Current Cancer Therapy Reviews - Volume 6, Issue 1, 2010

Inositol hexaphosphate (IP6) and its derivatives are naturally occurring, most abundant polyphosphorylated carbohydrates in organisms as diverse as yeast, endo-parasites, mammals and plants. IP6 represents a major metabolic pool in cellular phosphate pathways involved in vital functions such as signal transduction, regulation of cell proliferation and differentiation, RNA export, DNA repair, energy transduction and ATP regeneration. IP6 has been recognized as a natural antioxidant and agent preventing calcification and kidney stone formation, normalizing cholesterol concentrations, and reducing pathological platelet activity. The most striking effect of IP6 has been documented in cancer prevention by controlling tumor growth, progression and metastasis. Its anti-cancer actions involve boosting immunity, antioxidant properties, reducing cell proliferation and inducing differentiation of malignant cells. This is brought about via lowerphosphate inositol phosphates (IP1-5) and probably by the highly phosphorylated derivatives (PP-IP4 and PP-IP5); however the selectivity of its metabolite(s) in anti-cancer activity has not been adequately investigated. Preliminary in vitro studies show that IP6 synergistically acts with conventional anti-cancer drugs like tamoxifen overcoming its resistance thus enhancing the anticancer effect of conventional chemotherapy. In this review we present anti-cancer abilities of IP6 and its metabolites and discuss their future use as potential drug(s) for cancer prevention and therapy.

Glioblastoma multiforme (GBM) is one of the most intractable cancers in humans, and yet, in the past decade, incremental advances in the treatment of brain tumors have begun to suggest that effective therapies may be on the horizon. Here we review the latest treatments available to patients and focus on a promising radiotherapeutic strategy that employs the isotope 131Iodine conjugated to an antibody that binds the necrotic core found in all solid tumors. Historically, GBM patients who relapse have a median survival time of no more than 24 weeks; however, the Tumor Necrosis Therapy discussed here has already provided a good quality of life for several patients years beyond the historical median survival time. The cases of two long-term survivors are reviewed, and data are presented to show that initial post-treatment assessments of tumor progression actually turned out to be tumor necrosis and inflammation. Given the current lack of imaging modalities that can distinguish between tumor progression and pseudoprogression, these cases further highlight the challenges faced by physicians in differentiating disease progression or recurrence from necrosis.

Hepatocellular carcinoma (HCC) is a major worldwide health concern with an increasing incidence in the United States. Orthotopic liver transplantation (OLT) has been established as the gold standard for curative therapy of HCC. Because of limited organ supply and socioeconomic factors, OLT is often not a viable option. Surgical resection and ablation are also effective for providing long-term survival. However, most patients are ineligible for curative surgical therapy due to advanced disease. For these patients, effective treatment options have been lacking. Systemic chemotherapy and even recent biologic, targeted agents have shown little to minimal efficacy. Liver-directed regional therapies, including trans-arterial chemoembolization (TACE) and selective internal radiation treatment (SIRT) with Yttrium-90 radioembolization have emerged in recent years as effective therapies to provide local control of disease. Randomized trials have demonstrated a survival benefit for TACE, and SIRT has shown efficacy as an embolic alternative to TACE. Here we review the experience of liver-directed regional therapies and provide a clear rationale for their implementation in a multi-disciplinary algorithmic approach to the management of HCC.

Ranpirnase (ONCONASE®, a trademark of Alfacell Corporation), a cytotoxic amphibian ribonuclease, is known to be selectively tumoricidal against cancer cells. This article briefly summarizes in vitro and in vivo tumoricidal studies of ranpirnase. It proposes mechanisms of ranpirnase based on preclinical and clinical trials. Ranpirnase significantly inhibited oxygen consumption while demonstrating improvement in several tumor physiological parameters including tumor blood flow (TBF). Ranpirnase showed chemo-sensitization with various chemotherapeutic agents in vitro and in vivo. Ranpirnase significantly reduced the tumor hypertension, the major physiological barrier of therapeutic drug delivery to solid tumors. This resulted in increased tumor penetration and selectively increased TBF. This enhanced efficacy of chemotherapeutic agents including cisplatin and doxorubicin. The possible ranpirnase-related signal transduction pathways are discussed in the context of the enhanced induction of apoptosis and inhibition of protein synthesis. As a selective cancer killer ranpirnase may be a promising candidate for improving the treatment of mesothelioma and lung cancer patients.

