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.

scholarly journals Cytocidal Antitumor Effects against Human Ovarian Cancer Cells Induced by B-Lactam Steroid Alkylators with Targeted Activity against Poly (ADP-Ribose) Polymerase (PARP) Enzymes in a Cell-Free Assay

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1028
Author(s):  
Nikolaos Nikoleousakos ◽  
Panagiotis Dalezis ◽  
Aikaterini Polonifi ◽  
Elena G. Geromichalou ◽  
Sofia Sagredou ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Cell Lines ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Positive Control ◽  
Ovarian Cancer Cells ◽  
Antitumor Effects

We evaluated three newly synthesized B-lactam hybrid homo-aza-steroidal alkylators (ASA-A, ASA-B and ASA-C) for their PARP1/2 inhibition activity and their DNA damaging effect against human ovarian carcinoma cells. These agents are conjugated with an alkylating component (POPA), which also served as a reference molecule (positive control), and were tested against four human ovarian cell lines in vitro (UWB1.289 + BRCA1, UWB1.289, SKOV-3 and OVCAR-3). The studied compounds were thereafter compared to 3-AB, a known PARP inhibitor, as well as to Olaparib, a standard third-generation PARP inhibitor, on a PARP assay investigating their inhibitory potential. Finally, a PARP1 and PARP2 mRNA expression analysis by qRT-PCR was produced in order to measure the absolute and the relative gene expression (in mRNA transcripts) between treated and untreated cells. All the investigated hybrid steroid alkylators and POPA decreased in vitro cell growth differentially, according to the sensitivity and different gene characteristics of each cell line, while ASA-A and ASA-B presented the most significant anticancer activity. Both these compounds induced PARP1/2 enzyme inhibition, DNA damage (alkylation) and upregulation of PARP mRNA expression, for all tested cell lines. However, ASA-C underperformed on average in the above tasks, while the compound ASA-B induced synthetic lethality effects on the ovarian cancer cells. Nevertheless, the overall outcome, leading to a drug-like potential, provides strong evidence toward further evaluation.

Ovarian Cancer

2008 ◽  
Vol 6 (8) ◽  
pp. 766 ◽  
Author(s):  
_ _
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Clinical Presentation ◽  
Advanced Disease ◽  
Gynecologic Cancer ◽  
The United States ◽  
Epidemiologic Studies ◽  
Nccn Guidelines ◽  
New Information ◽  
Recent Version

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer and the fifth most common cause of cancer mortality in women in the United States. Fewer than 40% of women with ovarian cancer are cured, and 70% of patients present with advanced disease; because of the location of the ovaries, ovarian cancer has been difficult to diagnose at earlier stages. Epidemiologic studies have identified risk factors, including family history. The NCCN guidelines discuss epithelial ovarian cancer as well as less common ovarian histopathologies, including germ cell neoplasms, carcinosarcomas (malignant mixed Müllerian tumors of the ovary), and ovarian stromal tumors. For 2008, updates include the addition of platinum-based combination therapy as a possible treatment modality for recurrence and a listing of preferred agents for acceptable recurrence modalities. New information was also added to the section on clinical presentation. For the most recent version of the guidelines, please visit NCCN.org

scholarly journals Combination of triapine, olaparib, and cediranib suppresses progression of BRCA-wild type and PARP inhibitor-resistant epithelial ovarian cancer

PLoS ONE ◽  
2018 ◽  
Vol 13 (11) ◽  
pp. e0207399 ◽  
Author(s):  
Z. Ping Lin ◽  
Yong-Lian Zhu ◽  
Ying-Chun Lo ◽  
Jake Moscarelli ◽  
Amy Xiong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Parp Inhibitor ◽  
Wild Type

scholarly journals Disruption of the Gut Microbiota Attenuates Epithelial Ovarian Cancer Sensitivity to Cisplatin Therapy

2021 ◽  
Author(s):  
Laura M. Chambers ◽  
Emily Esakov ◽  
Chad Braley ◽  
Lexie Trestan ◽  
Zahraa Alali ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Tumor Suppressor ◽  
Antibiotic Therapy ◽  
Epithelial Ovarian Cancer ◽  
Gut Microbiome ◽  
Gynecologic Cancer ◽  
The United States ◽  
Additional Treatment ◽  
Cisplatin Therapy

