scholarly journals AKT Isoforms Interplay in High-Grade Serous Ovarian Cancer Prognosis and Characterization

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 304
Author(s):  
Eros Azzalini ◽  
Domenico Tierno ◽  
Michele Bartoletti ◽  
Renzo Barbazza ◽  
Giorgio Giorda ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Acquired Resistance ◽  
Digital Pcr ◽  
Parp Inhibitors ◽  
Clinicopathological Features ◽  
Cancer Prognosis ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Akt Isoforms ◽  
Ovarian Cancer Prognosis

High-grade serous ovarian cancer (HGSOC) is among the deadliest gynecological malignancies. The acquired resistance to platinum-based therapies and the intrinsic heterogeneity of the disease contribute to the low survival rate. To improve patients’ outcomes, new combinatorial approaches able to target different tumor vulnerabilities and enhance the efficacy of the current therapies are required. AKT inhibitors are promising antineoplastic agents able to act in synergy with PARP inhibitors, but the spectrum of patients who can benefit from this combination is unclear, since the role of the three different isoforms of AKT is still unknown. Here, we study the expression of AKT isoforms on a retrospective cohort of archive tissue by RT-droplet digital PCR (ddPCR) analyzing their association with the clinicopathological features of patients. Based on AKT1/AKT2 and AKT1/AKT3 ratios, we define four AKT classes which were related to patients’ survival, tumor morphology and BRCA1 expression. Moreover, our results show that high AKT3 expression levels were frequently associated with tumors having classic features, a low number of mitoses and the presence of psammoma bodies. Overall, our study obtains new insights on AKT isoforms and their associations with the clinicopathological features of HGSOC patients. These evidences could help to better define the subsets of patients who can benefit from AKT and PARP inhibitors therapy in future clinical trials.

scholarly journals PARP Inhibitors Display Differential Efficacy in Models of BRCA Mutant High-Grade Serous Ovarian Cancer

2021 ◽  
Vol 22 (16) ◽  
pp. 8506
Author(s):  
Kristie-Ann Dickson ◽  
Tao Xie ◽  
Christian Evenhuis ◽  
Yue Ma ◽  
Deborah J. Marsh
Keyword(s):  
Ovarian Cancer ◽  
Cell Line ◽  
Ovarian Cancer Cell Line ◽  
Acquired Resistance ◽  
Parp Inhibitors ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Cancer Genes ◽  
Chemical Structures

Several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are now in clinical use for tumours with defects in BReast CAncer genes BRCA1 or BRCA2 that result in deficient homologous recombination repair (HRR). Use of olaparib, niraparib or rucaparib for the treatment of high-grade serous ovarian cancer, including in the maintenance setting, has extended both progression free and overall survival for women with this malignancy. While different PARP inhibitors (PARPis) are mechanistically similar, differences are apparent in their chemical structures, toxicity profiles, PARP trapping abilities and polypharmacological landscapes. We have treated ovarian cancer cell line models of known BRCA status, including the paired cell lines PEO1 and PEO4, and UWB1.289 and UWB1.289+BRCA1, with five PARPis (olaparib, niraparib, rucaparib, talazoparib and veliparib) and observed differences between PARPis in both cell viability and cell survival. A cell line model of acquired resistance to veliparib showed increased resistance to the other four PARPis tested, suggesting that acquired resistance to one PARPi may not be able to be rescued by another. Lastly, as a proof of principle, HRR proficient ovarian cancer cells were sensitised to PARPis by depletion of BRCA1. In the future, guidelines will need to emerge to assist clinicians in matching specific PARPis to specific patients and tumours.

scholarly journals Role of tumor location on high-grade serous ovarian cancer prognosis

2021 ◽  
Author(s):  
Seval Ay ◽  
Deniz Tataroğlu Özyükseler ◽  
Mustafa Başak ◽  
Özgecan Dülgar ◽  
Serdar Arıcı ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Location ◽  
Cancer Prognosis ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Ovarian Cancer Prognosis

scholarly journals Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

2019 ◽  
Author(s):  
Elaine Sanij ◽  
Katherine M. Hannan ◽  
Shunfei Yan ◽  
Jiachen Xuan ◽  
Jessica E. Ahern ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Parp Inhibitors ◽  
Rna Polymerase I ◽  
High Grade ◽  
Replication Forks ◽  
Serous Ovarian Cancer ◽  
Damage Response ◽  
Polymerase I

