Current Cancer Therapy Reviews (v.5, #2)

Nanotechnology is a multidisciplinary field that brings together diverse fields of research and development such as engineering, biology, physics and chemistry. Formal definitions of nanotechnology refer to man-made devices, components and structures in the 1 - 100 nm range in at least one dimension. Advances in nanoscience are having a significant impact on many scientific fields, boosting the development of a variety of important technologies. Nanotechnology offers an unprecedented opportunity to interact with cancer cells in real time at the molecular and cellular scale. Because of their small size, nanoscale devices can readily interact with biomolecules on both the surface of cells and inside of cells. The concerted development of nanoscale devices, structures and components have provided essential breakthroughs in monitoring and fighting cancer at the earliest stages of the cancer process. Nanotechnology offers a wealth of tools that may provide researchers with new and innovative ways to diagnose and treat cancer - new imaging agents; systems for real-time assessments of therapeutic and surgical efficacy; multifunctional, targeted devices capable of bypassing biological barriers to deliver multiple therapeutic agents directly to cancer cells and tissues that play a critical role in cancer growth and metastasis; agents that can monitor predictive molecular changes allowing for preventive action against precancerous cells becoming malignant; minimizing costs for multiplex analysis. Nanotechnology, if properly integrated with conventional cancer research, may provide extraordinary prospects towards better diagnosis and effective therapy.

Status of Flavonols as P-Glycoprotein Inhibitors in Cancer Chemotherapy by Tripta Bansal, Manu Jaggi, Roop Khar, Sushama Talegaonkar (89-99).
Cancer treatment by drugs is seriously limited by P-glycoprotein (P-gp) associated multi-drug resistance (MDR) in various tumor cells. It is now widely recognized that P-gp influences drug transport across various biological membranes. P-gp transporter is widely present in various body tissues affecting absorption, distribution, metabolism and excretion of drugs. Clinical significance of above mentioned carrier is appreciated from the fact that more than fifty percent of existing anti-cancer drugs undergo inhibitable and saturable P-gp mediated efflux. Consequently, there is an increasing trend to optimize pharmacokinetics, enhance antitumour activity and reduce systemic toxicity of existing anticancer drugs by inhibiting P-gp mediated transport. Although a wide variety of P-gp inhibitors have been discovered, research efforts are underway to identify the most appropriate one. Flavanoids belong to the third generation, nonpharmaceutical category of P-gp inhibitors. Among different classes of flavonoids, flavonols are the most explored P-gp inhibitors by several research groups. This could possibly be because of the fact that the effects produced by these are found to be comparable to those of well-known potent P-gp inhibitors verapamil and cyclosporine. Identification of effective P-gp modulator among herbal compounds have an added advantage of being safe, thereby making them ideal candidates for bioavailability enhancement, tissue-penetration (e.g. blood brain barrier), decreasing biliary excretion and multidrug resistance modulating agents. The dual effects, i.e. P-gp modulation and antitumor activity, of these herbal derivatives may synergistically act in cancer chemotherapy. This paper presents an overview of the investigations on the feasibility and application of flavonols as P-gp modulators for improved efficacy of anti-cancer drugs. The review also focuses on flavonol-drug interactions as well as the reversal activity of flavonols useful against MDR.

GIST and Breast Cancer: 3 Case Reports and a Review of the Literature by Gaia Schiavon, Robert Maki, Monica Fornier (100-104).
Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors. Some cases of association with breast cancer have been described, but the possible etiological relationship between GIST and breast adenocarcinoma is unknown. Methods: We report on three patients with diagnoses of GIST and breast carcinoma at Memorial Sloan-Kettering Cancer Center. We review the literature regarding GIST-associated malignancies, with an emphasis on breast cancer. Results: We observed two cases of breast cancer patients diagnosed with GIST, which were detected during routine follow- up and staging procedures, respectively. A third case of breast ductal adenocarcinoma diagnosed in a patient with metastatic GIST with a long-term response to imatinib is also described. Clinical implications of an early diagnosis of otherwise generally asymptomatic neoplasms are described in this paper, together with the role of PET/CT in the staging and follow-up of both neoplasms. Conclusions: Reports of GIST associated with other neoplasms are becoming more common as patients live longer after diagnosis of other cancers, and as detection techniques improve in quality. It is difficult to exclude an incidental relationship between breast cancer and GIST, but the lack of an obvious increase in GIST in patients with familial breast cancer indicates that if there were a relationship, it would be through another genetic mechanism. Further studies are underway to clarify both the relationship of GIST with other cancers, as well as any possible role of c-kit in the development of breast adenocarcinoma.

