Ovarian cancer researchers have been on the forefront of developing serum biomarkers to detect cancer early and save lives. One of the earliest cancer serum biomarkers, the ovarian cancer marker CA 125, was discovered in the early 1980¿s. Recent advancements in biotechnologies ¿ RNA expression microarrays or mass-spectrometry proteomics ¿ have created excitement that a systematic approach to find and identify additional biomarkers could finally aid or replace CA 125 enough for clinical application. However, despite all of the efforts and several highly publicized claims progress has been frustratingly slow and few new markers are being evaluated clinically.

We hypothesize three reasons for this, and our proposal will attempt to circumvent each of them. We believe there are three criteria that must be addressed to advance progress on ovarian cancer biomarker discovery, and current approaches lack at least one of them. Biomarker discovery must have appropriate technology, serum samples of the highest quality, and an environment that promotes clinical evaluation of the biomarkers once identified.

Most technologies for serum biomarker discovery are not entirely appropriate: Despite the excitement regarding modern biotechnology ¿ genomics and proteomics ¿ to identify multiple biomarker candidates, few of the biomarkers will ever be evaluated clinically. This is because to further evaluate each marker one or more antibodies must be identified, a time consuming and costly undertaking that few research laboratories have the ability to undertake in large scale. Thus, at the present time our ability to identify potential targets is outpacing our ability to further evaluate them. In our research plan, we propose to develop a novel and comprehensive proteomics approach that can probe billions of potential protein biomarkers, and identify an antibody at the same time the biomarker is identified. The presence of an antibody will allow rapid further characterization and clinical evaluation of the biomarker.

Serum samples of the highest quality should be used in the discovery phase: Only the use of high quality samples can assure that biomarker discoveries have clinical utility. There are many risks to using poor quality samples, but perhaps the greatest comes from biases or false discoveries that come from samples having ascertainment biases, or markers not well characterized enough to assure that the women in most need of new discoveries (i.e., BRCA positive women, or women for whom current detection strategies fail). As part of our other funded research programs we have developed a high quality serum repository specifically curated for use in early detection research. Our serum samples include women at both high (i.e., BRCA-positive) and normal-risk women, and are characterized on many current research markers for ovarian cancer. We also have access to serum samples collected weeks and months before clinical diagnosis.

Identification of serum candidate biomarker candidates is only the first part of a longer process to bring biomarkers into clinical use. Our research group has several ongoing clinical research studies where women are undergoing routine ovarian cancer screening for research serum biomarkers. Once potential markers are identified by our group, we have the capacity to bring these markers into clinical evaluation rapidly as part of our Specialized Programs of Research Excellence early detection program (Dr. McIntosh and Dr. Karlan, co-leaders). Although it is not possible to predict when findings can make their way into clinical practice, it is within our resources to bring our discoveries into clinical research testing at the end of our study, or perhaps sooner.

With our proposed novel technology, stored serum samples, and ongoing clinical studies, we intend to develop a pipeline that can identify biomarkers that have the greatest utility for women; biomarkers that identify cancer early, work well for the women in most need of early detection, and can immediately be evaluated in clinically