Current Cancer Therapy Reviews (v.6, #4)

Colorectal cancer is a common malignancy in the United States and a significant cause of mortality yearly. Most recently, target-directed therapies have been added to the armamentarium. These include agents directed at the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR). These agents improve survival in some patients; however, they are associated with high costs and increased toxicities. It is, therefore, necessary for a biomarker to be developed to enrich the patient population receiving these agents. Numerous potential biomarkers have been investigated including EGFR copy number, EGFR mutations, PTEN, AKT, KRAS, and the development of the acneiform rash. Here we review the data on KRAS mutation status and the response to treatment of patients with metastatic colorectal cancer (mCRC). These patients have received the EGFR-directed agents, cetuximab and panitumumab. In addition, a cost analysis is also performed to determine the cost effectiveness of KRAS mutation analysis.

Apoptosis plays an essential role in the processes of eukaryotic cellular homeostasis, and is thought to be a contributing factor in the development of a variety of pathologies including cancer. Knowledge of the molecular mechanisms and mediators of apoptosis, coupled with the fact that many current anticancer therapies function by activating apoptosis, has led to realization that apoptotic processes not only serve as the crucial regulators of carcinogenesis but are also critical determinants in therapy responses. Defects in apoptosis signaling often lead to ineffective response to anti-cancer therapeutics in the clinic and contribute to development of drug-resistant phenotype. The mediators of apoptosis, therefore, are attractive and rational targets for design and development of apoptosis-promoting strategies to combat cancer. Here we present an overview of different approaches and proof-of-principle evidence for identification, development, and use of agents that target apoptosis signaling in cancer. A synopsis of different apoptosis pathways and the agents, currently in the clinic or in development pipeline, that target mediators of apoptosis is presented. Last, but not least, novel and emerging apoptosis signaling targets with potential utility in anti-cancer drug development are also discussed.

Irinotecan has been increasingly used for treatment of pediatric cancers over the past decade. Irinotecan has modest single-agent activity against common childhood solid tumors, and the low incidence of myelosuppression seen with protracted administration makes it well-suited for combination chemotherapy regimens. Data from mouse xenograft models and clinical trials suggest the activity of irinotecan can be improved by the addition of temozolomide, vincristine, or bevacizumab. These observations have led to focused investigation in at least seven different types of childhood cancer. This report summarizes the progress made in understanding the spectrum of activity, pharmacokinetics, pharmacogenetics, toxicity profile, and mechanisms of resistance of this agent. Also reviewed are the different schedules and routes of administration that have been investigated in pediatric clinical trials. Finally, potential applications for future use are discussed, including novel combinations with targeted therapies.

Gene Expression Signatures of Lymph Node Metastasis in Oral Cancer: Molecular Characteristics and Clinical Significances by Xiqiang Liu, Antonia Kolokythas, Jianguang Wang, Hongzhang Huang, Xiaofeng Zhou (294-307).
Even though lymph node metastasis accounts for the vast majority of cancer death in patients with oral cancer (OC), the molecular mechanisms of lymph node metastasis remain elusive. Genome-wide microarray analyses and functional studies in vitro and in vivo, along with detailed clinical observations, have identified a number of molecules that may contribute to lymph node metastasis. These include lymphangionenic cytokines, cell adhesion molecules, basement membrane-interacting molecules, matrix enzymes and relevant downstream signaling pathways. However, defined gene signatures from different studies are highly variable, which hinders their translation to clinically relevant applications. To date, none of the identified signatures or molecular biomarkers has been successfully implemented as a diagnostic or prognostic tool applicable to routine clinical practice. In this review, we will first introduce the significance of lymph node metastasis in OC, and clinical/experimental evidences that support the underlying molecular mechanisms. We will then provide a comprehensive review and integrative analysis of the existing gene expression studies that aim to identify the metastasis-related signatures in OC. Finally, the remaining challenges will be discussed and our insights on future directions will be provided.

Dietary Agents for Prostate Cancer Chemoprevention: An Overview by Natalie A. Venier, Laurence H. Klotz, Neil E. Fleshner, Vasundara Venkateswaran (308-316).
Prostate cancer (PCa) is the most common internal malignancy and the third most frequent cause of cancer death in men. It is estimated that in each week of 2009 over 490 Canadian men were diagnosed with PCa, and 85 will have died from the disease. The introduction of PSA (prostate-specific antigen) screening tests has contributed in part, to men being diagnosed and treated at an early stage. Chemoprevention is a strategy whereby patients are administered drugs, vitamins, or other agents to prevent/reduce the risk of cancer progression and/ or delay the development of its recurrence thereby decreasing patient morbidity and mortality. PCa has a long latency period, thereby offering plenty of opportunity to intervene through the implementation of chemopreventive therapies. A large body of epidemiologic evidence, together with published data from in vivo and in vitro studies, strongly supports relationships between dietary constituents and the risk of prostate cancer. This article aims to review the diverse aspects of chemoprevention including the benefit of both macro- and micronutrients that have been implicated in prostate cancer prevention. In addition we discuss perspectives on the putative mechanisms of selected chemopreventive agents and highlight several clinical studies using specific chemopreventive interventions.

Nuclear Receptor SHP as a Potential Therapeutic Target for Liver Cancer by Jenny Hatch, Shiguo Liu, Timothy Gayowski, John Sorensen, Li Wang (317-322).
Small heterodimer partner (SHP, NR0B2) is a nuclear receptor that exerts influence over the expression of several nuclear receptors and transcription factors. We have previously shown that SHP is involved in several metabolic and cellular processes. Of particular interest, SHP appears to play a crucial role as a tumor suppressor. We have recently published work demonstrating that SHP knockout (SHP-/-) mice spontaneously develop hepatocellular carcinoma. We have discovered that SHP is a potent inhibitor of cellular proliferation, and that activation of SHP induces apoptosis and inhibits tumor growth. In collateral studies, we have also found that SHP is a key regulator of microRNA gene transcription and through this process can activate apoptosis. Furthermore, we have also shown that SHP expression can be influenced by the degree of methylation. The ability to modulate key cellular processes, particularly cellular proliferation and apoptosis, has heightened interest in the ability of this protein to function as a therapeutic target in hepatomas, as well as other neoplasms. Future research will also examine the sensitivity and specificity of SHP to function as a biomarker for hepatocellular carcinoma.

The Role of Chronic Periodontitis in Prevention and Treatment of Head and Neck Cancers by Mine Tezal, Maureen A. Sullivan, James R. Marshall (323-333).
Morbidity and mortality from head and neck squamous cell carcinoma (HNSCC) are high and this has not improved in decades in spite of extensive research. Additional approaches are necessary to change this status quo. Chronic infection and inflammation have been linked to carcinogenesis in few organs. Periodontitis is a chronic oral infection caused by inflammatory reactions in response to gram negative anaerobic bacteria in the endogenous dental plaque. It leads to irreversible destruction of tissues around teeth clinically detectable as periodontal pockets and alveolar bone loss. Periodontal pockets were also suggested as reservoirs for human papillomavirus (HPV). Chronic proliferation and ulceration of the pocket epithelium may help HPV acquisition and persistence. The results from our NIH-funded study suggest a robust independent association between the history of periodontitis and incident HNSCC. Analyses from a small subset of this population also suggest a synergy between periodontitis and oral HPV infection. This review will summarize the evidence supporting: 1) the association between chronic periodontitis and HNSCC, 2) HPV-periodontitis synergy, 3) the biological mechanisms behind these two associations, and 4) implications for safe and practical treatment strategies for HNSCC.