scholarly journals MUTYH as an Emerging Predictive Biomarker in Ovarian Cancer

Diagnostics ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 84
Author(s):  
Megan L. Hutchcraft ◽  
Holly H. Gallion ◽  
Jill M. Kolesar
Keyword(s):  
Ovarian Cancer ◽  
Excision Repair ◽  
Adenosine Diphosphate ◽  
Predictive Biomarker ◽  
Genetic Alterations ◽  
Chemotherapeutic Agents ◽  
Cancer Resistance ◽  
Therapy Targets ◽  
Ovarian Cancers ◽  
Mutyh Gene

Approximately 18% of ovarian cancers have an underlying genetic predisposition and many of the genetic alterations have become intervention and therapy targets. Although mutations in MutY homolog (MUTYH) are best known for MUTYH associated polyposis and colorectal cancer, it plays a role in the development of ovarian cancer. In this review, we discuss the function of the MUTYH gene, mutation epidemiology, and its mechanism for carcinogenesis. We additionally examine its emerging role in the development of ovarian cancer and how it may be used as a predictive and targetable biomarker. MUTYH mutations may confer the risk of ovarian cancer by the failure of its well-known base excision repair mechanism or by failure to induce cell death. Biallelic germline MUTYH mutations confer a 14% risk of ovarian cancer by age 70. A monoallelic germline mutation in conjunction with a somatic MUTYH mutation may also contribute to the development of ovarian cancer. Resistance to platinum-based chemotherapeutic agents may be seen in tumors with monoallelic mutations, but platinum sensitivity in the biallelic setting. As MUTYH is intimately associated with targetable molecular partners, therapeutic options for MUTYH driven ovarian cancers include programed-death 1/programed-death ligand-1 inhibitors and poly-adenosine diphosphate ribose polymerase inhibitors. Understanding the function of MUTYH and its associated partners is critical for determining screening, risk reduction, and therapeutic approaches for MUTYH-driven ovarian cancers.

scholarly journals CCNE1 Amplification as a Predictive Biomarker of Chemotherapy Resistance in Epithelial Ovarian Cancer

Diagnostics ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 279
Author(s):  
Justin W. Gorski ◽  
Frederick R. Ueland ◽  
Jill M. Kolesar
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Chemotherapy Resistance ◽  
Predictive Marker ◽  
Predictive Biomarker ◽  
The United States ◽  
Genetic Alterations ◽  
Cyclin E1 ◽  
One Year ◽  
Line Setting

Ovarian cancer is the most-deadly gynecologic malignancy, with greater than 14,000 women expected to succumb to the disease this year in the United States alone. In the front-line setting, patients are treated with a platinum and taxane doublet. Although 40–60% of patients achieve complete clinical response to first-line chemotherapy, 25% are inherently platinum-resistant or refractory with a median overall survival of about one year. More than 80% of women afflicted with ovarian cancer will recur. Many attempts have been made to understand the mechanism of platinum and taxane based chemotherapy resistance. However, despite decades of research, few predictive markers of chemotherapy resistance have been identified. Here, we review the current understanding of one of the most common genetic alterations in epithelial ovarian cancer, CCNE1 (cyclin E1) amplification, and its role as a potential predictive marker of cytotoxic chemotherapy resistance. CCNE1 amplification has been identified as a primary oncogenic driver in a subset of high grade serous ovarian cancer that have an unmet clinical need. Understanding the interplay between cyclin E1 amplification and other common ovarian cancer genetic alterations provides the basis for chemotherapeutic resistance in CCNE1 amplified disease. Exploration of the effect of cyclin E1 amplification on the cellular machinery that causes dysregulated proliferation in cancer cells has allowed investigators to explore promising targeted therapies that provide the basis for emerging clinical trials.

scholarly journals The Non-Coding RNAs Inducing Drug Resistance in Ovarian Cancer: A New Perspective for Understanding Drug Resistance

2021 ◽  
Vol 11 ◽  
Author(s):  
Gaofeng Li ◽  
Jun Gong ◽  
Shulong Cao ◽  
Zhaoyang Wu ◽  
Dong Cheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Epithelial Mesenchymal Transition ◽  
Underlying Mechanism ◽  
Chemotherapeutic Agents ◽  
Circular Rnas ◽  
Cancer Resistance ◽  
Chemotherapeutic Resistance ◽  
Mesenchymal Transition ◽  
Non Coding Rnas

Ovarian cancer, a common malignant tumor, is one of the primary causes of cancer-related deaths in women. Systemic chemotherapy with platinum-based compounds or taxanes is the first-line treatment for ovarian cancer. However, resistance to these chemotherapeutic drugs worsens the prognosis. The underlying mechanism of chemotherapeutic resistance in ovarian cancer remains unclear. Non-coding RNAs, including long non-coding RNAs, microRNAs, and circular RNAs, have been implicated in the development of drug resistance. Abnormally expressed non-coding RNAs can promote ovarian cancer resistance by inducing apoptosis inhibition, protective autophagy, abnormal tumor cell proliferation, epithelial-mesenchymal transition, abnormal glycolysis, drug efflux, and cancer cell stemness. This review summarizes the role of non-coding RNAs in the development of chemotherapeutic resistance in ovarian cancer, including their mechanisms, targets, and potential signaling pathways. This will facilitate the development of novel chemotherapeutic agents that can target these non-coding RNAs and improve ovarian cancer treatment.

