Preclinical development and validation of targeted mass spectrometry assays for serous ovarian cancer diagnosis

University Of Minnesota, Minneapolis MN

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Ovarian cancer is the most lethal gynecologic malignancy. The majority of ovarian carcinomas are diagnosed at an advanced stage for which the treatment options are considerably limited and the 5-year survival rate is <30%. Despite their widespread use in the clinic, current immunoassay- and transvaginal ultrasound-based diagnostic tests for women with ovarian cancer have had a limited impact on reducing mortality rates due to their low sensitivity and specificity. Consequently, these methods have minimal utility to screen the general population for ovarian cancer. Targeted mass spectrometry (MS) assays that measure ovarian cancer protein biomarkers can fulfill a significantly unmet need in establishing sensitive and specific diagnostic biomarkers. Serum is an ideal biological fluid within which to measure these diagnostic biomarkers due to its non-invasive method of collection. We have identified a panel of candidate ovarian cancer protein biomarkers in patient serum, which may serve to differentiate healthy patients versus patients with serous ovarian cancer – the most common subtype of epithelial ovarian cancer. In the proposed work, we will develop and validate a sensitive and specific multiplexed targeted MS assay to quantify 9 of these diagnostic serous ovarian cancer protein biomarkers in serum. This will be accomplished using Parallel Reaction Monitoring (PRM) MS, which is a highly sensitive, selective and specific targeted MS method with a wide dynamic range and low limits of quantification, enabling streamlined method development and robust, multiplexed protein quantification. We will evaluate the analytical and clinical performance of our multiplexed PRM assay in measuring these prioritized biomarker candidates using a panel of >1,300 serum samples obtained from a geographically diverse cohort of women receiving gynecologic care at five cancer centers and academic health centers in the U.S. and one in Europe. Our multidisciplinary investigative team brings together researchers with diverse expertise in analytical chemistry, clinical chemistry, ovarian cancer biology, epidemiology, and biostatistics. The successful completion of the high impact pre-clinical studies described in this proposal will enable the differentiation of serous ovarian cancer patients from healthy patients based on the abundance of diagnostic serum protein biomarkers. This work will provide a foundation for the development and validation of novel multiplexed PRM assays that could readily be applied to other ovarian cancer patient cohorts to support diagnosis and early detection efforts.