Human papillomaviruses (HPVs) are small DNA viruses that infect various epithelial tissues. A subset of anogenital HPVs, the 'high risk'HPVs including HPV-16 and 18 genotypes, are associated with nearly all cervical carcinomas, as well as the majority of other anogenital cancers and a subset of head and neck cancers. Each year in the US, over 30,000 new cancers arise from high-risk HPV infections. Current regimens for treating these cancers rely on decades old strategies. Five-year survival rates for advanced grade cancers remain low. A recently FDA-approved HPV vaccine holds promise in preventing new infections, but it will not have an impact on cancer incidence until 2040 and beyond. Therefore there remains an urgent need to develop improved means for treating and/or preventing HPV-associated cancers and thereby increase survival rates and decrease suffering among those afflicted. The goal of this MMHCC application is to identify new, more effective regimens for treating and preventing HPV-positive cancers. We will make use of genetically engineered mouse strains that express the HPV16 E6 and E7 oncogenes in relevant tissues as the preclinical model in which to pursue these goals. These mice have been used to establish well-validated models for HPV associated cervical cancer and head and neck cancers. Three major goals will be pursued: 1) investigate the use of anti-estrogens in the treatment and prevention of cervical cancer, 2) validate kinase targets for therapy of HPV associated premalignant lesions and cancer, and 3) develop effective immunotherapies against HPV-associated cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA141583-04
Application #
8323100
Study Section
Special Emphasis Panel (ZCA1-SRLB-Q (M1))
Program Officer
Marks, Cheryl L
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$728,157
Indirect Cost
$104,270
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Park, Jung Wook; Nickel, Kwangok P; Torres, Alexandra D et al. (2014) Human papillomavirus type 16 E7 oncoprotein causes a delay in repair of DNA damage. Radiother Oncol 113:337-44
Gosmann, Christina; Frazer, Ian H; Mattarollo, Stephen R et al. (2014) IL-18, but not IL-12, induces production of IFN-? in the immunosuppressive environment of HPV16 E7 transgenic hyperplastic skin. J Invest Dermatol 134:2562-9
Meyers, Jordan M; Munger, Karl (2014) The viral etiology of skin cancer. J Invest Dermatol 134:E29-32
Tran, Le Son; Bergot, Anne-Sophie; Mattarollo, Stephen R et al. (2014) Human papillomavirus e7 oncoprotein transgenic skin develops an enhanced inflammatory response to 2,4-dinitrochlorobenzene by an arginase-1-dependent mechanism. J Invest Dermatol 134:2438-46
Depelsenaire, Alexandra C I; Meliga, Stefano C; McNeilly, Celia L et al. (2014) Colocalization of cell death with antigen deposition in skin enhances vaccine immunogenicity. J Invest Dermatol 134:2361-70
Bergot, Anne-Sophie; Ford, Neill; Leggatt, Graham R et al. (2014) HPV16-E7 expression in squamous epithelium creates a local immune suppressive environment via CCL2- and CCL5- mediated recruitment of mast cells. PLoS Pathog 10:e1004466
Bhat, Purnima; Leggatt, Graham; Matthaei, Klaus I et al. (2014) The kinematics of cytotoxic lymphocytes influence their ability to kill target cells. PLoS One 9:e95248
Yu, Chien-Hsiung; Nguyen, Tam T K; Irvine, Katharine M et al. (2014) Recombinant Wnt3a and Wnt5a elicit macrophage cytokine production and tolerization to microbial stimulation via Toll-like receptor 4. Eur J Immunol 44:1480-90
Son, Jieun; Park, Jung Wook; Lambert, Paul F et al. (2014) Requirement of estrogen receptor alpha DNA-binding domain for HPV oncogene-induced cervical carcinogenesis in mice. Carcinogenesis 35:489-96
Mesri, Enrique A; Feitelson, Mark A; Munger, Karl (2014) Human viral oncogenesis: a cancer hallmarks analysis. Cell Host Microbe 15:266-82

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