This project is based on the discovery of a specific cell population in the uterine cervix that the investigators propose to be the target of cancer causing human papillomaviruses (HPV) and the origin of cervical cancer. These cells are located at the squamo-columnar (S-C) junction of the cervix and their share attributes with preinvasive and invasive HPV-associated cervical neoplasms links support their role as progenitor cells. This project is designed to expand this investigation to accomplish three tasks. The first is to clarify the biologic differences of early cervical precancers with S-C junction specific attributes to better define the parameters that increase the empirical risk of eventually developing invasive cancer. Understanding these differences will permit a more precise classification of cervical precancers and reduce the likelihood of over-treatment and its reproductive sequelae. A related goal is to map the geography of these specialized S-C junction cells in the cervix to determine its influence on origin and successful removal of precancers. The second task is to grow these S-C junction cells in culture and determine both how they differentiate and if they express unique biomarkers relative to their surrounding cellular environment. Because the S-C junction is vulnerable to cancer causing HPV infections, these biomarkers could be exploited to devise novel therapies to selectively remove the S-C junction cells preemptively (for cancer prevention) via targeted therapy. The third task is to generate a transgenic animal model (mouse) in which a precise mimic of human cervical cancer could be generated at the S-C junction by introducing carcinogenic HPV-related oncogenes. Such models do not currently exist and their successful development could be an important advance in the creation of mouse models of human cervical cancer that could be used to test new therapeutics.

Public Health Relevance

Successful completion of this project will result in a major improvement in our ability to accurately determine which individuals with cervical precancers merit therapy and expand their treatment options. Moreover, new cell culture and, in particular, animal models of cervical cancer would provide important opportunities to test new therapies in a preclinical setting with a high relevance to human disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA173190-02
Application #
8613481
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Patriotis, Christos F
Project Start
2013-02-05
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$178,542
Indirect Cost
$40,043
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115