Current Cancer Therapy Reviews - Volume 7, Issue 2, 2011

Angiogenin (ANG), a 14 kDa angiogenic ribonuclease, is upregulated in human prostate cancers, especially in hormone refractory diseases, and is the highest upregulated gene in Akt-driven prostate intraepithelial neoplasia (PIN) in mice. ANG has been shown to undergo nuclear translocation in both prostate cancer cells and cancer-associated endothelial cells where it binds to the promoter region of ribosomal DNA (rDNA) and stimulates ribosomal RNA (rRNA) transcription. ANG thus plays an essential role in prostate cancer progression by stimulating both cancer cell proliferation and tumor angiogenesis. A variety of ANG antagonists, including its antisense oligonucleotide, siRNA, soluble binding proteins, monoclonal antibody, enzymatic inhibitors, and nuclear translocation blockers, have all been shown to inhibit prostate cancer in various animal models. Accumulating evidence indicates that ANG is a molecular target for prostate cancer drug development.

The medical community would benefit tremendously from a single test to screen for multiple cancers simultaneously with results that would allow the physician to tailor treatment to the individual. An ultimate goal is to utilize the same test to monitor treatment efficacy and prognosis. Critical components of such tests are likely to be biomarkers, molecules that indicate normal or pathogenic biological processes. The ability to systematically examine disease at the molecular level with high-throughput technologies, such as genomics and proteomics, has opened up new and exciting possibilities for biomarker discovery. Microarray analyses for example, have recently revealed gene expression ‘signatures’ of breast cancer. Additionally, recent advances in proteomics technology provide powerful analytical tools for the discovery and detection of differentially expressed and post-translationally-modified candidate protein biomarkers in tumors and blood. It is expected that new molecular markers will facilitate the move away from population based and toward personalized medicine. Unfortunately, the discovery of sensitive and specific biomarkers for human cancer has been hindered by undefined genetic and environmental heterogeneity. Large numbers of human clinical specimens may overcome these obstacles, but these are difficult to obtain. Furthermore, identification of low abundance proteins in plasma has been proven to be a daunting task due to the vast dynamic range of protein concentrations in the plasma proteome. These issues, coupled with the enormous volume of resulting data, create a bottleneck for identification of relevant biomarkers. An attractive alternative that acknowledges the shortcomings of the current technologies yet is still a comprehensive approach for biomarker discovery is to employ comparative studies in less complex biofluids followed by verification with targeted mass spectromerty analyses for differential expression in human disease plasma.

Worldwide more than 350,000 patients will be diagnosed with oral cancer this year; however, the survival of patients with oral cancer has not changed significantly over the last 30 years. Recent reports have demonstrated that epithelial-mesenchymal transition (EMT) not only contributes to cancer cell invasion and metastasis but it is also associated with treatment resistance. In this review, we will examine the data demonstrating the role of EMT in oral cancer and the extent to which it contributes to poor response to current therapeutic modalities. We will also examine the interplay between EMT and microRNAs and review the role of microRNAs in modulating resistance of oral cancer cells to current therapeutic modalities. Similarly, we will review how EMT contributes to the generation and maintenance of stem cells and examine the role of stem cells in oral cancer recurrence and in modulating treatment resistance. Finally, we will examine how EMT is involved in fibrosis, which can limit delivery of therapeutic agents to cancer cells. Overall, this review will summarize our understanding of how EMT contributes to oral cancer progression and identify additional therapeutic targets that may help to reduce the morbidity and mortality associated with oral cancer.

Bisphosphonates are the standard of care for preventing skeletal morbidity in patients with malignant bone disease. In this setting, zoledronic acid (intravenous; 4 mg monthly) is approved for the prevention of skeletal-related events in patients with bone lesions from multiple myeloma or bone metastases from breast cancer and other solid tumors (eg, genitourinary malignancies, lung cancer). Recent data from large phase III studies show that zoledronic acid (4 mg every 6 months) preserves bone mineral density and reduces disease recurrence in bone and at other sites during adjuvant endocrine therapy for early breast cancer in both pre- and postmenopausal women. There is a strong preclinical and early clinical rationale that zoledronic acid can inhibit cancer cell proliferation and viability and interfere with various steps in the metastatic process (effects on the cancer “seed”). In addition, bisphosphonates alter bone metabolism and may render the bone microenvironment (“soil”) less conducive to tumor growth. This article will summarize the current evidence in the context of the “seed and soil” theory of tumor metastasis, and will discuss how emerging new data and ongoing trials of bisphosphonates for the prevention of metastases in various tumor types might expand their role in the adjuvant therapy setting.

Breast cancer remains the most common malignancy amongst women and its incidence continues to increase worldwide. Breast cancer is a heterogeneous disease with distinct molecular subtypes characterized by differential response to targeted (tamoxifen) and chemotherapeutic agents (5-FluoroUracil, methotrexate). Epidemiological observations emphasize the hormone dependency of breast cancer and the importance of endocrine therapies to treat the hormonally dependent cancers. ATP Binding Cassette (ABC) transporters form one of the largest of all protein families and are central to many important biomedical phenomena, including resistance mechanism of cancers. They are able to transport a variety of compounds through membranes against steep concentration gradients at the cost of ATP hydrolysis. After providing an overview of their tissue distribution, and various procedures to experimentally quantify their transport activity, we summarized the current literature regarding the putative regulation of ABC transporter expression levels by hormonal therapies including estrogens and tamoxifen, as well as the potential impact on the overall health of patients with breast cancer. Elucidation of the resistance mechanisms in cancers is essential for the rational choice of anticancer and adjuvant therapies given to the patients.

For the past several decades, the understanding of the molecular mechanisms of cancer initiation, progression, and metastasis has increased. As data elucidating these mechanisms has been amassed, potential targets for therapy have been identified. Tyrosine kinases were first recognized in 1979 and subsequently their potential role in cancer has been established. There are approximately 90 known tyrosine kinases in human cells, about half of which are receptor tyrosine kinases. The receptor tyrosine kinases span the cell membrane and are activated by binding of a ligand. Cytoplasmic nonreceptor tyrosine kinases, or intracellular tyrosine kinases, are downstream of receptor tyrosine kinases. The receptor tyrosine kinases act in concert with intracellular tyrosine kinases to mediate cell behaviors, including growth and proliferation, angiogenesis, apoptosis, gene transcription, and intercellular interactions. Inappropriate activation of tyrosine kinases plays a significant role in the initiation and progression of human cancers. The critical role of tyrosine kinases in signal transduction, coupled with the frequent incidence of their increased expression levels and activating gene mutations in cancer, makes these enzymes attractive targets for therapeutic intervention in cancer treatment. This article provides a summary of current drugs targeting tyrosine kinases for cancer therapy, focusing on those being used in the clinic.