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Fox Chase, PA, United States

Burtness B.,Chase Medical | Bauman J.E.,University of New Mexico | Galloway T.,Fox Chase Cancer Center
The Lancet Oncology | Year: 2013

Cancers of the head and neck that arise from habitual exposure to carcinogens have lower cure rates than those that arise from infection with human papillomavirus (HPV), and intensification of cytotoxic chemotherapy and radiation has not improved outcomes. HPV-negative head and neck cancers abundantly express EGFR, and the monoclonal antibody cetuximab, directed against EGFR, is the only targeted therapy that has improved disease survival so far. However, response rates to single-agent cetuximab are lower than 15%, and cetuximab given with chemotherapy or radiation leads to only a modest effect on survival. Thus, investigating the mechanisms of resistance to EGFR inhibition in HPV-negative head and neck cancer might help identify novel and active therapies. In this Review, we focus on therapies in development that target redundant receptor tyrosine kinases (eg, HER2 and MET), reduce or abrogate nuclear functions of EGFR, affect cellular trafficking by inhibition of histone deacetylase, or treatments that might address resistance that arises in the EGFR signalling stream (eg, aurora-kinase inhibitors and STAT decoys). © 2013 Elsevier Ltd. Source

Enders G.H.,Fox Chase Cancer Center
Genes and Cancer | Year: 2012

Cyclin-dependent kinases (Cdks) drive cell cycle progression in all eukaryotes. Yeasts have a single major Cdk that mediates distinct cell cycle transitions via association with different cyclins. The closest homolog in mammals, Cdk1, drives mitosis. Mammals have additional Cdks-Cdk2, Cdk4, and Cdk6-that represent the major Cdks activated during interphase (iCdks). A large body of evidence has accrued that suggests that activation of iCdks dictates progression though interphase. In apparent contradiction, deficiency in each individual iCdk, respectively, in knockout mice proved to be compatible with live birth and in some instances fertility. Moreover, murine embryos could be derived with Cdk1 as the only functional Cdk. Thus, none of the iCdks is strictly essential for mammalian cell cycle progression, raising the possibility that Cdk1 is the dominant regulator in interphase. However, an absence of iCdks has been accompanied by major shifts in cyclin association to Cdk1, suggesting gain in function. After considerable tweaking, a chemical genetic approach has recently been able to examine the impact of acute inhibition of Cdk2 activity without marked distortion of cyclin/Cdk complex formation. The results suggest that, when expressed at its normal levels, Cdk2 performs essential roles in driving human cells into S phase and maintaining genomic stability. These new findings appear to have restored order to the cell cycle field, bringing it full circle to the view that iCdks indeed play important roles. They also underscore the caveat in knockdown and knockout approaches that protein underexpression can significantly perturb a protein interaction network. We discuss the implications of the new synthesis for future cell cycle studies and anti-Cdk-based therapy of cancer and other diseases. © The Author(s) 2013. Source

Taylor J.M.,Fox Chase Cancer Center
Seminars in Liver Disease | Year: 2012

Although much of the current understanding of the replication of hepatitis D virus (HDV) has been gained from ex vivo rather than in vivo studies, many seemingly unique aspects have been discovered. These include the ultra-small size and circular conformation of the RNA genome, the presence on the viral RNAs of two ribozymes, the role of RNA-directed RNA transcription by redirection of host enzymes, the requirement of site-specific, posttranscriptional RNA-editing, and more. This review addresses recent insights, remaining controversies, and just plain deficits in our understanding of HDV replication. ©Copyright 2012 by Thieme MedicalPublishers, Inc. Source

Taylor J.M.,Fox Chase Cancer Center
Cold Spring Harbor Perspectives in Medicine | Year: 2015

This work reviews specific related aspects of hepatitis delta virus (HDV) reproduction, including virion structure, the RNA genome, the mode of genome replication, the delta antigens, and the assembly of HDV using the envelope proteins of its helper virus, hepatitis B virus (HBV). These topics are considered with perspectives ranging from a history of discovery through to still-unsolved problems. HDV evolution, virus entry, and associated pathogenic potential and treatment of infections are considered in other articles in this collection. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved. Source

Grivennikov S.I.,Fox Chase Cancer Center
Seminars in Immunopathology | Year: 2013

Connection between inflammation and cancer is a rapidly developing field. Epidemiological data suggests that inflammation along with distinct arms of host immune system plays a very important role in the development and progression of many different cancers. Inflammatory bowel disease (IBD) is an important risk factor for the development of colon cancer, namely, colitis-associated cancer (CAC). The molecular mechanisms by which inflammation promotes cancer development are still being uncovered and may differ between CAC and other forms of colorectal cancer. Recent work has shed light on the role of distinct immune cells, cytokines, and other immune mediators in virtually all of the steps of colonic tumorigenesis, including tumor initiation and promotion as well as progression and metastasis. The close proximity of colonic tumors to the myriad of intestinal microbes, as well as instrumental role of microbiota in IBD, introduces microbes as new players capable of triggering inflammation and possibly promoting tumorigenesis. Various mechanisms of CAC tumorigenesis as well as new possible hints for the future approaches for prevention and therapy are discussed in this review. © 2012 Springer-Verlag Berlin Heidelberg. Source

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