Targeting SRC and tubulin in mucinous ovarian carcinoma.
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ABSTRACT:
SUBMITTER: Liu T
PROVIDER: S-EPMC3852199 | biostudies-literature | 2013 Dec
REPOSITORIES: biostudies-literature
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Project description:ObjectiveMucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents.MethodsWe analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166).ResultsMolecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184).ConclusionsAlthough genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.
| S-EPMC7056511 | biostudies-literature
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.
| S-EPMC10186160 | biostudies-literature
Project description:ObjectiveMucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients.MethodsWe performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration.ResultsMean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates.ConclusionIn summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.
| S-EPMC10374276 | biostudies-literature
Project description:The SRC proto-oncogene is commonly overexpressed or activated during cancer development. Src family kinase inhibitors are approved for the treatment of certain leukemias, and are in clinical trials for the treatment of solid tumors. Src signaling is activated in endometriosis, a precursor of clear cell and endometrioid subtypes of epithelial ovarian cancers (OCs). We examined the expression of phosphorylated Src (Src-pY416) in 381 primary OC tissues. Thirty-six percent of OCs expressed Src-pY416. Src-pY416 expression was most common in endometriosis-associated OCs (EAOCs) (P=0.011), particularly in clear cell OCs where 58.5% of cases expressed Src-pY416. Src-pY416 expression was associated with shorter overall survival (log rank P=0.002). In vitro inhibition of Src signaling using 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine (PP2) resulted in reduced anchorage-independent and -dependent growth, and in three-dimensional cell culture models PP2 disrupted aggregate formation in Src-pY416-positive but not in Src-pY416-negative cell lines. These data suggest that targeting active Src signaling could be a novel therapeutic opportunity for EAOCs, and support the further pre-clinical investigation of Src family kinase inhibitors for treating OCs expressing Src-pY416.
| S-EPMC5007828 | biostudies-literature
Project description:Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.
| S-EPMC6718426 | biostudies-literature
Project description:Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.
| S-EPMC4520768 | biostudies-literature
Project description:ObjectivesThe aim of the study was to explore the rate of upstaging after complete surgical staging among patients with apparent FIGO stage I ovarian mucinous carcinoma.MethodsOvarian mucinous carcinoma patients with surgical treatment at the Peking Union Medical College Hospital between October 2020 and January 1994 were retrospectively reviewed.ResultsIn total, 163 patients were included in this study. Surgical restaging was performed in 89 patients after initial incomplete surgical staging, and one-step complete surgical staging was performed in 74 patients. Among these initially incompletely staged patients, residual tumors were found in 16 patients (16/89, 17.9%). Among the 19 patients with apparent FIGO stage IA, no patient was found to have residual tumors after incomplete staging surgery, according to the final pathology result of restaging surgery. Ovarian cystectomy (OR=4.932, 95% CI= 1.347-18.058, P=0.016) was an independent risk factor for residual tumors after incomplete staging surgery. Among all 163 patients, upstaging occurred in 15 patients (15/163, 9.2%). Among 44 apparent FIGO stage IA patients, no patient was upstaged to FIGO II-IVB. Moreover, both a history of ovarian mucinous tumor (OR=4.745, 95% CI= 1.132-19.886, P=0.033) and bilateral ovary involvement (OR=9.739, 95% CI= 2.016-47.056, P=0.005) were independent risk factors for upstaging to FIGO stage II-IVB.ConclusionsFor patients with apparent FIGO stage IA disease, the possibility of residual tumors and upstaging is relatively low. For patients with cystectomy, bilateral mucinous carcinomas, or a history of ovarian mucinous tumors, complete staging surgery maintains greater significance.
| S-EPMC9508779 | biostudies-literature
Project description:ObjectivePathological features indicating metastatic mucinous carcinoma to the ovary (MMCO) have been rarely reported in primary mucinous ovarian carcinoma (PMOC). However, little is known about how often they are observed in PMOC and how they relate to patient prognosis. In this study, we investigated the pathological features indicating MMCO in a large cohort of PMOCs and analyzed their association with patient prognosis.MethodsWe reviewed surgically treated PMOC patients diagnosed at the Seoul National University Hospital from 1995 to 2019, according to the updated WHO classification, and investigated the presence of pathological features indicating MMCO.ResultsA total of 144 patients with PMOCs were included. The 5 pathological findings indicating MMCO, including an infiltrative invasive pattern, the absence of benign or borderline components, a smaller tumor size, the presence of signet ring cells and the presence of extracellular mucin were observed in PMOC (21.6%, 43.1%, 20.8%, 4.3% and 12.9%, respectively), and were significantly correlated with poor overall and progression-free survival rates in PMOC. The patient's prognosis worsened as the extent of the infiltrative invasive pattern increased (p<0.001). In addition, the prognostic power was stronger when the 5 pathological factors were analyzed together (new grouping system) than when analyzed individually (p<0.001) and the new grouping system was identified as an independent prognostic factor regardless of FIGO stage.ConclusionFive pathological findings indicating MMCO in PMOC were significantly associated with poor prognosis in PMOC patients. Also, the new grouping system combining these findings was identified as an independent prognostic factor.
| S-EPMC8899875 | biostudies-literature
Project description:Mucinous ovarian carcinoma (MOC) is a rare histological type of epithelial ovarian cancer. It has poor response to conventional platinum-based chemotherapy regimens and PARPi-based maintenance treatment, resulting in short survival and poor prognosis in advanced-disease patients. MOC is characterized by mucus that is mainly composed of mucin in the cystic cavity. Our review discusses in detail the role of mucins in MOC. Mucins are correlated with MOC development. Furthermore, they are valuable in the differential diagnosis of primary and secondary ovarian mucinous tumors. Some types of mucins have been studied in the context of chemoresistance and targeted therapy for ovarian cancer. This review may provide a new direction for the diagnosis and treatment of advanced MOC.
| S-EPMC10468386 | biostudies-literature
Project description:Mucinous ovarian carcinoma (MOC) is a unique form of ovarian cancer. MOC typically presents at early stage but demonstrates intrinsic chemoresistance; treatment of advanced-stage and relapsed disease is therefore challenging. We harness a large retrospective MOC cohort to identify factors associated with recurrence risk and survival. A total of 151 MOC patients were included. The 5 year disease-specific survival (DSS) was 84.5%. Risk of subsequent recurrence after a disease-free period of 2 and 5 years was low (8.3% and 5.6% over the next 10 years). The majority of cases were FIGO stage I (35.6% IA, 43.0% IC). Multivariable analysis identified stage and pathological grade as independently associated with DSS (p < 0.001 and p < 0.001). Grade 1 stage I patients represented the majority of cases (53.0%) and demonstrated exceptional survival (10 year DSS 95.3%); survival was comparable between grade I stage IA and stage IC patients, and between grade I stage IC patients who did and did not receive adjuvant chemotherapy. At 5 years following diagnosis, the proportion of grade 1, 2 and 3 patients remaining disease free was 89.5%, 74.9% and 41.7%; the corresponding proportions for FIGO stage I, II and III/IV patients were 91.1%, 76.7% and 19.8%. Median post-relapse survival was 5.0 months. Most MOC patients present with low-grade early-stage disease and are at low risk of recurrence. New treatment options are urgently needed to improve survival following relapse, which is associated with extremely poor prognosis.
| S-EPMC8616033 | biostudies-literature