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Chemoproteomics-based discovery of novel biomarkers for high-grade serous ovarian cancer recurrence through a patient-derived xenograft strategy

ABSTRACT: High grade serous ovarian carcinoma (HGSC) is the most common and lethal subtype of gynecologic malignancy in women. The current standard of treatment combines cytoreductive surgery and chemotherapy. Despite the efficacy of initial treatment, most patients develop cancer recurrence, and 70% of patients die within 5-years of initial diagnosis. CA125 is the current FDA-approved biomarker used in the clinic to monitor response to treatment and recurrence. Although increasing levels of CA125 precede clinical symptoms of recurrence, often second-look surgeries often reveal microscopic and macroscopic tumors present during remission. Here, we describe a novel strategy for the discovery of serum biomarkers aimed at earlier detection of cancer recurrence. We combined HGSC patient-derived xenograft models, chemoproteomic enrichment of N-glycosylated peptides and systematic development of targeted proteomics assays for rapid biomarker identification and orthogonal verification. The verification of candidates in two independent, longitudinal serum cohorts from HGSC patients (n=96 serum samples) identified four novel biomarker candidates for earlier detection of HGSC recurrence.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)

SUBMITTER: Dr. Thomas Kislinger

PROVIDER: MSV000082853 | MassIVE | Mon Aug 27 06:59:00 BST 2018

REPOSITORIES: MassIVE

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Project description:Background: There is a paucity of non-invasive markers for early detection of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC). Secretory proteomic approach based on quantitative tandem mass tag is believed to offer bright prospects for screening potential serum biomarkers for diseases. Methods: We used the secretory proteomics to identify up-regulated proteins in the highly brain metastatic cell line compared to the parental lung cancer cell line. Enzyme linked immunoassay and immunohistochemistry were performed on non-small cell lung cancer patients with brain metastasis and control samples from each cohort to verify the expression levels of candidate proteins. A logistic regression model was used to develop a biomarker panel composed of Cathepsin F (CTSF) and Fibulin-1 (FBLN1), and then an independent validation data set was used for verification. The diagnostic accuracy was evaluated by receiver operating characteristic (ROC) curve analysis. Changes in serum CTSF levels of patients were tracked to monitor the effect of treatment, and progression-free survival (PFS) and overall survival (OS) were analyzed to assess their prognostic relevance. Results: CTSF and FBLN1 levels were specifically upregulated in sera and tissues of patients with NSCLC BM. Importantly, the combined diagnostic performance of CTSF and FBLN1 was superior to their individual diagnostic performance (sensitivity and specificity). CTSF serum changes were found to reflect the therapeutic response of patients with NSCLC BM and the trends of resistance and progression were detected earlier than the MRI changes. Elevated expression of CTSF in NSCLC BM tissues was associated with poor PFS. Moreover, CTSF tissue expression was found to be an independent prognostic factor. Conclusions: CTSF and FBLN1 are potential novel and specific serum markers for early diagnosis of BM in patients with NSCLC. CTSF can also be used as a biomarker for monitoring therapeutic efficacy and prognostic assessment.

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Chemoproteomics-based discovery of novel biomarkers for high-grade serous ovarian cancer recurrence through a patient-derived xenograft strategy

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