scholarly journals Exploiting the Prevalence of Homologous Recombination Deficiencies in High-Grade Serous Ovarian Cancer

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1206 ◽  
Author(s):  
Sara Bouberhan ◽  
Lauren Philp ◽  
Sarah Hill ◽  
Linah F. Al-Alem ◽  
Bo Rueda
Keyword(s):  
Ovarian Cancer ◽  
Synthetic Lethality ◽  
Gynecologic Cancer ◽  
Genomic Analysis ◽  
The United States ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Early Phase Trials ◽  
Approved Drugs ◽  
Preclinical And Clinical Studies

High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecologic cancer in the United States. Genomic analysis revealed roughly half of HGSOC display homologous repair deficiencies. An improved understanding of the genomic and somatic mutations that influence DNA repair led to the development of poly(ADP-ribose) polymerase inhibitors for the treatment of ovarian cancer. In this review, we explore the preclinical and clinical studies that led to the development of FDA approved drugs that take advantage of the synthetic lethality concept, the implementation of the early phase trials, the development of companion diagnostics and proposed mechanisms of resistance.

scholarly journals ATM Inhibition Synergizes with Fenofibrate in High Grade Serous Ovarian Cancer Cells

2020 ◽  
Author(s):  
Chi-Wei Chen ◽  
Raquel Buj ◽  
Erika S. Dahl ◽  
Kelly E. Leon ◽  
Katherine M. Aird
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
The United States ◽  
Gene Set Enrichment Analysis ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Pparα Agonist

AbstractBackgroundEpithelial ovarian cancer (EOC) is the deadliest gynecological malignancy in the United States with high grade serous ovarian cancer (HGSOC) as the most commonly diagnosed subtype. While therapies targeting deficiencies in the homologous recombination (HR) pathway are emerging as the standard treatment for HGSOC patients, this strategy is limited to the 50% of patients with a deficiency in this pathway. Therefore, patients with HR-proficient tumors are likely to be resistant to these therapies and require alternative strategies.MethodsData from HGSOC patients in The Cancer Genome Atlas (TCGA) were analyzed for ATM status, ATM and PPARα expression, and used to perform Gene Set Enrichment Analysis (GSEA). Screening data from the Dependency Map were analyzed to identify FDA-approved drugs that preferentially inhibit ATM-low cancer cells. In vitro studies were performed to determine whether ATM inhibitors synergize with the PPARα agonist fenofibrate in HGSOC cell lines.ResultsThe HR gene Ataxia Telangiectasia Mutated (ATM) is wildtype in the majority of HGSOC patients and its kinase activity is upregulated compared to normal fallopian tube tissue. As high ATM has been associated with poor overall and progression-free survival, targeting ATM may be beneficial for a subset of HGSOC patients. Clinical trials of ATM inhibitors are commencing; however, ATM inhibitors are not effective as single agents. We aimed to explore novel therapeutic vulnerabilities of ATM deficient cells to develop a combinatorial therapy. Using data from TCGA, we found that multiple pathways related to metabolism are inversely correlated with ATM expression, suggesting that combining ATM inhibition and metabolic inhibition would be effective. Indeed, analysis of FDA-approved drugs from the Dependency Map demonstrated that ATM low cell lines are more sensitive to fenofibrate, a PPARα agonist that has been previously shown to affect multiple cellular metabolic pathways. Consistently, PPARα signaling is associated with ATM expression. We validated that combined inhibition of ATM and treatment with fenofibrate is synergistic in multiple HGSOC cell lines by inducing senescence.ConclusionsOur results suggest that metabolic changes induced by ATM inhibitors are a potential target for the treatment for HGSOC.

Genomic analysis of high-grade serous ovarian cancer in young and older women

2020 ◽  
Vol 159 ◽  
pp. 158
Author(s):  
O.T. Filippova ◽  
P. Selenica ◽  
S.S. Lee ◽  
X. Pei ◽  
N. Riaz ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Older Women ◽  
Genomic Analysis ◽  
High Grade ◽  
Serous Ovarian Cancer

scholarly journals Odd-skipped related 2 (OSR2) is differentially expressed in high-grade serous ovarian cancers.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Ovarian Cancer ◽  
Cell Fate ◽  
Microarray Data ◽  
Expression Profiles ◽  
Gynecologic Cancer ◽  
Differentially Expressed ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Primary Tumors ◽  
Ovarian Cancers

Ovarian cancer is the most lethal gynecologic cancer (1). We sought to identify genes associated with high-grade serous ovarian cancer (HGSC) by comparing global gene expression profiles of normal ovary with that of primary tumors from women diagnosed with HGSC using published microarray data (2,3). We previously identified forkhead box L2 (4), (FOXL2) as among the genes whose expression was most different in HGSC ovarian tumors when compared to the ovary. Here, we find that potential FOXL2 transcriptional target (5,6) odd-skipped related gene OSR2 (7) is differentially expressed in high-grade serous ovarian cancer, and could be observed in independent tumor microarray data (2,3). These data reveal perturbed expression of a target gene of a key transcription factor and specifier of ovarian cell fate in high-grade serous ovarian cancers.

