Criteria for the use of omics-based predictors in clinical trials.

The US National Cancer Institute (NCI), in collaboration with scientists representing multiple areas of expertise relevant to 'omics'-based test development, has developed a checklist of criteria that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. The checklist criteria cover issues relating to specimens, assays, mathematical modelling, clinical trial design, and ethical, legal and regulatory aspects. Funding bodies and journals are encouraged to consider the checklist, which they may find useful for assessing study quality and evidence strength. The checklist will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests will be used to guide therapy.

Criteria for the use of omics-based predictors in clinical trials: explanation and elaboration.

High-throughput 'omics' technologies that generate molecular profiles for biospecimens have been extensively used in preclinical studies to reveal molecular subtypes and elucidate the biological mechanisms of disease, and in retrospective studies on clinical specimens to develop mathematical models to predict clinical endpoints. Nevertheless, the translation of these technologies into clinical tests that are useful for guiding management decisions for patients has been relatively slow. It can be difficult to determine when the body of evidence for an omics-based test is sufficiently comprehensive and reliable to support claims that it is ready for clinical use, or even that it is ready for definitive evaluation in a clinical trial in which it may be used to direct patient therapy. Reasons for this difficulty include the exploratory and retrospective nature of many of these studies, the complexity of these assays and their application to clinical specimens, and the many potential pitfalls inherent in the development of mathematical predictor models from the very high-dimensional data generated by these omics technologies. Here we present a checklist of criteria to consider when evaluating the body of evidence supporting the clinical use of a predictor to guide patient therapy. Included are issues pertaining to specimen and assay requirements, the soundness of the process for developing predictor models, expectations regarding clinical study design and conduct, and attention to regulatory, ethical, and legal issues. The proposed checklist should serve as a useful guide to investigators preparing proposals for studies involving the use of omics-based tests. The US National Cancer Institute plans to refer to these guidelines for review of proposals for studies involving omics tests, and it is hoped that other sponsors will adopt the checklist as well.

NIH and NCI support for development of novel therapeutics in gynecologic cancer: a user's guide.

The development of novel therapeutics is a lengthy and often tortuous process. It frequently spans the identification of new targets, preclinical validation, discovery and refinement of novel therapies, safety studies, phase O, 1, 2, and 3 trials, and reverse translation. NIH and NCI provide via web sites a variety of resources and research tools of great value to investigators. NCI also provides tissue resources useful for discovery and validation, as well as extensive support for preclinical drug development. The NCI's effective partnership with industry and academia, as well as the ongoing NCI-supported clinical trials network, facilitates clinical development of novel therapeutics. Specialized NCI programs focused on cancer imaging, radiation research, and complementary and alternative medicine, also assist the development of novel agents. Finally, the NIH and the NCI sponsor a variety of grant mechanisms, supporting institutions, consortia, and individuals, which investigators seeking to develop novel therapeutics should make themselves familiar.

Current status of clinical testing for human papillomavirus in oropharyngeal squamous cell carcinoma.

While a variety of human papillomavirus (HPV) tests and surrogate markers are available, currently there is no consensus on the best detection method(s) that should be used to identify HPV-related oropharyngeal squamous cell carcinomas and serve as a standard test (or tests) for routine diagnostic use. As we begin to consider using the results of HPV testing for clinical purposes beyond simple prognostication, such as making decisions on treatment dose or duration or for targeted therapies that may be highly dependent on viral-mediated pathways, we need to be more rigorous in assessing and ensuring the performance of the test (or tests) used. Here we provide an overview of the platforms and technologies, including the strengths and limitations of each test, and discuss what steps are needed to generate confidence in their performance for use in clinical practice.

Nanotechnology platforms and physiological challenges for cancer therapeutics.

