Current Cancer Drug Targets - Volume 17, Issue 6, 2017

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Hepatitis C virus (HCV) infection is the predominant cause of chronic liver diseases and HCC, particularly in Western countries. Multiple molecular mechanisms are involved in the development and progression of HCV-related HCC, of which oxidative stress plays a pivotal role. HCV infection induces overproduction of reactive oxygen species (ROS) and impairs the function of endogenous antioxidants. Excessive amount of ROS directly damages DNA, lipids and proteins. Meanwhile, ROS indirectly activates a series of signaling cascades, and modulates the activity of many transcription factors, resulting in altered expression of genes that control cell survival, proliferation, angiogenesis, invasion and metastasis. In this review, we aim to summarize the possible molecular mechanisms underlying the link between the oxidative stress and hepatocarcinogenesis in HCV-infected individuals, in order to facilitate discovery of possible approaches or interventional targets for HCV-related HCC.

Background: Hepatocellular carcinoma (HCC) is the most deadly form of liver cancer. Chronic hepatitis and subsequent liver fibrosis and cirrhosis are the major causes of HCC. HBV infection results not only in HCC but also extra-hepatic cancers. However, the importance and approaches for HCC screening in HBV infected individuals, the risk factors of HCC, the possible mechanisms leading to HCC and the potential therapeutic approaches of HBV-related HCC have less been systematic reviewed. Methods: In this study, we reviewed the screening, risk, new biomarker, mechanism and therapeutic of HBV-related HCC. Results: Serum AFP should be used for the HCC screening in CHB patients. Higher HBV viral load is associated with increased risk of HCC. HBV genotype and genetic polymorphism contribute to the risk of HCC.Ku86, Ku86 antibody, miR-18a, miR-122 and miR-150 may be reliable markers of HBVrelated HCC. MicroRNAs and HBx play a key role in HBV-related HCC. Two types of drugs, conventional interferon (IFN), and nucleoside analogs (NAs), have recently become available for the treatment of CHB infection. However, treatment guidelines for these patients have not yet established. Conclusion: A comprehensive understanding of how HBV infection causes HCC is of great importance in developing more effective antiviral therapy and prevention of late stage consequences such as cirrhosis and HCC. Regular screening in HBV infected individuals is a practically useful approach in reducing the HCC incidence in these patients. More reliable markers for HCC early detection should be explored. Combining IFNs and NAs with other curative approaches have superior benefits in preventing HCC recurrence.

Background: Infection with human papillomavirus (HPVs) causes many cancers, which account for about 10-20% of total human cancers. Two recently developed prophylactic vaccines against virus infection confer strong immunogenicity to provide long-term protection. The use of these vaccines has contributed to a substantial decrease in the rates of cervical cancer the second most common cancer of women worldwide. However, therapeutic vaccines that can eliminate preexisting HPV infections and treat an existing HPV-caused cancer have not been developed. Method: In this short review, we discuss development of immunotherapy for HPV-associated cancers and recent progresses in our understanding of the immunopathology of HPV infection. Results: Recent research advances have shown that molecular approaches target to immunotherapy for HPV infection-induced cancers to have the great potential and promise for developing immunotherapeutic vaccines. So far, the vast majority of the immunotherapeutic vaccines that are being tested are designed to target HPV viral genes and their proteins especially two E6 and E7 oncogenes. Conclusion: The developing immunotherapeutic vaccines aim to boost cell-mediated immunity. The boosted cell-mediated immunity strengthens the body’s natural defenses to fight active infection and disease, thus to treat the existing cancers.

Background: Prostate cancer (PCa), a disease, is characterized by abnormal cell growth in the prostate - a gland in the male reproductive system. Although older age and a family history of the disease have been recognized as the risk factors of PCa, the cause of this cancer remains unclear. Currently, PCa is one of the leading causes of cancer death among men of all races. Method: In this review study, we first discuss the controversy of the contribution of virus infection to PCa, and subsequently summarize the development of oncolytic virotherapy for PCa in the past several years. Results: Mounting evidence suggests that infections with various viruses are causally linked to PCa pathogenesis. Published studies have provided strong evidence that at least two viruses (RXMV and HPV) contribute to prostate tumourigenicity and impact on the survival of patients with malignant PCa. Traditional therapies including chemotherapy and radiotherapy are unable to distinguish cancer cells from normal cells, which are a significant drawback and leads to toxicities for PCa patients undergoing treatment. So far, few other options are available for treating patients with advanced PCa. For PCa treatment, oncolytic virotherapy appears to be much more attractive, which uses live viruses to selectively kill cancer cells. Oncolytic viruses can be genetically engineered to induce cancer cell lysis through virus replication and expression of cytotoxic proteins. Conclusion: Virotherapy is being developed to be a novel therapy for cancers, which uses oncotropic and oncolytic viruses with their abilities to find and destroy malignant cells in the body. As oncolytic viruses are a relatively new class of anti-cancer immunotherapy agents, several important barriers still exist on the road to the use of oncolytic viruses for PCa therapy.

