BACKGROUND: Recently, considerable efforts have been directed toward antivascular therapy as a new modality to treat human cancers. However, targeting a therapeutic gene of interest to the tumor vasculature with minimal toxicity to other tissues remains the objective of antivascular gene therapy. Tumor necrosis factor‐α (TNF‐α) is a potent antivascular agent but has limited clinical utility because of significant systemic toxicity. At the maximum tolerated doses of systemic TNF‐α, there is no meaningful antitumor activity. Hence, the objective of this study was to deliver TNF‐α targeted to tumor vasculature by systemic delivery to examine its antitumor activity. METHODS: A hybrid adeno‐associated virus phage vector (AAVP) was used that targets tumor endothelium to express TNF‐α (AAVP‐TNF‐α). The activity of AAVP‐TNF‐α was analyzed in various in vitro and in vivo settings using a human melanoma tumor model. RESULTS: In vitro, AAVP‐TNF‐α infection of human melanoma cells resulted in high levels of TNF‐α expression. Systemic administration of targeted AAVP‐TNF‐α to melanoma xenografts in mice produced the specific delivery of virus to tumor vasculature. In contrast, the nontargeted vector did not target to tumor vasculature. Targeted AAVP delivery resulted in expression of TNF‐α, induction of apoptosis in tumor vessels, and significant inhibition of tumor growth. No systemic toxicity to normal organs was observed. CONCLUSIONS: Targeted AAVP vectors can be used to deliver TNF‐α specifically to tumor vasculature, potentially reducing its systemic toxicity. Because TNF‐α is a promising antivascular agent that currently is limited by its toxicity, the current results suggest the potential for clinical translation of this strategy. Cancer 2009. Published 2008 by the American Cancer Society.

Although comprehensive molecular diagnostics and personalized medicine have sparked excitement among researchers and clinicians, they have yet to be fully incorporated into today's standard of care. This is despite the discovery of disease-related oncogenes, tumor-suppressor genes and protein biomarkers, as well as other biological anomalies related to cancer. Each year, new tests are released that could potentially supplement or surpass standard methods of diagnosis, including serum, protein and gene expression analyses. All of these novel approaches have shown great promise, but initial enthusiasm has diminished as difficulties in reproducibility, expense, standardization and proof of significance beyond current protocols have emerged. This review will focus on current and novel molecular diagnostic tools applied to breast cancer with special attention to the exciting new field of microRNA analysis Keywords breast cancer; microarray; microRNA; molecular diagnostics; predictive value; prognostic value Breast cancer is a major public health issue worldwide. In 2004, the most recent year available for global data, there were 1.15 million new breast cancer cases and over 500,000 deaths reported around the world [1,2]. More than half of all cases occurred in industrialized nations † Author for correspondence, Pathogenetics Unit, Laboratory of Pathology and Urological, Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, tangream@mail.nih.gov. NIH Public Access Author ManuscriptExpert Rev Mol Diagn. Author manuscript; available in PMC 2010 May 1. Published in final edited form as:Expert Rev Mol Diagn. 2009 July ; 9(5): 455-467. doi:10.1586/erm.09.25. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript [1,3]. The higher incidence of breast cancer observed in more developed regions of the world is most likely attributed to the availability of screening programs used to detect breast cancer, which may otherwise have never been diagnosed [4]. The total overall cost for the treatment of patients with breast cancer increases with higher stages of the disease [5]. Therefore, screening and diagnosis of breast cancer at earlier stages both benefits the patient and minimizes the financial burden [5].The traditional clinical approach to treat in situ and invasive breast cancer involves a combination of existing surgical-, chemical-and radiation-based therapies. Surgical options include lumpectomy, quadrantectomy, mastectomy and modified radical mastectomy. These procedures are sometimes followed by adjuvant therapy, such as hormonal and/or chemotherapy, which are administered in a case-dependent manner [6]. Hormonal therapies include selective estrogen receptor modulators (SERMs), such as tamoxifen, and aromatase inhibitors, such as anastrozole. Chemotherapy includes traditional chemotherapies as well as specific drugs such as trastuzumab, a monoclonal antibody to the HER2/neu receptor. Although these therapies have shown great promise in decreasing disease...