molecule inhibitors, transcription factor decoys (TFD), chemotherapeutic drugs, chemoprevention agents, siRNA and natural products will be explored.

Somatic cells show a spontaneous decline in growth rate in continuous culture. This is not related to elapsed time but to an increasing number of population doublings, eventually terminating in a quiescent but viable state, termed replicative senescence. These cells are commonly multinucleated and do not respond to mitogens or apoptotic stimuli. Cells displaying characteristics of senescent cells can also be observed in response to other stimuli, such as oncogenic stress, DNA damage or cytotoxic drugs, and have been reported to be found in vivo. Most tumors show unlimited replicative potential, leading to the hypothesis that cellular senescence is a natural antitumor program. Recent findings suggest that cellular senescence is a natural mechanism to prevent undesired oncogenic stress in somatic cells that has been lost in malignant tumors. Given that the ultimate goal of cancer research is to find the definitive cure for as many tumor types as possible, exploration of cellular senescence to drive towards antitumor therapies may decisively influence the outcome of new drugs. In the present work we will review the potential of cellular senescence to be used as target for anticancer therapy.

Although Hox genes have been identified as master regulatory genes controlling embryonic development, an alternative view on the role of the Hox gene network suggests that it regulates crucial processes at cellular level in eukaryotic organisms. The Hox network acts at the nuclear cell level as a decoding system for external inductive signals to activate specific genetic programs. Cancer can be considered as an anomalous structure growing inside the human body and following, from an architectural viewpoint, the rules controlling body shape as occurs during embryonic development. As a consequence of this viewpoint, it has been proposed that the whole HOX gene network is involved in controlling phenotype cell identity and three-dimensionality of tissues and organs and, furthermore, that specific HOX genes or groups of genes are implicated in the neoplastic alterations of organs and tissues such as kidney, colon, lung, skin, bladder, breast, prostate. Despite our limited understanding of the mechanisms involved, it has already been possible to identify the specific HOX genes perturbed in certain types of human cancers with greater benefit for cancer patients than for better known oncogenes. Here we foresee the start of clinical trials with the purpose of targeting specific HOX genes in order to achieve a therapeutic effect in cancer patients.

Prostate cancer is predicted to be the most common cancer diagnosed in American men in 2006 with an estimated 230,000 new cases in the United States alone [1]. It is likely to result in over 27,000 deaths in 2006, and the average male will have a one in six chance of developing this malady in his lifetime [1]. These statistics illustrate the need to have screening and treatment systems in place that possess both a high degree of sensitivity as well as proven effectiveness. With the recent strides made in the field of molecular and cellular biology, it is now possible to analyze and tailor treatments to an individual's tumor. As the methods of analysis become more refined, researchers are better able to sift through the vast amounts of data and hone in on promising new targets. Molecular prognostic markers are already beginning to appear as a result of modern genomic analysis, and more are on the way. These markers are appearing in a variety of pathways including signal transduction, apoptosis, cell cycle regulation, angiogenesis, and cell adhesion. The emergence of viable prognostic markers indicative of specific tumor types holds the potential of greatly improving cancer screening methods as well as overall patient survival.

Allogeneic stem cell transplantation has become an important treatment option for many children with malignant and non malignant diseases during the past decades. However, this therapy was for a long time restricted to patients having an “HLA identical donor”. In most recent years donor registries all over the world have extended and the numbers of registered volunteers have substantially increased during the last 20 years. In spite of this progress, there is still a substantial number of children lacking a well matched donor. Virtually all little patients have at least one “haploidentical” parent who could potentially serve as a stem cell donor. These donors are immediately available, are highly motivated and could be asked for a further time if the graft would have been rejected. In the post transplant course parents are repeatedly available for additional donor cell transfusions for preemptive immunotherapy. Moreover using haploidentical parents as donors can avoid the inauguration of new registries and banking expenditures in countries whose population is not very much represented in existing large donor registries. For long years, graft rejection, graft versus host disease (GVHD) and delayed recovery of the immune system used to be the limiting factors for haploidentical transplantation. Substantial progress has been made in the clinical application of haploidentical stem cell transplantation in children with leukemia as well as non malignant diseases in the last years. Recurrence of the underlying disease and delayed immune recovery, however, remained major cause for treatment failure yet to overcome to offer this procedure to a wider range of patients. Nevertheless, haploidentical stem cell transplantation has become a valuable alternative procedure for patients lacking an HLA identical donor. The development and recent advance is reviewed in the following.