Targeting the upregulation of the AKT pathway and homologous recombination repair as a therapeutic strategy for epithelial ovarian cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13125-e13125
Author(s):  
Elena Ratner ◽  
Z-Ping Lin ◽  
Thomas J. Rutherford ◽  
Masoud Azodi ◽  
Alessandro Santin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Epithelial Ovarian Cancer ◽  
Cell Lines ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Gynecologic Cancer ◽  
The United States ◽  
Platinum Drugs ◽  
Wild Type

e13125 Background: Epithelial ovarian cancer (EOC) is the second most common gynecologic cancer in the United States, and carries the highest mortality in this category in the West. The progression free survival and overall survival depend greatly on tumor sensitivity to a platinum chemotherapy. Once platinum resistance is encountered, response rates of only 6–30% are achieved. A relatively new modality in EOC that would allow targeted treatments is a PARP inhibitor, a drug that inhibits the enzyme poly (ADP-ribose) polymerase (PARP), which is showing promise for the treatment of EOC with mutations in the BRCA1 or BRCA2 tumor suppressors. Triapine, a novel small-molecule drug developed in our laboratory, potently inhibits the activity of ribonucleotide reductase involved in the key step of DNA synthesis and replication. Methods: 1. Cell sensitivity to varying ratios of treating drug combinations (Triapine with cisplatin; PARP inhibitor, olaparib) was carried out by clonogenic survival assays using multiple EOC cell lines (A2780, Caov-3, EFO, IGROV-1, BG-1, PEO1, SKOV3). 2. AKT level was measured in the cell lines before and after treatment. 3. BRCA1 wild-type and BRCA1-knockdown EOC cells were treated with cisplatin or PARP alone and in combination with Triapine. Drug-induced DNA damage was assessed by the levels of g-H2AX, the marker of double stranded breaks (DSBs), and of Rad51 foci, a marker of HR repair of DSBs. Results: Treatment with Triapine leads to synergistic sensitization of BRCA1 wild-type EOC cells to platinum drugs and to olaparib. Both platinum drugs and olaparib induce DNA damage that is repaired by HR. This suggests that Triapine inhibits HR and sensitizes EOC cells to these drugs. Triapine attenuates olaparib-induced Rad51 foci in BRCA1-wild type cells, which resembles the impairment of such foci formation in BRCA1-knockdown cells. Triapine causes down-regulation of AKT activity in EOC cells. Conclusions: Triapine produces synthetic lethality by inhibiting both DNA repair and pro-survival pathways. Combination of Triapine and platinum drugs/PARP inhibitors represents a rational and innovative therapy that targets EOC with a high level of AKT activity.

Gynecologic Cancer InterGroup (GCIG) Consensus Review for Ovarian and Primary Peritoneal Low-Grade Serous Carcinomas

2014 ◽  
Vol 24 (Supp 3) ◽  
pp. S9-S13 ◽  
Author(s):  
Charlie Gourley ◽  
John Farley ◽  
Diane M. Provencher ◽  
Sandro Pignata ◽  
Linda Mileshkin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clear Cell ◽  
Gynecologic Cancer ◽  
Low Grade ◽  
Tumor Type ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Histological Subtypes ◽  
Specific Data ◽  
Younger Age

AbstractLow-grade serous ovarian cancer is a recently described histological subtype of ovarian cancer that is clinically and molecularly distinct from the 4 other main histological subtypes (high-grade serous, clear cell, endometrioid, and mucinous). In particular, it differs from high-grade serous ovarian cancer in that it presents at a much younger age, is more indolent, and is relatively chemoresistant. Very few clinical trials have been performed exclusively in this tumor type; and as such, specific data guiding optimal management are limited.