Nanotechnology is considered to be an emerging, disruptive technology that will have significant impact in all industrial sectors and across-the-board applications in cancer research. There has been tremendous investment in this area and an explosion of research and development efforts in recent years, particularly in the area of cancer research. At the National Institutes of Health, nanomedicine is one of the priority areas under its Roadmap Initiatives. Moreover, in 2005 the National Cancer Institute alone committed $144.3 million over 5 years for its Alliance for Nanotechnology in Cancer program. Much research and development is progressing in the areas of cancer diagnostics, devices, biosensors, and microfluidics, but this review will focus on therapeutics. Current nanotechnology platforms for cancer therapeutics encompass a vast array of nanomaterials and nanodevices. This review will focus on six of the most prominent and most widely studied: nanoshells, carbon nanotubes, dendrimers, quantum dots, superparamagnetic nanoparticles, and liposomes. All of these nanotechnology platforms can be multifunctional, so they are frequently touted as "smart" or "intelligent." This review will discuss the shared approaches in the design and development of these nanotechnology platforms that bestow such characteristics to the nanoparticles. Finally, the review will raise awareness of the physiological challenges for the application of these therapeutic nanotechnologies, in light of some recent advances in our understanding of tumor biology.

Clinical Utility of Epstein-Barr Virus DNA Testing in the Treatment of Nasopharyngeal Carcinoma Patients.

Epstein-Barr virus (EBV) DNA analysis has been shown to be useful for early detection, prognostication, and monitoring of treatment response of nasopharyngeal carcinoma (NPC), and the recent literature provides growing evidence of the clinical utility of EBV DNA testing, particularly to inform treatment decisions for NPC patients. Despite the fact that NPC is a rare disease, the NRG Oncology cooperative group has successfully activated a phase 2/3 randomized clinical trial for NPC with international partners and in that process has discovered that the development of a harmonized EBV DNA test is absolutely critical for integration into clinical trials and for future deployment in clinical and central laboratories. In November 2015, the National Cancer Institute (NCI) convened a workshop of international experts in the treatment of NPC and EBV testing to provide a forum for discussing the state of EBV DNA testing and its clinical utility, and to stimulate consideration of future studies and clinical practice guidelines for EBV DNA. This review provides a summary of that discussion.

Current State of PCR-Based Epstein-Barr Virus DNA Testing for Nasopharyngeal Cancer.

Clinical studies have shown plasma Epstein-Barr virus (EBV) DNA level to be an independent prognostic biomarker for nasopharyngeal carcinoma (NPC). However, the proportion of NPC patients whose tumors are associated with EBV vary with geographic location, and there are a variety of assays for plasma EBV. To develop the level of evidence needed to demonstrate the clinical utility of plasma EBV DNA detection for NPC patients and encourage widespread adoption of this biomarker test in clinical laboratories, validated harmonized assays are needed. In 2015, the National Cancer Institute (NCI) convened a Workshop on Harmonization of EBV Testing for Nasopharyngeal Cancer, where experts in head and neck oncology and laboratory medicine addressed the limitations of currently available polymerase chain reaction-based EBV DNA quantitation assays and discussed strategies for advancing the development of harmonized EBV DNA assays and their appropriate clinical use. This article presents the key recommendations to direct future efforts in assay harmonization and validation.

Designing biomarker studies for head and neck cancer.

Although there is ample literature reporting on the identification of molecular biomarkers for head and neck squamous cell carcinoma, none is currently recommended for routine clinical use. A major reason for this lack of progress is the difficulty in designing studies in head and neck cancer to clearly establish the clinical utility of biomarkers. Consequently, biomarker studies frequently stall at the initial discovery phase. In this article, we focus on biomarkers for use in clinical management, including selection of therapy. Using several contemporary examples, we identify some of the common deficiencies in study design that hinder success in biomarker development for this disease area, and we suggest some potential solutions. The purpose of this article is to provide guidance that can assist investigators to more efficiently move promising biomarkers in head and neck cancer from discovery to clinical practice

Identification of a novel promoter in the E2 open reading frame of the human papillomavirus type 18 genome.

Northern blot and RT-PCR analyses indicated that the human papillomavirus E4 open reading frame is expressed in HeLa cells. Because integration at the E1 or E2 open reading frame would place the viral upstream regulatory region downstream of the viral late genes, the expression of E4 in HeLa cells is most likely regulated by host cellular promoter(s) or unidentified viral promoter(s) in the E2 region. Primer extension analysis and transient transfection experiments with luciferase reporter constructs under the transcriptional control of various subgenomic fragments of HPV-18 were carried out to identify and characterize functional promoters within the E2 region. The in vivo activity of a novel promoter located within the 5'-end region of the E2 open reading frame of human papillomavirus type 18 is demonstrated.