The proposed work is an interdisciplinary effort to identify new screening tests to detect ovarian cancer before it spreads outside the ovary and becomes very difficult to cure. Current methods for detecting early stage disease include a blood test that measures the level of cancer-related proteins secreted by ovarian tumors (CA-125) and Transvaginal Sonography (TVS), which can be used to detect cancer by imaging of a mass. CA-125 and TVS are not used in the general population because CA-125 is not sensitive enough; it can detect only about half of ovarian cancers while they are still small enough to be curable; and TVS is not specific enough. It detects many benign ovarian masses, which must then be removed surgically to confirm that they are not cancer. Investigators will study tumor tissue and blood from women with ovarian cancer, women with benign ovarian disease, and women with no ovarian disease in an effort to identify genetic changes that can be used to develop an inexpensive and accurate ovarian cancer screening test for use in the general population.

This work is a collaboration among experts in oncology, immunology, molecular biology, and statistical methods. Two novel technologies will be explored as means to discover new detection markers. In Project 1, molecular biologists will use high density array hybridization (HDAH) to compare the expression of genes in normal and malignant tissue. This technology uses libraries of genetic information maintained on high-output computer systems and robotics to compare patterns of gene expression to one another. This approach will directly identify a large number of genes whose expression is modified during the course of malignant transformation. Statistical and clinical input is the key to evaluation of the gene expression patterns to select the genes that are the best candidates for development as useful screening tests.

The other approach is to look directly in sera for antibodies to cancer-related proteins. Preliminary evidence suggests that cancer causes an immune system response that can be measured. In Project 2, immunologists will use a new technology called SEREX to identify ovarian cancer-associated proteins that elicit antibody responses in patients, but not in women without ovarian malignancy. Candidate genes discovered by this approach will be sequenced and developed as serum tests. The SEREX technology has not been used before to identify a marker for early-stage cancer. Using the immune system response as a possible screening test for cancer is similar to what is currently done for detecting Tuberculosis and HIV. The blood tests for serum antibodies (ELISA) can be performed inexpensively and accurately. Three oncogenic proteins (p53, HER/2-neu, and Myc) have already been shown to elicit antibody responses in patients with cancers of the breast, colon, and lung. An ELISA screen for responses to these three proteins as an indicator of early-stage ovarian cancer will be refined, validated, and utilized for development of assays measuring immune responses of novel oncogenic proteins discovered in the course of these studies.

An antibody-based serum marker would have the potential to detect cancer very early in the disease process. However, it is also likely that protein based on mRNA-based blood tests will be useful as a screening tool, and we expect that an accurate and efficient screening test to be used in the general population will need to incorporate several molecular markers. Ultimately, new markers will be evaluated for their individual and combined accuracy in the detection of malignancy. We proposed a research strategy that ensures that promising discoveries are systematically and appropriately evaluated and developed for clinical application. We anticipate that the work we propose will result in several useful products that will move the field forward, including (1) the identification of two or more novel molecular markers that are potentially useful for the detection of early-stage ovarian cancer; (2) a report on the frequency of the joint and unique expression of p53, H2N, and Myc in malignant ovarian tissue by stage of cancer diagnosis; and (3) an evaluation of the sensitivity and specificity of antibody-based serum markers of p52, H2N, and Myc in detecting ovarian cancer, used individually and in combination.