Accumulating evidence indicates that regulatory T cells (Treg) are a distinct group of immune cells that are essential in maintaining immunologic homeostasis, largely by their ability to suppress responses mediated by other populations of immune cells. In a microbial infection, this suppressive function can be temporally overridden via different mechanisms so that the immune system can mount efficient antimicrobial immunity. However, if Treg's suppressive function is not restored after the elimination of pathogens, the resulting immune hyperactivity would injure self tissues and autoimmune diseases may occur. In case of cancer, the overexpressed self-antigens can induce tumor/self-specific Treg cells that suppress effective antitumor responses. A wealth of evidence clearly shows that some microbes and their products, such as CpG-ODN, OK-432 and BCG, are effective in cancer treatment, most likely by suppression of Treg's function. Therefore, the search for approaches which can override Treg's suppressive functions and trigger an efficient antitumor immunity is crucial to the development of effective cancer immunotherapy.

MicroRNAs (miRNAs) are a class of naturally occurring small non-coding RNAs that control gene expression at the post-transcriptional level. To date, over 700 human miRNA precursors with over 1,000 mature miRNAs have been reported. miRNAs are related to, but distinct from, short interfering RNAs (siRNAs). A key difference between siRNAs and miRNAs is that siRNAs require almost identical sequences to targets to exert their silencing function, whereas miRNAs usually bind to the 3'-untranslated region (3'-UTR) of target genes through partial sequence homology. Because of this unique feature, a single miRNA has multiple targets and thus, miRNAs could regulate a large fraction of proteincoding genes. This may explain why miRNAs play a fundamental role in regulation of diverse cellular processes such as cell growth, proliferation, differentiation and apoptosis and thus, deregulation of miRNA expression can lead to a variety of disorders including cancer. In this regard, miRNAs can function as either oncogenes or tumor suppressors. For example, miR-21 is an oncogenic miRNA which has been shown to promote tumor growth and metastasis in several types of cancers by targeting multiple tumor suppressors. Therefore, targeting miR-21 may provide a promising strategy for cancer intervention. In this review, we will discuss our current understanding of miR-21-mediated gene silencing, tumor growth and metastasis, and the potential of miR-21 as a cancer biomarker. We will also provide a perspective on targeting miR-21 for cancer therapy.

Treatment options for hormone-dependent advanced breast cancer (BC) have evolved from surgical oophorectomy, first proposed over a century ago. The discovery of steroid hormones, steroid hormone receptors and the concept that inhibition of steroid biosynthesis or hormone receptor blockade prevents tumor growth, have been introduced and tested clinically. Today, the aromatase inhibitors are the current standard of care for metastatic hormone-sensitive BC in postmenopausal women. To get to this point, many others drugs have been investigated in the continuing search for improved treatment of advanced BC. Agents as high dose estrogens, progestins, antiprogestins, androgens and somatostatin analogues were tested time ago and novel and promising agents, as fulvestrant or sulfatase inhibitors are currently going through a comprehensive clinical trial program. By reviewing the clinical data on the endocrine therapy of advanced BC, we project those areas of future clinical research, beyond the well-known and established tamoxifen and aromatase inhibitors.

Many promising anti-cancer compounds fail in the clinical phase despite extensive testing in animal models. Reasons for this failure are varied, ranging from inadequate mouse models to dosing schemes that cannot be applied in humans. The apparent shortcomings of exisiting pre-clinical studies suggests a need for improved mouse models. Furthermore, the development of an increasing number of targeted drugs requires that biomarkers and/or the in vivo imaging of the tumor or its environment need to be established, ideally before the clinical candidate is selected. In this review, we focus on recent progress in mouse models, emphasizing imaging techniques, biomarker development, the tumor microenvironment and orthotopic metastatic tumor models. We discuss the application of the latter models to drug testing, making comparisons with classical subcutaneous xenograft models, and also models utilizing transgenic animals. Imaging modalities used to detect orthotopically implanted cells in the mouse, e.g. fluorescence or luciferase, which allow relatively high throughput measurements, will be compared to PET, CT, or MRI, which are closer to the clinical application. Examples for a combination of the latter imaging systems with luciferase or fluorescence in the mouse to develop or improve clinical imaging will be presented. Finally, the value of biomarkers in mouse models and strategies to identify novel targetspecific biomarkers in mouse models will be discussed.