Cancer Stem Cells of Head and Neck Squamous Cell Carcinoma by Mathilde Lechevrel, Brigitte Sola (105-110).
Homeostasis of most tissues and organs is maintained by tissue-specific somatic or adult stem cells (SCs) and their early progenitors possessing two main properties: self-renewal and differentiation. To fulfil these two functions, they must undergo either symmetrical division for stem cell expansion, necessary after injury for example, or asymmetrical division for stem cell maintenance and progenitor production. The and#x201C;cancer stem cell hypothesisand#x201D; postulates that tumours arise from adult stem cells called cancer stem cells (CSCs) that possess stem cell properties. There is growing evidence that most solid tumours and haematological malignancies are driven by CSCs as a result of advances in stem cell biology and the development of animal models. This has fundamental implications for understanding the biology of cancers and also for developing new therapeutic strategies. The recent characterisation of CSC in head and neck squamous cell carcinoma (HNSCC) prompted us to re-examine the disease development and to discuss the limited effects of conventional therapies.

Obesity is a well-recognized cancer risk factor. The increase in risk for colorectal, endometrial, breast and esophageal cancers associated with obesity ranges from 1.5- to as much as 3-fold. Obese patients develop more aggressive cancers that are less responsive to treatment. Here, we review the available data on an obesity-linked gene, SH2-domaincontaining inositol 5-phosphatase-2 (SHIP2), in light of new experimental and clinical evidence of its pro-oncogenic role. A putative diabetes drug target, SHIP2 is an important negative regulator of insulin signaling that acts downstream of phosphoinositide 3-kinase (PI3-kinase). In mice, SHIP2 levels are increased by a high-fat diet, and its knockout prevents diet-induced obesity. Taking together these findings, we propose that SHIP2 is a potential anti-cancer target with a high therapeutic index owing to its cancer-specific overexpression and/or differential function combined with the absence of major untoward effects upon its loss of function in normal cells. We compare and contrast the pro-oncogenic function of SHIP2 with the current understanding of cancer-relevant functions of PTEN and PTP-1B, two negative regulators of insulin function. The provocative idea that a negative regulator of insulin function will positively influence oncogenesis presents the intriguing possibility that its inhibition will be a beneficial strategy for two major therapeutic areas: metabolic diseases (such as obesity and diabetes) and cancer.

Apoptotic Signaling in Pancreatic Cancer – Therapeutic Application (Supplemental Data) by Felix Ruckert, Christian Pilarsky, Hans-Detlev Saeger, Robert Grutzmann (122-133).
Pancreatic cancer is an exceptionally devastating and incurable disease, the treatment of which has largely been unsuccessful due to the higher resistance of pancreatic tumor cells to oncologic treatment. PDAC cells have accumulated different molecular mechanisms, which enable survival against cytotoxic therapies. Defects of the apoptosis pathway play a crucial role. For the last 10 years, many investigations were underway to get insights into the details of the anti-apoptotic mechanisms of PDAC cells. The present review provides a comprehensive description of the molecular signaling of the apoptotic pathway, an incentive on the potential pathogenetic role of different molecular defects on existing oncologic treatments and an appraisal of the most recent therapeutic strategies applied at a cell biochemical level.

Dendritoma Vaccine for Cancer: A Hopeful Approach by Yanzhang Wei, Jinhua Li, Thomas Wagner (134-141).
Cancer vaccines based on dendritic cells (DCs) have been among the most vigorously studied new cancer therapies during the last decade. Although DCs, the most potent antigen-presenting cells in the body, can be loaded with tumor antigens through varying approaches, such as pulsing and gene transfer, DC-tumor fusion represents the most effective way of engaging DCs with tumor antigens. A significant amount of effort has been given to DC-tumor fusion vaccines, yet in most cases the clinical responses have been discouraging. Therefore, further improvement of this promising cancer therapy is urgently required in order to optimize its clinical efficacy. In this review, we briefly summarize the history and current status of DC-tumor fusion vaccines. Then, we focus on discussions of the technology and the clinical applications of the dendritoma vaccine, a highly purified DC-tumor cell vaccine that uniquely presents a tumor's entire antigen diversity.

Anal Carcinoma by Wayne Frederick, Neil Bhayani, Debra Ford, Gary Yang, Charles Thomas Jr. (142-150).
Anal carcinoma accounts for less than 2and#x25; of all gastrointestinal malignancies. The incidence of anal cancer is increasing and may be associated with an increase in anal receptive intercourse or higher number of sexual partners. Such behaviors have also increased the risk of infection with both HIV and human papilloma virus (HPV). HPV appears to induce dysplasia in the anal mucosa, which is readily detectable and treatable. The strong association of HPV has even spurred research into primary prevention in high-risk patients. Models suggest that screening in the highest risk patients would not only confer a survival benefit but also be cost effective. While the overall prognosis is only a 55and#x25; survival at 5 years, survival for localized disease remains near 80and#x25;. Traditional staging by cross-sectional imaging may be giving way to endorectal ultrasound and sentinel node biopsy. The standard of care for anal canal carcinoma is now combined modality therapy (CMT) with chemoradiation therapy obtaining excellent oncologic results as well as organ preservation. Advances in intensity modulated radiation therapy (IMRT) and brachytherapy have significantly decreased toxicity. Surgery improves survival in patients with persistent or residual disease Within the next decade, anal cancer may emerge as a preventable form of cancer.