scholarly journals Sense and anti-sense transcripts at the PGM5 locus are differentially expressed in high-grade serous ovarian cancers.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Ovarian Cancer ◽  
Microarray Data ◽  
Expression Profiles ◽  
Gynecologic Cancer ◽  
Gene Expression Profiles ◽  
Global Gene Expression ◽  
High Grade ◽  
Normal Ovary ◽  
Serous Ovarian Cancer ◽  
Primary Tumors

Ovarian cancer is the most lethal gynecologic cancer (1). We sought to identify genes associated with high-grade serous ovarian cancer (HGSC) by comparing global gene expression profiles of normal ovary with that of primary tumors from women diagnosed with HGSC using published microarray data (2, 3). Here, we report significant differential sense and anti-sense transcription at the PGM locus in high-grade serous ovarian tumors.

scholarly journals Synthetic lethality in CCNE1-amplified high grade serous ovarian cancer through combined inhibition of Polo-like kinase 1 and microtubule dynamics

Oncotarget ◽  
2018 ◽  
Vol 9 (40) ◽  
pp. 25842-25859 ◽  
Author(s):  
Sabrina Noack ◽  
Monika Raab ◽  
Yves Matthess ◽  
Mourad Sanhaji ◽  
Andrea Krämer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Synthetic Lethality ◽  
Microtubule Dynamics ◽  
High Grade ◽  
Serous Ovarian Cancer

scholarly journals Genomic Analysis Using Regularized Regression in High-Grade Serous Ovarian Cancer

2018 ◽  
Vol 17 ◽  
pp. 117693511875534 ◽  
Author(s):  
Yanina Natanzon ◽  
Madalene Earp ◽  
Julie M Cunningham ◽  
Kimberly R Kalli ◽  
Chen Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Copy Number ◽  
Genomic Analysis ◽  
Penalized Regression ◽  
Regulatory Elements ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Regularized Regression ◽  
Germline Variation

High-grade serous ovarian cancer (HGSOC) is a complex disease in which initiation and progression have been associated with copy number alterations, epigenetic processes, and, to a lesser extent, germline variation. We hypothesized that, when summarized at the gene level, tumor methylation and germline genetic variation, alone or in combination, influence tumor gene expression in HGSOC. We used Elastic Net (ENET) penalized regression method to evaluate these associations and adjust for somatic copy number in 3 independent data sets comprising tumors from more than 470 patients. Penalized regression models of germline variation, with or without methylation, did not reveal a role in HGSOC gene expression. However, we observed significant association between regional methylation and expression of 5 genes ( WDPCP, KRT6C, BRCA2, EFCAB13, and ZNF283). CpGs retained in ENET model for BRCA2 and ZNF283 appeared enriched in several regulatory elements, suggesting that regularized regression may provide a novel utility for integrative genomic analysis.

scholarly journals Interleukin-16 expression associates with patient survival in high-grade serous ovarian cancer.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Ovarian Cancer ◽  
Expression Profiles ◽  
Gynecologic Cancer ◽  
Gene Expression Profiles ◽  
Progression Free Survival ◽  
Global Gene Expression ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Significant Differential Expression ◽  
Free Survival

Ovarian cancer is the most lethal gynecologic cancer (1). We sought to identify genes associated with enhanced survival in high-grade serous ovarian cancer (HGSC) by comparing global gene expression profiles of tumors from women diagnosed with HGSC with the best and worst progression-free survival (2). We found significant differential expression of the gene encoding the cytokine interleukin-16 (IL-16) when comparing tumor transcriptomes based on progression-free survival. IL-16 was expressed at significantly lower levels in high-grade serous ovarian tumors of women with the longest progression-free survival.

scholarly journals Expression of the interleukin-1 receptor antagonist associates with patient survival in high-grade serous ovarian cancer.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Ovarian Cancer ◽  
Receptor Antagonist ◽  
Expression Profiles ◽  
Interleukin 1 ◽  
Gynecologic Cancer ◽  
Progression Free Survival ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Significant Differential Expression ◽  
Free Survival

Ovarian cancer is the most lethal gynecologic cancer (1). We sought to identify genes associated with enhanced survival in high-grade serous ovarian cancer (HGSC) by comparing global gene expression profiles of tumors from women diagnosed with HGSC with the best and worst progression-free survival (2). We found significant differential expression of the gene encoding the receptor antagonist for the cytokine interleukin-1 (IL-1) (IL-1RN) when comparing tumor transcriptomes based on progression-free survival. IL-1RN was expressed at significantly lower levels in high-grade serous ovarian tumors of women with the longest progression-free survival.

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