Human papillomavirus (HPV)-associated cancers represent 5% of all human cancers and are among the most common malignancies arising in the HIV-infected population. While highly effective prophylactic vaccines are available, their utilization in the United States remains low. Meanwhile HPV-associated cancers, particularly anal cancer, are increasing in their prevalence here in the US especially among the HIV-infected population. Treatment of these cancers relies upon decades old approaches using radiation and traditional chemotherapeutic agents. In many cases, these treatments are not curative, with limited options for effective second or third line treatments. The goal of our research is to define the factors that drive HPV-associated carcinogenesis with the ultimate goal to define ways to better treat patients with these cancers. This is particularly of concern to the HIV-infected population who are at increasing risk of developing these cancers. We have assembled a tool chest of unique model reagents with which to address this goal including genetically engineered mouse (GEM) models, as well as patient derived xenografts (PDXs) and associated cell strains from patients with anal, cervical and head/neck cancers. We have expanded our experimental tool chest to include MmuPV1, a mouse papillomavirus that models high-risk cutaneous HPVs in both its pathogenesis and molecular activities. Using these models we will explore new therapeutic targets for the prevention and/or treatment of HPV-associated disease/cancers. Of particular relevance to HIV-associated neoplasia, we will use PDX models for anal cancer to compare responses to targeted therapies between cancers arising in HIV- infected versus uninfected patients to learn if there are differences of potential clinical importance. The proposed studies build upon insights we have gained over the past 2+ decades studying our GEM and PDX models for HPV-associated cancers.

Public Health Relevance

Human papillomaviruses cause 5% of all human cancers. HIV-infected individuals are at increased risk of developing these cancers. Over the past 2+ decades, we have developed laboratory models to study these cancers. Using insights gained from those studies and recent advances in identifying genetic changes that arise in these cancers, we propose studies to identify new approaches to treat these cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
1R35CA210807-01A1
Application #
9411343
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2017-08-01
Project End
2024-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
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
Uberoi, Aayushi; Yoshida, Satoshi; Lambert, Paul F (2018) Development of an in vivo infection model to study Mouse papillomavirus-1 (MmuPV1). J Virol Methods 253:11-17
Shin, Myeong-Kyun; Payne, Susan N; Bilger, Andrea et al. (2018) Activating Mutations in Pik3caContribute to Anal Carcinogenesis in the Presence or Absence of HPV-16 Oncogenes. Clin Cancer Res :
Nyman, Patrick E; Buehler, Darya; Lambert, Paul F (2018) Loss of Function of Canonical Notch Signaling Drives Head and Neck Carcinogenesis. Clin Cancer Res 24:6308-6318
Uberoi, Aayushi; Lambert, Paul F (2017) Rodent Papillomaviruses. Viruses 9:
Xue, Xiang-Yang; Majerciak, Vladimir; Uberoi, Aayushi et al. (2017) The full transcription map of mouse papillomavirus type 1 (MmuPV1) in mouse wart tissues. PLoS Pathog 13:e1006715