scholarly journals Exploring the Frequency of Homologous Recombination DNA Repair Dysfunction in Multiple Cancer Types

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 354 ◽  
Author(s):  
Lucy Gentles ◽  
Bojidar Goranov ◽  
Elizabeth Matheson ◽  
Ashleigh Herriott ◽  
Angelika Kaufmann ◽  
...  
Keyword(s):  
Overall Survival ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Ex Vivo ◽  
Primary Cultures ◽  
Ovarian Cancer Cells ◽  
Continuous Exposure ◽  
Multiple Cancer ◽  
Brca Mutations ◽  
Platinum Chemotherapy

Dysfunctional homologous recombination DNA repair (HRR), frequently due to BRCA mutations, is a determinant of sensitivity to platinum chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi). In cultures of ovarian cancer cells, we have previously shown that HRR function, based upon RAD51 foci quantification, correlated with growth inhibition ex vivo induced by rucaparib (a PARPi) and 12-month survival following platinum chemotherapy. The aim of this study was to determine the feasibility of measuring HRR dysfunction (HRD) in other tumours, in order to estimate the frequency and hence wider potential of PARPi. A total of 24 cultures were established from ascites sampled from 27 patients with colorectal, upper gastrointestinal, pancreatic, hepatobiliary, breast, mesothelioma, and non-epithelial ovarian cancers; 8 were HRD. Cell growth following continuous exposure to 10 μM of rucaparib was lower in HRD cultures compared to HRR-competent (HRC) cultures. Overall survival in the 10 patients who received platinum-based therapy was marginally higher in the 3 with HRD ascites (median overall survival of 17 months, range 10 to 90) compared to the 7 patients with HRC ascites (nine months, range 1 to 55). HRR functional assessment in primary cultures, from several tumour types, revealed that a third are HRD, justifying the further exploration of PARPi therapy in a broader range of tumours.

scholarly journals The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression

2019 ◽  
Vol 116 (28) ◽  
pp. 14174-14180 ◽  
Author(s):  
Ameer L. Elaimy ◽  
John J. Amante ◽  
Lihua Julie Zhu ◽  
Mengdie Wang ◽  
Charlotte S. Walmsley ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Strand Break ◽  
Vegf Receptor ◽  
Vegf Signaling ◽  
Dna Double Strand Break ◽  
Essential Enzyme ◽  
And Function ◽  
Platinum Chemotherapy ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) signaling in tumor cells mediated by neuropilins (NRPs) contributes to the aggressive nature of several cancers, including triple-negative breast cancer (TNBC), independently of its role in angiogenesis. Understanding the mechanisms by which VEGF–NRP signaling contributes to the phenotype of such cancers is a significant and timely problem. We report that VEGF–NRP2 promote homologous recombination (HR) in BRCA1 wild-type TNBC cells by contributing to the expression and function of Rad51, an essential enzyme in the HR pathway that mediates efficient DNA double-strand break repair. Mechanistically, we provide evidence that VEGF–NRP2 stimulates YAP/TAZ-dependent Rad51 expression and that Rad51 is a direct YAP/TAZ–TEAD transcriptional target. We also discovered that VEGF–NRP2–YAP/TAZ signaling contributes to the resistance of TNBC cells to cisplatin and that Rad51 rescues the defects in DNA repair upon inhibition of either VEGF–NRP2 or YAP/TAZ. These findings reveal roles for VEGF–NRP2 and YAP/TAZ in DNA repair, and they indicate a unified mechanism involving VEGF–NRP2, YAP/TAZ, and Rad51 that contributes to resistance to platinum chemotherapy.

scholarly journals Simultaneous targeting of DNA replication and homologous recombination in glioblastoma with a polyether ionophore

2019 ◽  
Author(s):  
Yi Chieh Lim ◽  
Kathleen S Ensbey ◽  
Carolin Offenhäuser ◽  
Rochelle C J D’souza ◽  
Jason K Cullen ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
First Generation ◽  
Ex Vivo ◽  
Drug Efficacy ◽  
Tumor Formation ◽  
Dna Lesions ◽  
Dual Functions