Corilagin Reduces Resistance to PARP Inhibitors by Inhibiting the ERK Signaling Pathway in Ovarian Cancers

2021 ◽  
Author(s):  
Baoxin Luan ◽  
Hongbo Zhao ◽  
Robert C. Bast ◽  
Zhen Lu ◽  
Yinhua Yu
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Excision Repair ◽  
Resistant Cell ◽  
Erk Signaling ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Ovarian Cancers ◽  
Resistant Cells

Abstract Background: Corilagin is a compound with hepatoprotective and antiviral activity extracted from Phyllanthus niruri L. Our previous work demonstrated that corilagin inhibits the growth of ovarian cancer cells by regulating the TGF-β/AKT/ERK signaling. Corilagin was also found to sensitize ovarian cancer cells to paclitaxel and carboplatin by inhibiting the Snail-glycolysis pathway. We have now studied whether corilagin could overcome resistance of ovarian cancer cells to poly ADP ribose polymerase inhibitors (PARPi). PARPi block DNA base excision repair and have been approved for treatment of ovarian cancers. Drug resistance has limited efficacy of PARPi. Methods: We have assessed the effect of corilagin alone and in combination with PARPi in two pairs of ovarian cancer cell lines-A2780CP/A2780CP_R and UWB1.289/UWB1.289_R-that are sensitive or resistant to PARPi. CulcuSyn software (BIOSOFT-Software for Science, Cambridge, U.K.) was used to calculate synergy between two drug combinations. Results: Corilagin was active against all four cell lines and enhanced BMN673 activity synergistically in both PARPi resistant cell lines. PARPi-BMN673 down-regulated the expression levels of PARP and up-regulated pH2AX, it decreased pERK activity in sensitive cell lines, but not in resistant cell lines. While corilagin affected DNA repair function to some extent, it inhibited pERK activity in both PARPi sensitive and resistant cells in a dose dependent manner. Corilagin, but not the BMN673, inhibited ZEB1 in resistant cells. Conclusions: Corilagin deserves further evaluation as a drug that could enhance the activity of PARPi in PARPi-resistant ovarian cancer cells.

scholarly journals Determination of chemoresistance of ovarian cancer cells in vitro

2019 ◽  
Vol 6 (4) ◽  
pp. 8-25
Author(s):  
K. A. Kuzin ◽  
T. I. Fetisov ◽  
R. I. Knyazev ◽  
L. Ya. Fomina ◽  
L. V. Meheda ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Cells ◽  
Experimental Testing ◽  
Primary Cultures ◽  
Chemotherapeutic Agents ◽  
Biomedical Literature ◽  
Ovarian Cancer Cells ◽  
Cancer Resistance ◽  
Metabolic Activities

Objectives: to provide a rationale for existing approaches for the evaluation of chemoresistance of ovarian cancer in vitro, to perform a comparative analysis of the methods and to assess the perspectives of their further application.Materials and methods. For the review preparation, we analyzed articles on experimental testing of ovarian cancer resistance to chemotherapeutic agents, available at biomedical literature databases SciVerse Scopus (158), PubMed (323), Web of Science (285), RSCI (64). The review cited 37 recent publications, 12 of them being published over the past three years, and 16 articles being referred as pioneer publications on techniques previously and used today.Results. Peculiarities of the main methods for assessing the resistance and sensitivity of a cancer to various chemotherapeutic drugs using primary cultures of tumor cells obtained from biopsy or surgical material are analyzed. Proliferative and metabolic activities as well as the level of cell death were considered as the main evaluated characteristics of tumor cells. The methodological features of the described methods are discussed, as well as the prospects for their further application.Conclusion. Predictive detection of chemoresistance of ovarian cancer is based on testing the viability of tumor cells in the presence of a chemotherapeutic drug. The results of studies of the key mechanisms of chemoresistance development in tumor cells provide the rationale for improving in vitro testing.

scholarly journals Plasma Protein Biomarkers Associated with Higher Ovarian Cancer Risk in BRCA1/2 Carriers

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2300
Author(s):  
Hee-Sung Ahn ◽  
Jung Yoon Ho ◽  
Jiyoung Yu ◽  
Jeonghun Yeom ◽  
Sanha Lee ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Plasma Protein ◽  
Normal Subjects ◽  
Genetic Alterations ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ovarian Cancer Risk ◽  
Protein Markers ◽  
Protein Biomarkers ◽  
Proteomics Approach ◽  
Risk Reducing