AbstractHigh-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer and has a dismal prognosis. PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient HGSOC. However, acquired resistance to PARPi by complex mechanisms including HR restoration and stabilisation of replication forks is a major challenge in the clinic. Here, we demonstrate CX-5461, an inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress at rDNA leading to activation of DNA damage response and DNA damage involving MRE11-dependent degradation of replication forks. CX-5461 cooperates with PARPi in exacerbating DNA damage and enhances synthetic lethal interactions of PARPi with HR deficiency in HGSOC-patient-derived xenograft (PDX)in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi and destabilises replication forks irrespective of HR pathway status, overcoming two well-known mechanisms of resistance to PARPi. Importantly, CX-5461 exhibits single agent efficacy in PARPi-resistant HGSOC-PDX. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. Therefore, CX-5461 is a promising therapy alone and in combination therapy with PARPi in HR-deficient HGSOC. CX-5461 is also an exciting treatment option for patients with relapsed HGSOC tumors that have poor clinical outcome.

scholarly journals Examining the interaction between TGFBR3 and ESRRA in ovarian cancer prognosis

2016 ◽  
Author(s):  
Alun Passey ◽  
Robert Brown ◽  
Charlotte S. Wilhelm-Benartzi
Keyword(s):  
Ovarian Cancer ◽  
Conflicts Of Interest ◽  
The Cancer Genome Atlas ◽  
Cancer Prognosis ◽  
Serous Ovarian Cancer ◽  
Cancer Genome Atlas ◽  
A Cell ◽  
Funding Support ◽  
Functional Investigation ◽  
Ovarian Cancer Prognosis

ABSTRACTThe authors found that ESRRA when co-expressed at high levels with TGFβR3 may be prognostic for serous ovarian cancer overall survival in data from the Cancer Genome Atlas; however, this result was not validated in further datasets. A cell line was also identified in this study for future functional investigation of interactions between ESRRA and TGFβR3 in the context of oestrogen signaling in order to further elucidate their potential roles as prognostic biomarkers for serous ovarian cancer.FUNDING SUPPORTThis work was supported by Cancer Research UK program A6689 (RB and CSWB) and the Medical Research Council (AP)CONFLICT OF INTEREST DISCLOSURESThe authors have declared no conflicts of interest.AUTHOR CONTRIBUTIONSCSWB designed the study. AP, CSWB, and RB developed the methodology. AP and CSWB collected the data. AP, CSWB, and RB wrote the manuscript. CSWB is responsible for the overall content.

scholarly journals MiRNA-103/107 in Primary High-Grade Serous Ovarian Cancer and Its Clinical Significance

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2680
Author(s):  
Milosz Wilczynski ◽  
Michal Kielbik ◽  
Daria Senderowska ◽  
Tomasz Krawczyk ◽  
Bozena Szymanska ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
Clinicopathological Features ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Expression Levels ◽  
Ovarian Cancer Cell Lines

High levels of miRNA-103/107 are associated with poor outcomes in the case of breast cancer patients. MiRNA-103/107-DICER axis may be one of the key regulators of cancer aggressiveness. MiRNA-103/107 expression levels have never been related to patients’ clinicopathological data in epithelial ovarian cancer. We aimed to assess miRNA-103/107 expression levels in high grade serous ovarian cancer tissues. Expression levels of both miRNAs were related to the clinicopathological features and survival. We also evaluated expression levels of miRNA-103/107 and DICER in selected ovarian cancer cell lines (A2780, A2780cis, SK-OV-3, OVCAR3). We assessed the relative expression of miRNA-103/107 (quantitative reverse transcription-polymerase chain reaction) in fifty archival formalin-fixed paraffin-embedded tissue samples of primary high grade serous ovarian cancer. Then, miRNA-103/107 and DICER expression levels were evaluated in selected ovarian cancer cell lines. Additionally, DICER, N-/E-cadherin protein levels were assessed with the use of western blot. We identified miRNA-107 up-regulation in ovarian cancer in comparison to healthy tissues (p = 0.0005). In the case of miRNA-103, we did not observe statistically significant differences between cancerous and healthy tissues (p = 0.07). We did not find any correlations between miRNA-103/107 expression levels and clinicopathological features. Kaplan–Meier survival (disease-free and overall survival) analysis revealed that both miRNAs could not be considered as prognostic factors. SK-OV-3 cancer cell lines were characterized by high expression of miRNA-103/107, relatively low expression of DICER (western-blot), and relatively high N-cadherin levels in comparison to other ovarian cancer cell lines. Clinical and prognostic significance of miRNA-103/107 was not confirmed in our study.

scholarly journals 824P Real-world-data (RWD) on platinum (Pt) outcomes after PARP inhibitors (PARPi) progression in high grade serous ovarian cancer (HGSOC) patients (p)

2020 ◽  
Vol 31 ◽  
pp. S622
Author(s):  
A. Plaja Salarich ◽  
I. Teruel García ◽  
B. Pardo Burdalo ◽  
M. Gil-Martin ◽  
J.M. Piulats ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Real World ◽  
Parp Inhibitors ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Real World Data ◽  
World Data
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