Mass Spectrometry–Based Protein Biomarker Discovery: Solving the Remaining Challenges to Reach the Promise of Clinical Benefit

Featured Article: Petricoin EF, Ardekani AM, Hitt BA, Levine PJ, Fusaro VA, Steinberg SM, et al. Use of proteomic patterns in serum to identify ovarian cancer. Lancet 2002;359:572–7.2 This report in The Lancet generated a great deal of excitement about the application of mass spectrometry (MS) to discover candidate protein biomarkers for early-stage ovarian cancer. MS-based serum/plasma biomarker profiling was launched in a flourish of optimism to meet the urgent need for biomarkers of early-stage cancer, a need that still exists today. Before 1998, very few investigators used MS (MALDI-TOF or electrospray ionization) to directly analyze blood, because serum was considered too complex and “dirty” for direct introduction into expensive and sophisticated MS research instruments. The door was opened to the use of MS for biomarker research in 1998 with SELDI, a new modification of MALDI-TOF technology. Researchers were immediately intrigued by the SELDI-TOF approach because body fluids could be applied directly to the chip surface and then analyzed to generate an ion fingerprint (1, 2). SELDI had relatively low resolution and could not identify the ions directly. Nevertheless, it provided a fresh approach in the search for the ion signatures of hundreds of candidate biomarkers. We saw SELDI-TOF as a means to test a new hypothesis that was emerging in the protein biomarker field. Investigators had proposed that tumor–host interactions in the tissue microenvironment were generating cascades of biomarkers. A corollary of the hypothesis was that a panel of biomarkers could achieve diagnostic sensitivity and specificity superior to those of previously failed one-at-a-time searches for cancer biomarkers.