Current Cancer Therapy Reviews - Volume 7, Issue 1, 2011

In 2011, Bentham Science Publishers will release the 7th volume of the prestigious cancer therapy review journal: “Current Cancer Therapy Reviews”. In 2011, it is an honor to take over the position of the Editor-in-Chief from Dr. Allan Lipton, Pennsylvannia State University, The Milton S. Hershey Medical Center, USA. Advances of cancer therapy have occured over the last decade in many fields. In every issue of “Current Cancer Therapy Reviews” manuscripts have been published which gave the reader a state-of-the-art overview in cancer research of novel translational approaches from the bench to the bedside. I like to thank the Editors and the members of the Editorial Advisory Board that - since 6 years - they have opened up an avenue of a premium scientific publication forum by establishing this journal within the scientific community. Now, it is worth pausing to put this journal in a slightly moving context. A diagnosis of cancer can be so overwhelming, and our health care system so bewildering and impersonal, that one often does not know where to turn or whom to trust. Cancer and cancer treatment is a universe in itself, has a history, a politics, a mainstream, a lunatic fringe. There are a multitude of choices and treatment decisions to be made, some are specific to cancer, others are adjunctive or palliative; some are supportive for generalized health and healing. Each has potential risks and benefits, which need to be weighed according to the specific of the disease, one's life situation and personal value - in one word, we are knocking at the door of “Personalized Medicine”. Personalized medicine is the management of health (preventive medicine/oncology) and the treatment of disease that is specific for the genetic and the epigenetic make-up of the individual, embedded into her/his pyschological and (bio-)social context. The challenges are great since there are no historical models, but the opportunities for discovery and innovation are significant (see: Personalized Cancer Medicine: Towards individualized cancer treatments. 21 - 23 February, 2011, Matrix, Biopolis, Singapore, organized by Enrico Mihich, Harvard University Medical School, USA; Edison Liu, Genome Institute of Singapore, Singapore; Kurt S. Zanker, University Witten/Herdecke, Germany). The declared paradigm is the development of “personalized and tailored drugs” that precisely target the specific molecular defects of a patient's tumor together with holistic supportive care regimens; supportive care can be described as a system or complex network of state-of-the-art medical, psysochological, and social interventions delivered at various times and places with different intentions. What we urgently need are visions and views for novel cancer therapy treatment strategies, based on what has been achieved but having a mental picture on the future demands of medicine in oncology. We can not achieve this goal in the “West” neither in the “East” alone or, even in a separated manner, we need the “brains” of all scientists and clinicians in one unified world, fighting against cancer. Above all, as between 2000 and 2030, the global absolute number of cancer cases is projected by UN agencies to double, most of all in the middle- and low income countries of Africa and Asia due to the increase in population; and, in the West, due to ageing of the population and malnutrition. As incoming Editor-in-Chief, I invite all scientists and clinicians to join the fight against cancer by chosing “Current Cancer Therapy Reviews” as one of their communication platform. We all want to know what is important for clinicians Today and Tomorrow, and we to distribute new findings without any boarders. As Editor-in-Cief, and, of course all peers, we feel ourselves responsible for good science, reliable and pausible clinical data, which can be reproduced in hospitals all over the world, and, if necessary, we shall improve and up-grade by the advice of experts any peer-reviewed manuscript submitted to “Current Cancer Therapy Reviews”. Established by oncologists for oncologists, the journal challenges its readers to understand what is new, to glimpse the future and how we want to explore cancer medicine throughout the 21st century - your opinion is important!

Non-small cell lung cancer (NSCLC) tumors originating in the superior sulcus have undergone a significant evolution in terms of both therapy and prognosis over the course of the last 80 years. Initially thought to portend universal mortality, the Pancoast tumor and syndrome, with its characteristic refractory pain and neurologic dysfunction resultant from significant local invasion, was met with a sense of helplessness. The transition from palliative to neoadjuvant radiation, and ultimately to trimodality therapy with neoadjuvant chemoradiation and surgical resection, has dramatically altered the outlook in terms of longevity and quality of life for patients with Pancoast tumors. Combined-modality chemoradiation, followed by surgical resection, has now improved the survival for Pancoast tumors to have a better prognosis than comparatively-staged NSCLC originating in other locations within the lung parenchyma. Problems with local control have largely become supplanted by the most common cause of mortality for NSCLC of all stages: distant failure rates. Ongoing efforts to improve the resectability and to decrease the occurrence of distant metastatic disease will need to be the focus of future clinical trials. The application of improved radiotherapeutic technology, as well as the development of systemically active molecularly targeted agents with lower toxicity profiles than standard cytotoxic chemotherapy, may help guide the next steps in improving the outcomes for superior sulcus tumors.