According to the American Cancer Society, there will be an estimated 14,520 new cases of esophageal cancer and 174,470 new cases of lung cancer in 2005 [1]. Close to 60% of these patients with esophageal cancer will present at an advanced stage not amenable to cure, but still will require palliation of their dysphagia [2]. Conventional plastic stents (CPS) were used initially, and with continuous improvement in technology, insertion of selfexpanding metal stents (SEMS) has become the palliative treatment of choice in the majority of these patients [3-7]. SEMS are effective in palliating malignant dysphagia in 85%-100% of patients [7-9]. More recently, a new selfexpanding plastic stent (SEPS) has been designed which in early studies has been very effective in palliating dysphagia [10-13]. Similarly, the majority of patients with lung cancer will present at an advanced stage and approximately 20% of these patients will have an endobronchial component requiring some form of palliation for relief of airway obstruction [14]. Currently airway stents are either made of self-expanding metal for more permanent use, or silicone if a more temporary solution is needed. Complications similar to the esophageal stents may arise. The purpose of this article is to provide an evidence based review of stents in the palliative setting for esophageal and lung cancer and briefly explore their potential use and expanding indications in the neoadjuvant setting.

Adenocarcinoma of the pancreas is the fourth leading cause of cancer death in the United States. Because of the poor therapeutic responsiveness of pancreatic cancer to surgery, chemotherapy, and radiation therapy, survival beyond five years is rare with median survival less than six months. K-ras mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in the molecular pathogenesis. Ras overexpression leads to increased production of reactive oxygen species (ROS) through activation of the NADPH oxidase system resulting in downstream propagation of mitogenic signaling leading to cell growth and tumor progression. The superoxide dismutases (SOD) convert O2 .- into H2O2. Extracellular SOD (ECSOD) is the only isoform of SOD that is expressed extracellularly, manganese-containing superoxide dismutase (MnSOD) is localized in the mitochondria, and copper- and zinc-containing superoxide dismutase (CuZnSOD) in the cytoplasm. The catalases and peroxidases convert H2O2 into water. Catalase is located in peroxisomes and cytoplasm and peroxidases are in many subcellular compartments. Antioxidant enzymes that scavenge specific ROS have inhibited the in vitro and in vivo growth of pancreatic cancer. Additionally, food-derived polyphenols, which may act by scavenging reactive oxygen species, can also inhibit pancreatic cancer growth. This review will concentrate on the sophisticated antioxidant defense system, which may shed insight into the etiology, diagnosis, and treatment of pancreatic cancer.

Breast cancer remains the commonest malignancy amongst women and its incidence continues to increase worldwide. This inexorable rise in numbers of women suffering from the disease is particularly notable in those countries which previously had a relatively low incidence of breast cancer but have now adopted Western lifestyles with changes in reproductive behaviour and greater usage of the oral contraceptive pill. These epidemiological observations emphasize the hormone dependency of breast cancer and the importance of endocrine factors for tumour initiation and promotion. There has been a resurgence of interest in hormonal therapies with the advent of third generation aromatase inhibitors (AI) which represent the most significant advance in endocrine management of breast cancer since the introduction of tamoxifen 3 decades ago. This article will recount the historical development of endocrine therapies and the biological rationale for hormonal manipulation as a therapeutic goal. The application of AI's in the clinical setting will be critically discussed with citation of seminal studies. Like many novel agents for treatment of breast cancer, AI's were initially used in the advanced disease setting where they offered advantages over tamoxifen and progestins as first- and second-line therapies respectively. Aromatase inhibitors are widely used in the neoadjuvant setting for hormone sensitive tumours and can permit subsequent breast conservation surgery when mastectomy would otherwise have been indicated. However, it is in the adjuvant setting that AI's have stimulated much interest and generated an element of uncertainty in the optimum form of adjuvant hormonal therapy for post-menopausal women with oestrogen receptor positive tumours. It seems likely that any blanket policy is no longer appropriate and a selective strategy with tailoring of therapy based on risk of relapse is the preferred option. Those patients at greatest risk of relapse may benefit most from an upfront AI whilst those with lower hazard rates for relapse may be best treated with an ‘early switch’ regimen involving tamoxifen for 2 - 3 years followed by an AI for a total duration of 5 years. Benefits in terms of disease-free and overall survival must be balanced against longer term adverse effects on bone health and cognitive function as well as cost. Some patients at very low risk of relapse may derive minimal additional benefit from incorporation of an AI into their treatment schedule and should receive tamoxifen only. The three oral AI's are of comparable efficacy and are potentially interchangeable. Longitudinal studies must be undertaken with gathering of longer term data on side-effect profiles before any definitive pronouncements on clinical utility. There are particular concerns about severe oestrogen depletion amongst women receiving an AI for chemoprevention and ongoing evaluation of treatment related morbidity is essential.