Abstract Background: Epithelial Ovarian Cancer (EOC) is the second most common gynecologic malignancy in the United States, but the leading cause of gynecologic cancer death. Despite many achieving remission with first-line therapy, up to 80% of patients will recur and require additional treatment. Antibiotic therapy is frequently used during cancer treatments for both prophylaxis and treatment of infections, although this profoundly impacts the gut microbiome. Multiple studies suggest that an unperturbed gut microbiome may provide a protective microenvironment, and disruption may be permissive to tumor growth and chemotherapy resistance, including platinum agents. Experimental Design: We assessed whether antibiotic therapy would impact growth of EOC and sensitivity to cisplatin in murine models. Immune competent or compromised mice were given control or antibiotic (ABX) containing water (metronidazole, ampicillin, vancomycin, and neomycin) for two weeks before being intraperitoneally injected with murine ID8 or ID8-VEGF EOC cells. Tumors were monitored and cisplatin therapy was administered weekly until endpoint. Stool was collected throughout the study to assess for microbial population effects over time. Cecal microbiota transplants (CMTs) of contents derived from ABX or control treated donor mice were performed on ABX treated recipient mice. Results: Both immune competent and immune compromised ID8 and ID8 VEGF tumor-bearing mice demonstrated a decreased response to cisplatin therapy in ABX treated groups with an increase in overall tumor burden. RNAseq analysis showed enrichment of multiple cell proliferation and stem cell pathways, and stem cell genes SOX2, WNT and PAX2. The self-renewal of cancer cells derived from tumors of ABX treated mice was increased compared to tumors from control mice, indicative of a microbiota derived tumor suppressor. Conclusion: Collectively, these studies indicate an intact microbiome provides a tumor suppressor and maintains chemosensitivity that is disrupted by ABX treatment.

scholarly journals INPP1 is differentially expressed in platinum-resistant ovarian cancers.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Gynecological Cancer ◽  
The United States ◽  
Differentially Expressed ◽  
Platinum Resistance ◽  
Platinum Drugs ◽  
Cancer Death ◽  
Primary Tumors ◽  
Platinum Resistant

Ovarian cancer is the most common reason for a gynecological cancer death in the developed world and fifth leading cause of cancer death in women in the United States (1, 2). Chemotherapy includes the use of platinum drugs (3) and resistance to platinum drugs is a serious problem for women diagnosed with ovarian cancer (4, 5, 6). We found, using two published datasets (7, 8) that INPP1 was one of the genes most differentially expressed when comparing the transcriptomes of platinum-resistant and platinum-sensitive tumors and cell lines but that the pattern of differential expression was opposite in cell lines versus that in primary tumors from patients. Manipulation of INPP1 expression should be assessed for its ability to reverse platinum resistance.

scholarly journals Disruption of the gut microbiota attenuates epithelial ovarian cancer sensitivity to cisplatin therapy

2020 ◽  
Author(s):  
Laura M. Chambers ◽  
Emily L. Esakov ◽  
Chad Braley ◽  
Lexie Trestan ◽  
Zahraa Alali ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Antibiotic Therapy ◽  
Epithelial Ovarian Cancer ◽  
Gut Microbiome ◽  
Gynecologic Cancer ◽  
Chemotherapy Resistance ◽  
The United States ◽  
Additional Treatment ◽  
Cisplatin Therapy

AbstractBackgroundEpithelial Ovarian Cancer (EOC) is the second most common gynecologic malignancy in the United States, but the leading cause of gynecologic cancer death. Despite many achieving remission with first-line therapy, up to 80% of patients will recur and require additional treatment. Antibiotic therapy is frequently used during cancer treatments for both prophylaxis and treatment of infections, although this profoundly impacts the gut microbiome. Multiple studies suggest that an unperturbed gut microbiome may provide a protective microenvironment, and disruption may be permissive to tumor growth and chemotherapy resistance, including platinum agents.Experimental DesignWe assessed whether antibiotic therapy would impact growth of EOC and sensitivity to cisplatin in murine models. Immune competent or compromised mice were given either metronidazole, ampicillin, vancomycin, and neomycin (ABX) containing or control water for two weeks before being intraperitoneally injected with murine ID8 or ID8-VEGF EOC cells. Tumors were monitored and cisplatin therapy was administered weekly until endpoint. Stool was collected throughout the study to asses for microbial population effects over time.ResultsBoth immune competent and immune compromised ID8 and ID8 VEGF tumor-bearing mice demonstrated a decreased response to cisplatin therapy in ABX treated groups with an increase in overall tumor burden. RNAseq analysis showed enrichment of multiple cell proliferation and stem cell pathways, and stem cell genes SOX2, WNT and PAX2. The self-renewal of ABX treated tumor cells was also increased.ConclusionCollectively, these studies indicate an intact microbiome provides a tumor suppressive microenvironment and enhances sensitivity to cisplatin.

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 Disruption of the Gut Microbiota Attenuates Epithelial Ovarian Cancer Sensitivity to Cisplatin Therapy

2020 ◽  
Author(s):  
Laura Chambers ◽  
Emily Esakov ◽  
Chad Braley ◽  
Lexie Trestan ◽  
Zahraa Alali ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Antibiotic Therapy ◽  
Epithelial Ovarian Cancer ◽  
Gut Microbiome ◽  
Gynecologic Cancer ◽  
Chemotherapy Resistance ◽  
The United States ◽  
Additional Treatment ◽  
Cisplatin Therapy

