To date, specific human tumor viruses have been causally associated with at least 15-20% of all human cancers and are widely suspected to contribute to additional cancers. Recent research in our Program and elsewhere further shows that, for many or most virus-associated cancers, viral gene functions are required both for tumor development and also for continued survival of malignant cells in the final tumor. Thus, inhibiting tumor virus infection, tumor virus replication and maintenance, and/or selected viral gene functions could prevent or cure many cancers.

To achieve their goals of understanding and controlling human tumor viruses and their associated cancers, Program members collaborate with each other and with members of many other UW Carbone Cancer Center programs in studies that encompass five of the six established human tumor viruses, plus selected advanced, relevant model systems with substantial advantages for accelerating research progress. To illuminate the infection and replication mechanisms of these viruses and their oncogenic effects, these studies integrate a variety of shared, synergistic approaches including studies of conventional and organotypic cell cultures, transgenic mouse models of specific cancers, and selected virus-associated and virus-negative human tumor sample collections. The results are providing new viral and cellular targets and new approaches for control of tumor virus infection and pathogenesis, as well as new approaches for diagnosis and treatment selection.

Program Profile

Membership:
10 members
   6 departments
   3 schools

Project Funding as of 9/2006 (direct costs):

Peer-reviewed	$ 4.7M	16
NCI	$2.2M	5
NIH	$1.5M	7
ACS	$0.1M	1
NSF	$0.1M	1
Other P-R	$0.8M	2
Non peer-reviewed	$0.2M	2
Total	$4.9M	18

Scientific Goals

To accomplish the mission outlined above, members of the Human Cancer Virology Program and their interprogrammatic collaborators share a focused set of interactive research goals, including:

• To elucidate the pathways by which diverse tumor viruses infect, replicate, interact with their hosts, and maintain their presence through the years to decades typically associated with tumor progression, as well as approaches to inhibit these viral functions.
• To determine the mechanisms by which tumor viruses promote the induction and maintenance of tumors, including identifying viral and host genes essential to the continuing survival of tumor cells and how to block these functions.
• To define the spectrum of molecular changes defining the differences and relationships among normal tissues, virus-associated tumors, virus-free tumors at the same anatomical sites, and relevant precancerous lesions.
• To identify biomarkers for improved diagnosis and prognosis of virus-associated and other important cancers.
• To characterize the nature and extent of virus association with established and suspected virus-associated cancers.
• To use the results of all of the above studies to develop novel and improved approaches to prevent and treat tumor virus infection, replication and tumor induction.

Significant Recent Discoveries

• Identification of MCM7 as a biomarker for cervical cancer and likely other important cancers induced by human papillomavirus. (Cancer Res 63:8173-8180, 2003)
• Identification of ERRα and ERRγ as prognostic biomarkers for breast cancer. (Cancer Res 62:6510-6518, 2002)
• Discovery that Epstein-Barr virus protein EBNA1 is an anti-apoptotic survival factor essential for the continuing survival of EBV-associated Burkitt's lymphoma cells, and perhaps all EBV-associated cancers; inhibiting EBNA1 thus kills EBV-associated tumor cells. (Proc Natl Acad Sci USA 100:14269-14274, 2003)
• Discovery that estrogen contributes not only to development and malignant progression of cervical cancers but also to their persistence, implying that anti-estrogen therapies may be valuable in cervical cancer treatment. (Proc Natl Acad Sci USA 102:2490-2495, 2005).
• Overcoming major barriers to studying early steps in human papillomavirus infection by developing methods that uncouple infectious virion production from epithelial cell differentiation, increase virion yield 1000-fold, and accelerate virus production from 3 weeks to 2 days. (Proc Natl Acad Sci USA 102:9311- 9316, 2005)
• Discovery of unexpected parallels linking genome replication by three of the six major classes of viruses, thus elucidating replication of distinct tumor viruses such as hepatitis C virus, hepatitis B virus, and retroviruses, and linking previously separated bodies of data. (Molecular Cell 9:505-514, 2002, and Nature Reviews Microbiol 4:371-382, 2006)

Recent Human Cancer Virology Publications