SMARCB1 Loss in Poorly Differentiated Chordomas Drives Tumor Progression.

Poorly differentiated (PD) chordoma, a rare, aggressive tumor originating from notochordal tissue, shows loss of SMARCB1 expression, a core component of the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes. To determine the impact of SMARCB1 re-expression on cell growth and gene expression, two SMARCB1-negative PD chordoma cell lines with an inducible SMARCB1 expression system were generated. After 72 hours of induction of SMARCB1, both SMARCB1-negative PD chordoma cell lines continued to proliferate. This result contrasted with those observed with SMARCB1-negative rhabdoid cell lines in which SMARCB1 re-expression caused the rapid inhibition of growth. We found that the lack of growth inhibition may arise from the loss of CDKN2A (p16INK4A) expression in PD chordoma cell lines. RNA-sequencing of cell lines after SMARCB1 re-expression showed a down-regulation for rRNA and RNA processing as well as metabolic processing and increased expression of genes involved in cell adhesion, cell migration, and development. Taken together, these data establish that SMARCB1 re-expression in PD chordomas alters the repertoire of SWI/SNF complexes, perhaps restoring those associated with cellular differentiation. These novel findings support a model in which SMARCB1 inactivation blocks the conversion of growth-promoting SWI/SNF complexes to differentiation-inducing ones, and they implicate SMARCB1 loss as a late event in tumorigenic progression. Importantly, the absence of growth inhibition after SMARCB1 restoration creates a unique opportunity to identify therapeutic vulnerabilities.

A Cell-Based Renilla Luminescence Reporter Plasmid Assay for High-Throughput Screening to Identify Novel FDA-Approved Drug Inhibitors of HPV-16 Infection.

Like cervical cancer, anal cancer is caused by human papillomavirus (HPV). HPV is the most common sexually transmitted agent and is found in the anal canal of almost all HIV-positive men who have sex with men (MSM). Rates of HPV anal cancer are disproportionately higher in this population. Although the nanovalent HPV vaccine is efficacious in protecting against oncogenic HPV types, a substantial proportion of MSM remains unvaccinated and anal HPV infection continues to be an important public health burden. Therefore, it is important to identify strategies to prevent HPV infection. We report on two promising and interlinked strategies: (1) the development of a cell-based Renilla luminescence reporter assay using HPV-16 pseudovirions that encapsidate SV40-driven Renilla luminescence reporter expression plasmid and (2) use of this assay for high-throughput screening (HTS) of FDA- and internationally approved drugs to identify those that could be repurposed to prevent HPV infection. We conducted a screen of 1906 drugs. The assay was valid with a Z' of 0.67 ± 0.04, percent coefficient of variance of 10.0, and signal-to-background noise window of 424.0 ± 8.0. Five drugs were chosen for further analyses based on selection parameters of ≥77.0% infection of HPV-16 pseudovirion-driven Renilla expression with <20.0% cytotoxicity. Of these, the antifungal pentamidine and a gamma-amino butyric acid receptor agonist securinine exhibited ≥90.0% infection with <10.0% cytotoxicity. This luminescent cell-based reporter expression plasmid assay for HTS is a valid method to identify FDA- and internationally approved drugs with the potential to be repurposed into prevention modalities for HPV infection.

Remodeling the cancer epigenome: mutations in the SWI/SNF complex offer new therapeutic opportunities.

INTRODUCTION: Cancer genome sequencing studies have discovered mutations in members of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex in nearly 25% of human cancers. The SWI/SNF complex, first discovered in S. cerevisiae, shows strong conservation from yeast to Drosophila to mammals, contains approximately 10-12 subunits and regulates nucleosome positioning through the energy generated by its ATPase subunits. The unexpected finding of frequent mutations in the complex has fueled studies to identify the mechanisms that drive tumor development and the accompanying therapeutic vulnerabilities. Areas covered: In the review, we focus upon the potential roles different SWI/SNF subunit mutations play in human oncogenesis, their common and unique mechanisms of transformation and the potential for translating these mechanisms into targeted therapies for SWI/SNF-mutant tumors. Expert opinion: We currently have limited insights into how mutations in different SWI/SNF subunits drive the development of human tumors. Because the SWI/SNF complex participates in a broad range of normal cellular functions, defining specific oncogenic pathways has proved difficult. In addition, therapeutic options for SWI/SNF-mutant cancers have mainly evolved from high-throughput screens of cell lines with mutations in different subunits. Future studies should follow a more coherent plan to pinpoint common vulnerabilities among these tumors.

Human Papillomavirus Biology, Pathogenesis, and Potential for Drug Discovery: A Literature Review for HIV Nurse Clinical Scientists.

Persistent oncogenic human papillomavirus (HPV) infection increases the probability that precancerous anal high-grade squamous intraepithelial lesions will progress to invasive anal cancer. Anal neoplasia associated with HPV disproportionately affects HIV-infected individuals, especially men who have sex with men. Prevention is limited to HPV vaccine recommendations, highlighting the need for new treatments. The purpose of this review is to provide HIV information to nurse clinical scientists about HPV-related cancer to highlight the connection between: (a) HPV biology and pathogenesis and (b) the development of drugs and novel therapeutic methods using high-throughput screening. PubMed and CINAHL were used to search the literature to determine HPV-related epidemiology, biology, and use of high-throughput screening for drug discovery. Several events in the HPV life cycle have the potential to be developed into biologic targets for drug discovery using the high-throughput screening technique, which has been successfully used to identify compounds to inhibit HPV infections.

The application of Kingdon's Multiple Streams Theory for human papillomavirus-related anal intraepithelial neoplasia.

AIMS: This paper presents a discussion of the advantages and disadvantages of redefining human papillomavirus-related anal intraepithelial neoplasia as a problem of sexually active people by using Kingdon's Multiple Streams Theory to examine possible policy solutions for increasing anal cancer screening. BACKGROUND: Human papillomavirus is the most common sexually transmitted infection worldwide. Anal cancer associated with human papillomavirus infections is increasing in incidence in both men and women. The prevalence of anal cancer does not decrease with age. DATA SOURCE: Pubmed was searched for articles and internet references from 1995-2012. DISCUSSION: Although a large body of literature suggests that human papillomavirus-related anal intraepithelial neoplasia is a problem, no effective policy solutions have emerged. However, as almost the entire sexually active population is exposed to human papillomavirus, it should be thought of as every person's problem. This suggests that human papillomavirus-related anal intraepithelial neoplasia calls for different types of problem definitions and policy solutions to address the disease. The issue of anal cancer is typically defined as a problem of HIV-positive individuals. IMPLICATIONS FOR NURSING: Nurses are focused on improving patient outcomes. We play a key role in helping to identify problems, moving problems onto policymaker's agendas, and influencing the creation of new healthcare policies. CONCLUSION: Human papillomavirus-related anal intraepithelial neoplasia demands attention and the development of national level policies to ensure public health and safety. Kingdon's Multiple Streams Theory has provided a pragmatic framework to evaluate the problem.