Thomas Kislinger

Targeted Mass Spectrometry of Longitudinal Patient Sera Reveals LTBP1 as a Potential Surveillance Biomarker for High-Grade Serous Ovarian Carcinoma

High-grade serous ovarian carcinoma (HGSC) is the most prevalent subtype of epithelial ovarian cancer. The combination of a high rate of recurrence and novel therapies in HGSC necessitates an accurate assessment of the disease. Currently, HGSC response to treatment and recurrence are monitored via immunoassay of serum levels of the glycoprotein CA125. CA125 levels predictably rise at HGSC recurrence; however, it is likely that the disease is progressing even before it is detectable through CA125. This may explain why treating solely based on CA125 increase has not been associated with improved outcomes. Thus, additional biomarkers that monitor HGSC progression and cancer recurrence are needed. For this purpose, we developed a scheduled parallel reaction monitoring mass spectrometry (PRM-MS) assay for the quantification of four previously identified HGSC-derived glycopeptides (from proteins FGL2, LGALS3BP, LTBP1, and TIMP1). We applied the assay to quantify their longitudinal expression profiles in 212 serum samples taken from 34 HGSC patients during disease progression. Analyses revealed that LTBP1 best-mirrored tumor load, dropping as a result of cancer treatment in 31 out of 34 patients and rising at HGSC recurrence in 28 patients. Additionally, LTBP1 rose earlier during remission than CA125 in 11 out of 25 platinum-sensitive patients with an average lead time of 116.4 days, making LTBP1 a promising candidate for monitoring of HGSC recurrence.

Proteomics of High-Grade Serous Ovarian Cancer Models Identifies Cancer-Associated Fibroblast Markers Associated with Clinical Outcomes

The tumor microenvironment has recently emerged as a critical component of high-grade serous ovarian cancer (HGSC) disease progression. Specifically, cancer-associated fibroblasts (CAFs) have been recognized as key players in various pro-oncogenic processes. Here, we use mass-spectrometry (MS) to characterize the proteomes of HGSC patient-derived CAFs and compare them to those of the epithelial component of HGSC to gain a deeper understanding into their tumor-promoting phenotype. We integrate our data with primary tissue data to define a proteomic signature of HGSC CAFs and uncover multiple novel CAF proteins that are prognostic in an independent HGSC patient cohort. Our data represent the first MS-based global proteomic characterization of CAFs in HGSC and further highlights the clinical significance of HGSC CAFs.

High-throughput approaches for precision medicine in high-grade serous ovarian cancer

AbstractHigh-grade serous carcinoma (HGSC) is the most prevalent and aggressive subtype of ovarian cancer. The large degree of clinical heterogeneity within HGSC has justified deviations from the traditional one-size-fits-all clinical management approach. However, the majority of HGSC patients still relapse with chemo-resistant cancer and eventually succumb to their disease, evidence that further work is needed to improve patient outcomes. Advancements in high-throughput technologies have enabled novel insights into biological complexity, offering a large potential for informing precision medicine efforts. Here, we review the current landscape of clinical management for HGSC and highlight applications of high-throughput biological approaches for molecular subtyping and the discovery of putative blood-based biomarkers and novel therapeutic targets. Additionally, we present recent improvements in model systems and discuss how their intersection with high-throughput platforms and technological advancements is positioned to accelerate the realization of precision medicine in HGSC.