Introduction: EBV-associated Gastric Cancer (EBVaGC) comprises about 9% of all cases of GC and constitutes a distinct clinicopathological and molecular entity. The pattern of viral expression in EBVaGC cannot be set to any of the previously EBV-associated malignancies. Several lines of evidence support that viral expression in EBVaGC is characterized by high transcription of the BamH1- A rightward transcript (BART), low-levels of EBNA-1 and lack of LMP1. The high transcription activity of the BamH1-A region is importantly directed to express BART miRNAs, supporting a critical role for these miRNAs during epithelial cell infection and carcinogenesis. Several studies have shown that promoter hypermethylation is also a prominent feature of EBVaGC. Based on the recent TCGA report, the specific fingerprint of genomic alterations in EBVaGC is marked by mutations in PIK3CA, ARID1A and BCOR genes, and amplification of 9p24.1 that harbors the genes for the JAK2, PD-L1 and PD-L2 proteins. The specific programs of viral gene expression, promoter methylation and genomic mutations found in EBVaGC target cell signaling pathways leading to increased proliferation, increased cell survival, immune evasion, augmented EMT and acquisition of stemness features. Less understood is the participation of EBV in chronic gastric inflammation, but some studies argue that EBV, similar to and together with Helicobacter pylori, is an early participant in the GC oncogenic process through promoting chronic inflammation and increased tissue damage. Conclusion: Here, we discuss the principal and distinctive carcinogenic routes promoted by EBV in the gastric epithelium.

Background: G9a is the primary enzyme for mono- and dimethylation at Lys 9 of histone H3 and forms predominantly the heteromeric complex as a G9a-GLP (G9a-like protein) that is a functional histone lysine methltransferase in vivo. Mounting evidence suggests that G9a catalyzes methylation of histone and nonhistone proteins, which plays a crucial role in diverse biological processes and human diseases. Methods: In this study, the current knowledge on biological functions of G9a and inhibitors were summarized. Results: we review the current knowledge on biological functions of G9a, with particular emphasis on regulating gene expression and cell processes, and involvement in human diseases. We outline a perspective on various classes of G9a inhibitors to date from both articles and patents with an emphasis on their discovery, activity and the current research status. Conclusion: We highlight the key knowledge on potential biological functions and various human diseases. We also reviewed the discovery and characterization of the reported G9a inhibitors. However, we also propose the challenges and future opportunities in study of G9a. This review could make a crucial contribution to the long journey to develop drug-like molecules targeting G9a.

Background: Neuroblastoma (NB) constitutes about 8% of all childhood tumors, yet accounts for more than 15% of deaths, with an unacceptable overall survival rate. These rates are despite the current multimodal therapeutic approaches involving surgery, radiation, chemotherapy and myeloablation with hematopoietic stem cell rescue. Hence, efforts have intensified to identify new targets and novel therapeutic approaches to improve cure rates in these children. Numerous new agents for adult malignancies are developed and evaluated for cancer each year, providing an invaluable resource, with the added advantage of available pharmacologic and toxicity data for consideration. Methods: To identify potential therapeutic targets, we screened a small molecule library of 151 small kinase inhibitors against NB cell lines. Based on our initial screening data, we further examined the potential of Bcr-Abl targeting small molecule inhibitors to affect the growth and survival of NB cells. Results: There is diverse activity among the currently available Bcr-Abl inhibitors, possibly reflecting the molecular heterogeneity and off-target activity in each combination. In depth analyses of ponatinib, an oral multi-target kinase inhibitor and effective agent in the treatment of refractory Philadelphia chromosome (Ph) positive leukemia, show growth inhibition at sub-micromolar concentrations. In addition, we also identified the potential of this agent to interfere with insulin-like growth factor-1 receptor (IGF-1R) signaling pathways and Src activity, inhibit cell migration and induce apoptosis. Conclusion: Our findings provide initial data on ponatinib's potential to target key growth regulatory pathways and provide the rationale for further studies and evaluation in future early phase clinical trials for the treatment of refractory NB.