Developing Methods to Detect and Prevent Cancer
The role of Human Papillomavirus (HPV) in the development and detection of cervical cancer has been a major focus of investigation at the clinical, translational and basic science levels by Joan Walker, MD, Michael Gold, MD, and Rosemary Zuna, MD, along with scientists Brian Ceresa, PhD, S. Terrence Dunn, PhD, and Adam Zlotnik, PhD. Under the direction of Drs. Walker and Gold, the Women's Cancers Program at OUCI was a major contributor to the nationwide NCI-sponsored Clinical Management of atypical squamous cells of undetermined significance (ASCUS) & low-grade squamous intraepithelial lesion (LSIL) of Uterine Cervix (ALTS) trial. This trial demonstrated that HPV testing is sensitive in detecting underlying precancerous lesions among women with ASCUS and led to the FDA approval of HPV tests (82, 83). Rosemary Zuna, MD, evaluated specimens from this study and found that HPV testing is not useful for women with a Pap test diagnosis of LSIL (84, 85). This study also found that variability among experts in interpreting Pap tests and biopsies should be taken into consideration when using these interpretations and when developing standards of practice, and that colposcopically directed biopsy is not completely sensitive in detecting precancerous lesions (83, 86).
The followup NCI study, A Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED), which requires careful processing of clinical specimens for molecular analysis, is being conducted using OUCI as the sole site (87). A preliminary finding of this study is that standard precolposcopic procedures do not substantially affect the overall gene expression patterns in the normal cervix (88). Robert Hamm, PhD, and Dewey Schied, MD, MPH, are studying the psychosocial burden of illness among women experiencing HPV-related illness or screening intervention, and women's emotional and rational response to high risk HPV (89, 90). Current clinical trials ongoing in our program include include intravaginally administered 851B gel for treatment of high risk HPV infection and A-007 Topical Gel for high-grade squamous intraepithelial lesions (HSIL), ZYC101a for high-grade cervical intraepithelial lesions (CIN2/3), and celecoxib for CIN3 (61, 91-93). Dr. Benbrook is evaluating biomarkers of response in clinical specimens from the celecoxib study (61).
Collaborative research on HPV and cervical cancer risk conducted at OUCI by Drs. Zuna and Dunn found that risk for progression to invasion in squamous intraepithelial lesions (SILs) was closely related to HPV genotype (94) and that HPV genotyping of high-grade SILs may be important in assessing risk for progression to invasion (95). They also participated in a study of the worldwide genomic diversity of the high-risk human papillomavirus types (88, 96-98). Dr. Ceresa has been studying how the epidermal growth factor receptor (EGFR) is endocytosed by the cell and how this and other cellular characteristics are alter by the HPV E5 protein (99-102). Adam Zlotnik, PhD, is applying his expertise in the structural basis of the assembly of virus capsids and developing assays to identify compounds that can disrupt viral assembly to studies of HPV (103-118).
Collaborative research of gynecologic oncologist members found that the type of surgical procedure to remove abnormal cervical tissue needs to be altered depending on the number of pregnancies a woman has had in order to accurately detect the presence of cancer in the tissue (119).
Ovarian cancer remains one of the most lethal malignancies due to lack of early detection methods. One of the major obstacles to developing diagnostic assays for ovarian cancer is the lack of early stage ovarian cancer specimens. This is because early ovarian cancer is most often detected when a patient is undergoing surgery for a pelvic mass, when it is too late to obtain the patient's consent to collect the specimens. Dr. Benbrook designed a national study to consent women undergoing surgery for pelvic mass for the collection of benign and cancer specimens to establish a centralized database with specimen, laboratory, epidemiologic and clinical data to be utilized in epidemiologic, genomic, proteomic and immunological analysis of ovarian cancer diagnosis and prognosis (120). Drs. H.K. Lin and McMeekin are using microarray analysis to study molecular signatures to diagnose ovarian cancer. Our gynecologic oncologist members are collaborating on a study evaluating serial analysis of CA125 as a diagnostic assay of ovarian cancer (121).
In breast cancer, Hong Liu, PhD (Norman Campus), is developing prototype systems for high spatial resolution digital mammography, digital radiography and for image guided therapy. He is conducting comprehensive measurements using phantoms, preclinical models, surgically biopsied specimens, and human subjects to characterize the medical efficacy of these novel technologies. Dr. Dooley is studying ductoscopic biopsy and molecular marker panels to increase accuracy of cytologic interpretation in screening for premalignant changes and identifying targets for developing effective chemoprevention strategies (122-124). Eleni Tolma is studying motivation to obtain an initial screening mammogram in Greek women (125-127). Drs. Scheid and Hamm are developing individualized computerized balance sheets to support the decision to screen for breast cancer (128). Patti Landers, PhD, is working on nutritional studies to decrease breast cancer risk and improve survival Shibo Li, MD, PhD, found that patterns of chromosomal imbalances identified in leiomyosarcoma of the breast are similar to those reported in leiomyosarcoma of soft tissue and uterus and are different from those reported for leiomyoma, indicating that these alterations may be important for development of malignant smooth-muscle tumors regardless of site or organ of origin (129). Jay Hanas, PhD, and collaborators utilized a breast carcinogenesis animal model to evaluate gene expression signatures associated with the initiation and development of cancer, stem cell infusion as a therapeutic strategy and leuprolide, a gonadotropin releasing hormone agonist, as a chemoprevention agent (130-133). Patti Landers, PhD, is working on nutritional studies to decrease breast cancer risk and improve survival. John Mulvihill, MD, has been studying genetic alterations in cancer and collaborated on the development of an FDA approved clinical test for breast cancer risk licensed by Intergenetics, a small company in the OUHSC research park (129, 134).
In addition to these studies of diagnostic methods, our program is also actively involved in evaluating prevention strategies. The gynecologic oncologists participated in multiple trials evaluating HPV vaccines for prevention of cervical cancer and a study of fenretinide for chemoprevention of ovarian cancer (135). Dr. Dooley is evaluating soy protein dietary supplement for prevention of progression of premalignant breast lesions (136). Dr. Yang demonstrated that low-dose dietary phytoestrogens can abrogate tamoxifen-associated breast cancer in a preclinical model and is evaluating Rab interacting proteins as cancer biomarkers (137). Dr. Ding demonstrated that the fatty acid, docosahexaenoic acid, and the antibiotic, Clioquinol, exhibit activity and synergy against gynecologic and breast cancer cells (138-140). He and Dr. Benbrook meet weekly and are collaborating on studies of how their drugs work through the nuclear factor-kB (NF-kB).
Several investigators are studying carcinogenesis at the basic science level. Dr. Ihnat is studying a very common environmental toxicant, arsenite (As(III)), in carcinogenesis (141). Dr. Benbrook developed an organotypic model of endometrial carcinogenesis and chemoprevention using the Flex-Het drug, SHetA2. Microarray analysis of this model by Dr. Centola identified several potential biomarkers of endometrial cancer. Using systems biology, Igor Dozmorov, PhD, identify interacting pathways involved in endometrial carcinogenesis and chemoprevention. Hiro Matsumoto, PhD, is studying the proteomic profiles in this model.
The potential clinical application of the chemoprevention activity of the Flex-Het drugs, SHetA2, was recognized by the National Cancer Institutes (NCI's) Rapid Access to Preventive Intervention Development (RAPID) program, which provides preclinical testing needed to prepare and submit an IND to the FDA for initiating chemoprevention trials with SHetA2.
