Ovarian cancer has the highest mortality of all gynecologic cancers, and 70% of women with ovarian cancer die of their disease within 5 years. Survival is high with early stage disease, yet ovarian cancer is not| usually detected earlier than Stage III or IV because its presentation is vague, the ovary is difficult to access, and little is known about preinvasive lesions. Efforts to understand ovarian cancer etiology and to develop effective detection and treatments for this disease have been hampered by lack of appropriate and well- characterized animal models. Recently, models that directly expose the rodent ovary to low doses of the carcinogen 7, 12?Dimethylbenz[a]anthracene (DMBA) have been reported to develop human-like (pre)neoplastic lesions. We are improving upon this carcinogen model by combining it with a follicle-deplete, ovary-intact rat model of menopause. This improved model will be useful for determining the differential susceptibility of post-menopausal women to ovarian cancer. The overall goal of this research is to develop two capabilities critically needed in the fight against ovarian cancer: 1) a rat model of ovarian cancer that closely resembles the human disease, and 2) minimally-invasive imaging modalities sensitive to early neoplastic changes. We expect our research to aid in identification of early neoplastic changes that predict cancer. This proposal has four specific aims: 1. Develop a peri- and post-menopausal rat ovarian cancer model. Optimum dosing, administration and timing will be determined for the creation of a novel ovary-intact rat model of menopause using 4- Vinylcyclohexene Diepoxide (VCD) and DMBA. Anatomical and biochemical changes will be evaluated. 2. Develop optical imaging technologies to permit high resolution ex vivo and time-serial in vivo imaging of rat ovary. Miniaturized optical coherence tomography (OCT), laser induced fluorescence (LIF), and high resolution optical coherence microscopy (OCM) will be developed to enable minimally invasive imaging in our improved animal model. 3. Determine mechanisms of contrast in normal, follicle deplete, and cancerous ovarian tissues. We will undertake a comprehensive ex vivo study to elucidate mechanisms of contrast in the three imaging modalities developed in specific aim 2. 4. Perform in vivo, serial imaging studies of ovarian carcinogenesis. We will perform minimally- invasive, time-serial imaging order to follow carcinogenesis in our rat models. The goal of this study is to determine early anatomical or biochemical changes visible on OCT, OCM, or LIF that predict future development of neoplasms, and to determine if the time sequence of lesions is different for cycling and follicle-deplete animals.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA119200-05
Application #
7993066
Study Section
Special Emphasis Panel (ZRG1-SBIB-P (02))
Program Officer
Menkens, Anne E
Project Start
2006-12-11
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2011
Total Cost
$274,008
Indirect Cost
Name
University of Arizona
Department
Type
Organized Research Units
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Welge, Weston A; DeMarco, Andrew T; Watson, Jennifer M et al. (2014) Diagnostic potential of multimodal imaging of ovarian tissue using optical coherence tomography and second-harmonic generation microscopy. J Med Imaging (Bellingham) 1:025501
Watson, Jennifer M; Marion, Samuel L; Rice, Photini F et al. (2014) In vivo time-serial multi-modality optical imaging in a mouse model of ovarian tumorigenesis. Cancer Biol Ther 15:42-60
Watson, Jennifer M; Marion, Samuel L; Rice, Photini F et al. (2013) Two-photon excited fluorescence imaging of endogenous contrast in a mouse model of ovarian cancer. Lasers Surg Med 45:155-66
Watson, Jennifer M; Rice, Photini F; Marion, Samuel L et al. (2012) Analysis of second-harmonic-generation microscopy in a mouse model of ovarian carcinoma. J Biomed Opt 17:076002
Korde, Vrushali R; Liebmann, Erica; Barton, Jennifer K (2011) Design of a handheld optical coherence microscopy endoscope. J Biomed Opt 16:066018
Hariri, Lida P; Liebmann, Erica R; Marion, Samuel L et al. (2010) Simultaneous optical coherence tomography and laser induced fluorescence imaging in rat model of ovarian carcinogenesis. Cancer Biol Ther 10:438-47
Li, Peng; Waldman, Scott A (2010) Corruption of homeostatic mechanisms in the guanylyl cyclase C signaling pathway underlying colorectal tumorigenesis. Cancer Biol Ther 10:211-8
Craig, Zelieann R; Davis, John R; Marion, Samuel L et al. (2010) 7,12-dimethylbenz[a]anthracene induces sertoli-leydig-cell tumors in the follicle-depleted ovaries of mice treated with 4-vinylcyclohexene diepoxide. Comp Med 60:10-7
Hoyer, P B; Davis, J R; Bedrnicek, J B et al. (2009) Ovarian neoplasm development by 7,12-dimethylbenz[a]anthracene (DMBA) in a chemically-induced rat model of ovarian failure. Gynecol Oncol 112:610-5