Epothilones are a novel class of natural cytotoxic compounds, originally isolated from the myxobacterium Sorangium cellulosum in the early 1990s. They induce hyperstabilization of microtubules similar to the taxanes leading to cell cycle arrest and finally to apoptosis. The natural epothilones are characterized by the letters A - F. Their chemical structure consists of a 16-membered macrocyclic ring system with a common side chain that differs in its oxydation status. Currently, natural epothilones, such as epothilone B (patupilone) and D (KOS-862), semisynthetic (ixabepilone, BMS-310705) and fully synthetic epothilones (sagopilone and KOS-1584) are in clinical development. Whereas paclitaxel and docetaxel provide significant clinical benefit in the treatment of a number of tumor types, their use is often limited by the development of multidrug resistance. Preclinical results indicate that natural epothilones are not subject to multidrug resistance to the same extent as the taxanes. Whether this translates into additional clinical benefit is currently the objective of extensive investigations. Ixabepilone, like the taxanes a substrate for PgP, has recently been approved for the treatment of metastatic breast cancer in the USA. However, the European agency CHMP declined a positive opinion due to an insufficient benefit /risk ratio. Other epothilones are in different stages of development, the most advanced being patupilone in Phase III in ovarian cancer and sagopilone in Phase II in a number of different tumor types. Although their mechanism of action is identical and their chemical structures are very similar, epothilones exhibit a highly differentiated picture of activity, safety and tolerability profiles. For ixabepilone, the major adverse event is hematological toxicity followed by peripheral sensory neuropathy. Patupilone, on the other hand, is mainly characterized by gastrointestinal side effects, which require pretreatment and concomitant therapy. In the case of sagopilone, peripheral sensory neuropathy is the major clinically relevant side effect. This review summarizes both preclinical and clinical results for the epothilones currently in clinical development.

Reactive oxygen species (ROS) are continuously generated in living cells mainly as a consequence of aerobic metabolism. If ROS production exceeds the capacity of antioxidant systems, oxidative stress may induce damage in all cellular macromolecules. Hypoxia, derived from inappropriate and inadequate vasculature, is a characteristic of rapidly proliferating tumors. A hypoxic environment promotes ROS production which further activates hypoxia-derived pathways, e.g. those regulated by hypoxia inducible factor 1. Based on the increasing and significant amount of data available already, hypoxia and oxidative stress are widely linked to many stages of carcinogenesis. On the other hand, the effects of the major chemotherapeutics, used in the treatment of gynecological cancers, are based directly or indirectly on the excessive production of ROS and high antioxidant levels can increase resistance to these drugs. The measurement of tumor hypoxia, oxidative stress markers and antioxidant levels may become potential predictive and prognostic biomarkers in the future, as already is the case in some types of carcinomas. Either by down or upregulating ROS levels in tumor cells may provide novel pharmacological interventions in the treatment of these malignancies. There are currently several anticancer redox drugs in various phases of pre-clinical and clinical trials which will be discussed in this review.

About 40 - 60% of the patients with prostate cancer in the hormone independent stage respond to a secondary hormonal manipulation with a temporary decrease of the serum prostate-specific antigen (PSA). PSA progression can be delayed for 4 - 8 months and the onset of a taxane-based chemotherapy with its potentially toxic side effects can be postponed. Traditionally second line antiandrogens, inhibitors of adrenal testosterone production, estrogens or progestin have been applied in secondary hormonal manipulation. Recently somatostatin analogs have been suggested for the treatment of hormone independent prostate cancer. By modulating intracellular pro-proliferative and anti-apoptotic signaling cascades somatostatin analogs influence the tumor cell micro-environment and inhibit tumor progression. In this review we focus on the mode of action and the clinical application of somatostatin analogs in the treatment of hormone- independent prostate cancer. The concept of an “anti-survival factor therapy” is discussed.

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Despite therapy with surgery, radiation and chemotherapy, the prognosis remains poor, and the demand for more effective treatments is high. Research has increased our understanding of the molecular pathways important for gliomagenesis and disease progression, including the epidermal growth factor receptor (EGFR) and downstream phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway. Targeted therapeutics have been developed against these receptors and pathways. This article will review the rationale and current evidence for inhibitors of this signaling axis.

The evidence as to the prognostic significance of perineural invasion in adenoid cystic carcinoma of the salivary glands is equivocal. Nevertheless, many head and neck surgeons and oncologists take account of histologically proven perineural invasion when planning treatment for adenoid cystic carcinoma. This review presents a digest of the data showing how neural involvement by adenoid cystic carcinoma of the salivary glands relates to local anatomy, and how this influences the extent of surgery and planning of radiotherapy.