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
Chandra, Janin; Miao, Yan; Romoff, Natasha et al. (2016) Epithelium Expressing the E7 Oncoprotein of HPV16 Attracts Immune-Modulatory Dendritic Cells to the Skin and Suppresses Their Antigen-Processing Capacity. PLoS One 11:e0152886
Abd Warif, Nor Malia; Stoitzner, Patrizia; Leggatt, Graham R et al. (2015) Langerhans cell homeostasis and activation is altered in hyperplastic human papillomavirus type 16 E7 expressing epidermis. PLoS One 10:e0127155
Tran, Le Son; Mittal, Deepak; Mattarollo, Stephen R et al. (2015) Interleukin-17A Promotes Arginase-1 Production and 2,4-Dinitrochlorobenzene-Induced Acute Hyperinflammation in Human Papillomavirus E7 Oncoprotein-Expressing Skin. J Innate Immun 7:392-404
Bergot, Anne-Sophie; Monnet, Nastasia; Le Tran, Son et al. (2015) HPV16 E7 expression in skin induces TSLP secretion, type 2 ILC infiltration and atopic dermatitis-like lesions. Immunol Cell Biol 93:540-7
McKee, Sara J; Bergot, Anne-Sophie; Leggatt, Graham R (2015) Recent progress in vaccination against human papillomavirus-mediated cervical cancer. Rev Med Virol 25 Suppl 1:54-71
Haigh, Oscar; Depelsenaire, Alexandra C I; Meliga, Stefano C et al. (2014) CXCL1 gene silencing in skin using liposome-encapsulated siRNA delivered by microprojection array. J Control Release 194:148-56
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
Gosmann, Christina; Mattarollo, Stephen R; Bridge, Jennifer A et al. (2014) IL-17 suppresses immune effector functions in human papillomavirus-associated epithelial hyperplasia. J Immunol 193:2248-57
Spurgeon, Megan E; Chung, Sang-Hyuk; Lambert, Paul F (2014) Recurrence of cervical cancer in mice after selective estrogen receptor modulator therapy. Am J Pathol 184:530-40
Gosmann, Christina; Frazer, Ian H; Mattarollo, Stephen R et al. (2014) IL-18, but not IL-12, induces production of IFN-γ in the immunosuppressive environment of HPV16 E7 transgenic hyperplastic skin. J Invest Dermatol 134:2562-9

Showing the most recent 10 out of 42 publications