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A new method for network bioinformatics identifies novel drug targets for mucinous ovarian carcinoma.

ABSTRACT: Mucinous ovarian carcinoma (MOC) is a subtype of ovarian cancer that is distinct from all other ovarian cancer subtypes and currently has no targeted therapies. To identify novel therapeutic targets, we developed and applied a new method of differential network analysis comparing MOC to benign mucinous tumours (in the absence of a known normal tissue of origin). This method mapped the protein-protein network in MOC and then utilised structural bioinformatics to prioritise the proteins identified as upregulated in the MOC network for their likelihood of being successfully drugged. Using this protein-protein interaction modelling, we identified the strongest 5 candidates, CDK1, CDC20, PRC1, CCNA2 and TRIP13, as structurally tractable to therapeutic targeting by small molecules. siRNA knockdown of these candidates performed in MOC and control normal fibroblast cell lines identified CDK1, CCNA2, PRC1 and CDC20, as potential drug targets in MOC. Three targets (TRIP13, CDC20, CDK1) were validated using known small molecule inhibitors. Our findings demonstrate the utility of our pipeline for identifying new targets and highlight potential new therapeutic options for MOC patients.

SUBMITTER: Craig O

PROVIDER: S-EPMC11344246 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature

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A new method for network bioinformatics identifies novel drug targets for mucinous ovarian carcinoma.

Craig Olivia O Lee Samuel S Pilcher Courtney C Saoud Rita R Abdirahman Suad S Salazar Carolina C Williams Nathan N Ascher David B DB Vary Robert R Luu Jennii J Cowley Karla J KJ Ramm Susanne S Li Mark Xiang MX Thio Niko N Li Jason J Semple Tim T Simpson Kaylene J KJ Gorringe Kylie L KL Holien Jessica K JK

NAR genomics and bioinformatics 20240824 3

Mucinous ovarian carcinoma (MOC) is a subtype of ovarian cancer that is distinct from all other ovarian cancer subtypes and currently has no targeted therapies. To identify novel therapeutic targets, we developed and applied a new method of differential network analysis comparing MOC to benign mucinous tumours (in the absence of a known normal tissue of origin). This method mapped the protein-protein network in MOC and then utilised structural bioinformatics to prioritise the proteins identified ...[more]

PMID: 39184376

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Project description:BackgroundPrevious clinical trials regarding the therapy in epithelial ovarian tumors have involved patients with all types of ovarian tumors. Mucinous borderline tumors may progress to invasive carcinoma even after therapy and Patients with mucinous ovarian cancer (MOC) often have a worse prognosis. Our objectives were to investigate the use of hyperthermic intraperitoneal perfusion therapy (HIPE) and the clinicopathological features of mucinous borderline ovarian tumor (MBOT) and MOC.MethodsA retrospective study was conducted on 240 patients with MBOT or MOC. The clinicopathologic feature included age, preoperative serum tumor markers, surgical procedures, surgical and pathological staging, frozen pathology, treatment, and recurrence. The effect of HIPE in MBOT and MOC were examined and the occurrence of adverse events was analyzed.ResultsThe median age was 34 years in 176 MBOT patients. Some 40.1% of patients had elevated CA125, 40.2% had elevated CA199, and 5.6% had elevated HE4. The accuracy rate for frozen pathology of resected specimen was 43.8%. The was no statistical difference in the recurrence rate between fertility-sparing and non-fertility-sparing surgery. Due to a short follow-up time in the HIPE group, no significant recurrence rate was found. The median age was 59 years in 64 MOC patients. Some 90.5% patients had elevated CA125, 95.3% had elevated CA199, and 75% had elevated HE4. There were 28 patients diagnosed with Federation International of Gynecology and Obstetrics (FIGO) stage I or II. For FIGO stage III and IV patients, the median progression-free survival (PFS) was 27 months in the HIPE group and the median overall survival (OS) in patients treated with HIPE was 53 months, which was significantly longer than that the other group (19 and 42 months). There was no severe fatal complication in all HIPE group.ConclusionsMBOT was usually diagnosed at an early stage and has a good prognosis. Hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) can improve the survival of patients with advanced MOC and is safety. Combined use of CA125, CA199, HE4 can assist in the differential diagnosis of mucinous borderline neoplasms and mucinous carcinoma. Randomized studies evaluating dense HIPEC in the management of advanced ovarian cancer should be warranted.

Dataset Information

A new method for network bioinformatics identifies novel drug targets for mucinous ovarian carcinoma.

Publications

A new method for network bioinformatics identifies novel drug targets for mucinous ovarian carcinoma.

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