Abstract Background: Epithelial Ovarian Cancer (EOC) is the second most common gynecologic malignancy in the United States, but the leading cause of gynecologic cancer death. Despite many achieving remission with first-line therapy, up to 80% of patients will recur and require additional treatment. Antibiotic therapy is frequently used during cancer treatments for both prophylaxis and treatment of infections, although this profoundly impacts the gut microbiome. Multiple studies suggest that an unperturbed gut microbiome may provide a protective microenvironment, and disruption may be permissive to tumor growth and chemotherapy resistance, including platinum agents. Experimental Design: We assessed whether antibiotic therapy would impact growth of EOC and sensitivity to cisplatin in murine models. Immune competent or compromised mice were given either metronidazole, ampicillin, vancomycin, and neomycin (ABX) containing or control water for two weeks before being intraperitoneally injected with murine ID8 or ID8-VEGF EOC cells. Tumors were monitored and cisplatin therapy was administered weekly until endpoint. Stool was collected throughout the study to asses for microbial population effects over time.Results: Both immune competent and immune compromised ID8 and ID8 VEGF tumor-bearing mice demonstrated a decreased response to cisplatin therapy in ABX treated groups with an increase in overall tumor burden. RNAseq analysis showed enrichment of multiple cell proliferation and stem cell pathways, and stem cell genes SOX2, WNT and PAX2. The self-renewal of ABX treated tumor cells was also increased.Conclusion: Collectively, these studies indicate an intact microbiome provides a tumor suppressive microenvironment and enhances sensitivity to cisplatin.

scholarly journals Homologous Recombination Deficiency Assays in Epithelial Ovarian Cancer: Current Status and Future Direction

2021 ◽  
Vol 11 ◽  
Author(s):  
Ying-Cheng Chiang ◽  
Po-Han Lin ◽  
Wen-Fang Cheng
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Epithelial Ovarian Cancer ◽  
Recurrent Disease ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Current Status ◽  
Homologous Recombination Deficiency ◽  
Platinum Based Chemotherapy ◽  
Future Direction

Epithelial ovarian cancer (EOC) patients are generally diagnosed at an advanced stage, usually relapse after initial treatments, which include debulking surgery and adjuvant platinum-based chemotherapy, and eventually have poor 5-year survival of less than 50%. In recent years, promising survival benefits from maintenance therapy with poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) has changed the management of EOC in newly diagnosed and recurrent disease. Identification of BRCA mutations and/or homologous recombination deficiency (HRD) is critical for selecting patients for PARPi treatment. However, the currently available HRD assays are not perfect predictors of the clinical response to PARPis in EOC patients. In this review, we introduce the concept of synthetic lethality, the rationale of using PARPi when HRD is present in tumor cells, the clinical trials of PARPi incorporating the HRD assays for EOC, the current HRD assays, and other HRD assays in development.

Gynecologic Cancer

2014 ◽  
Author(s):  
Stephen A Cannistra ◽  
Christina I Herold
Keyword(s):  
United States ◽  
Ovarian Cancer ◽  
Cervical Cancer ◽  
Differential Diagnosis ◽  
Endometrial Cancer ◽  
Epithelial Ovarian Cancer ◽  
Uterine Cancer ◽  
Gynecologic Cancer ◽  
The United States ◽  
Improvement In Survival

This chapter focuses on the three types of gynecologic cancer—epithelial cancer of the ovary, cancer of the uterine cervix, and cancer of the endometrium (uterine cancer)—and reviews their epidemiology, diagnosis, differential diagnosis, surgical features, and staging, as well as their risk factors and clinical features. Also discussed are methods of treatment and the management of relapse. Epithelial ovarian cancer occurs at a mean age of 60 years in the United States and is the most lethal of gynecologic tract tumors. However, a recent trial has demonstrated a survival advantage through the use of intraperitoneal chemotherapy for appropriate patients with optimally debulked ovarian cancer. Invasive cervical cancer is uncommon in developed countries, partly because of the effectiveness of Pap smear screening. Nevertheless, cancer of the uterine cervix is the third most common gynecologic cancer diagnosis and cause of death among gynecologic cancers in the United States. However, for women with early-stage cervical cancer, data from several randomized trials indicate an improvement in response rate and survival through the use of combination platinum-based regimens for platinum-sensitive relapse. Also noted is an improvement in survival using combined-modality chemoradiation in appropriate patients with locally advanced cervical cancer. Endometrial cancer is the most frequent tumor of the gynecologic tract; it is estimated that it occurred in over 46,000 women and caused more than 8,000 deaths in the United States in 2011. Recent data indicate improvement in survival using adjuvant platinum-based chemotherapy in appropriate patients with high-risk endometrial cancer. Tables in this chapter review the common histologic types of epithelial ovarian cancer, selected signs and symptoms of ovarian cancer, the International Federation of Gynecology and Obstetrics (FIGO) staging system for epithelial ovarian cancer, differential diagnosis of a complex cyst detected by transvaginal sonography, selected adverse prognostic factors in epithelial ovarian cancer, common chemotherapy agents used in the treatment of epithelial ovarian cancer, the FIGO surgical staging of endometrial cancer, and postoperative management considerations for patients with uterine cancer. Figures illustrate the four histologic subtypes of epithelial ovarian cancer, the intraoperative appearance of stage III epithelial ovarian cancer, and FIGO staging of cervical cancer. This review contains 6 highly rendered figures, 8 tables, and 150 references.

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