Anal cancer is of growing concern in the United States and elsewhere, particularly among HIV-positive men who have a much higher than normal incidence of this human papillomavirus-associated neoplasia. Standard of care chemoradiotherapy has remained unchanged for decades and is of limited value in treating patients with advanced or recurrent disease. Anal cancer is a poorly understood disease owing to the absence of preclinical models for its study. We have developed the first preclinical animal models for anal cancer. Using these models, we have begun to study the role of viral oncogenes in this cancer. Furthermore, we discovered that the mTOR pathway is highly activated in anal cancer and is a valuable target for treating this cancer. In this grant applicatin we propose experiments using these new preclinical models to understand the role and temporal requirements for individual HPV oncogenes in anal carcinogenesis, and their influences on the responses of anal cancer to chemoradiation. We will also carry out studies to investigate further the value of drugs targeting the mTOR and MEK/ERK pathways in treating anal cancer. Lastly we will investigate if PI3K activation, which is upstream of the MTOR and MEK/ERK pathways, drives anal carcinogenesis together with HPV oncogenes. The studies described in this grant will provide new insights into more effective ways for treating human anal cancer.

Public Health Relevance

Anal Cancer is of growing significance particularly amongst HIV-infected individuals who are at greater than 50 times the risk of developing this cancer compared to the general population. Patients with metastatic or recurrent anal cancers have poor prognoses. We propose studies to define new therapeutic targets for treating anal cancer using our first-of-their-kind preclinical models for this debilitating disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA171873-02
Application #
8737208
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2013-09-18
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Madison
State
WI
Country
United States
Zip Code
53715
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