Ovarian cancer (OC) is the most lethal gynecologic malignancy and in-time diagnosis is limited because of the absence of effective biomarkers. Germline BRCA1/2 genetic alterations are risk factors for hereditary OC; risk-reducing salpingo-oophorectomy (RRSO) is pursued for disease prevention. However, not all healthy carriers develop the disease. Therefore, identifying predictive markers in the BRCA1/2 carrier population could help improve the identification of candidates for preventive RRSO. In this study, plasma samples from 20 OC patients (10 patients with BRCA1/2 wild type (wt) and 10 with the BRCA1/2 variant (var)) and 20 normal subjects (10 subjects with BRCA1/2wt and 10 with BRCA1/2var) were analyzed for potential biomarkers of hereditary OC. We applied a bottom-up proteomics approach, using nano-flow LC-MS to analyze depleted plasma proteome quantitatively, and potential plasma protein markers specific to the BRCA1/2 variant were identified from a comparative statistical analysis of the four groups. We obtained 1505 protein candidates from the 40 subjects, and SPARC and THBS1 were verified by enzyme-linked immunosorbent assay. Plasma SPARC and THBS1 concentrations in healthy BRCA1/2 carriers were found to be lower than in OC patients with BRCA1/2var. If plasma SPARC concentrations increase over 337.35 ng/ml or plasma THBS1 concentrations increase over 65.28 mg/ml in a healthy BRCA1/2 carrier, oophorectomy may be suggested.

scholarly journals A radiomic nomogram based on arterial phase of CT for differential diagnosis of ovarian cancer

2021 ◽  
Author(s):  
Yumin Hu ◽  
Qiaoyou Weng ◽  
Haihong Xia ◽  
Tao Chen ◽  
Chunli Kong ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Ovarian Cancer ◽  
Clinical Data ◽  
Arterial Phase ◽  
Multivariable Logistic Regression Analysis ◽  
Clinical Factors ◽  
Good Discrimination ◽  
Training Cohort ◽  
Ovarian Cancers ◽  
Radiomics Signature

Abstract Purpose To develop and validate a radiomic nomogram based on arterial phase of CT to discriminate the primary ovarian cancers (POCs) and secondary ovarian cancers (SOCs). Methods A total of 110 ovarian cancer patients in our hospital were reviewed from January 2010 to December 2018. Radiomic features based on the arterial phase of CT were extracted by Artificial Intelligence Kit software (A.K. software). The least absolute shrinkage and selection operation regression (LASSO) was employed to select features and construct the radiomics score (Rad-score) for further radiomics signature calculation. Multivariable logistic regression analysis was used to develop the predicting model. The predictive nomogram model was composed of rad-score and clinical data. Nomogram discrimination and calibration were evaluated. Results Two radiomic features were selected to build the radiomics signature. The radiomics nomogram that incorporated 2 radiomics signature and 2 clinical factors (CA125 and CEA) showed good discrimination in training cohort (AUC 0.854), yielding the sensitivity of 78.8% and specificity of 90.7%, which outperformed the prediction model based on radiomics signature or clinical data alone. A visualized differential nomogram based on the radiomic score, CEA, and CA125 level was established. The calibration curve demonstrated the clinical usefulness of the proposed nomogram. Conclusion The presented nomogram, which incorporated radiomic features of arterial phase of CT with clinical features, could be useful for differentiating the primary and secondary ovarian cancers.

scholarly journals FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1866
Author(s):  
Katia A. Mesquita ◽  
Reem Ali ◽  
Rachel Doherty ◽  
Michael S. Toss ◽  
Islam Miligy ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
High Throughput Screening ◽  
Nuclear Translocation ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Progression Free Survival ◽  
Ovarian Cancer Cells ◽  
Physical Interaction ◽  
Base Excision

FEN1 plays critical roles in long patch base excision repair (LP-BER), Okazaki fragment maturation, and rescue of stalled replication forks. In a clinical cohort, FEN1 overexpression is associated with aggressive phenotype and poor progression-free survival after platinum chemotherapy. Pre-clinically, FEN1 is induced upon cisplatin treatment, and nuclear translocation of FEN1 is dependent on physical interaction with importin β. FEN1 depletion, gene inactivation, or inhibition re-sensitizes platinum-resistant ovarian cancer cells to cisplatin. BRCA2 deficient cells exhibited synthetic lethality upon treatment with a FEN1 inhibitor. FEN1 inhibitor-resistant PEO1R cells were generated, and these reactivated BRCA2 and overexpressed the key repair proteins, POLβ and XRCC1. FEN1i treatment was selectively toxic to POLβ deficient but not XRCC1 deficient ovarian cancer cells. High throughput screening of 391,275 compounds identified several FEN1 inhibitor hits that are suitable for further drug development. We conclude that FEN1 is a valid target for ovarian cancer therapy.

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