Abstract Background Despite significant endeavor having been applied to identify effective therapies to treat glioblastoma (GBM), survival outcomes remain intractable. The greatest nonsurgical benefit arises from radiotherapy, though tumors typically recur due to robust DNA repair. Patients could therefore benefit from therapies with the potential to prevent DNA repair and synergize with radiotherapy. In this work, we investigated the potential of salinomycin to enhance radiotherapy and further uncover novel dual functions of this ionophore to induce DNA damage and prevent repair. Methods In vitro primary GBM models and ex vivo GBM patient explants were used to determine the mechanism of action of salinomycin by immunoblot, flow cytometry, immunofluorescence, immunohistochemistry, and mass spectrometry. In vivo efficacy studies were performed using orthotopic GBM animal xenograft models. Salinomycin derivatives were synthesized to increase drug efficacy and explore structure-activity relationships. Results Here we report novel dual functions of salinomycin. Salinomycin induces toxic DNA lesions and prevents subsequent recovery by targeting homologous recombination (HR) repair. Salinomycin appears to target the more radioresistant GBM stem cell–like population and synergizes with radiotherapy to significantly delay tumor formation in vivo. We further developed salinomycin derivatives which display greater efficacy in vivo while retaining the same beneficial mechanisms of action. Conclusion Our findings highlight the potential of salinomycin to induce DNA lesions and inhibit HR to greatly enhance the effect of radiotherapy. Importantly, first-generation salinomycin derivatives display greater efficacy and may pave the way for clinical testing of these agents.

scholarly journals Experimental models in the study of pathogenesis and the development of treatments for ovarian cancer (systematic review)

2021 ◽  
Vol 67 (4) ◽  
pp. 463-473
Author(s):  
Galina ZHUKOVA ◽  
Ekasterina Verenikina ◽  
Tatiana Protasova ◽  
Daria Yakubova ◽  
Anastasia Volkova
Keyword(s):  
Systematic Review ◽  
Ovarian Cancer ◽  
Animal Models ◽  
Web Of Science ◽  
Ex Vivo ◽  
Primary Cultures ◽  
Genetically Engineered ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Immunodeficient Mice

A systematic review of modern methods of experimental study of ovarian cancer using traditional (immunocompetent, genetically engineered and immunodeficient) and non-traditional (that don’t belong to the mammals) animal models,established and primary cultures of human ovarian cancer, including three-dimensional organotypic spheroids (3D- models ex vivo) is presented. The prospects of the considered models for studying of the pathogenesis of various molecular-genetic and histological variants of ovarian cancer, as well as for developing methods of personalized treatment, are discussed. The limitations of modern animal models are indicated. The greatest attention is paid to studies on immunodeficient animals using xenografts based on established cultures of human ovarian cancer cells and on tumor tissue obtained directly from the patients (patient derived xenografts, PDX). The questions of various variants of xenograft transplantation with an emphasis on the problems of orthotopic transplantation of human ovarian cancer into immunodeficient mice and the relevance of methods for local humanization in heterotopic transplantation are considered. The most promising, from the point of the author’s view, approaches to studying the effectiveness of drug therapy for ovarian cancer in immunodeficient animal models are outlined. To prepare a systematic review, a literature search was carried out on the Scopus, Web of Science, Med Line, PubMed, Cyber Leninka, RSCI databases. The analysis used literature sources indexed in the Scopus and Web of Science databases (97%) and the RSCI. More than 60% of the works amount has been published over the past 5 years.

scholarly journals Sublethal concentrations of 17-AAG suppress homologous recombination DNA repair and enhance sensitivity to carboplatin and olaparib in HR proficient ovarian cancer cells

Oncotarget ◽  
2014 ◽  
Vol 5 (9) ◽  
pp. 2678-2687 ◽  
Author(s):  
Young Eun Choi ◽  
Chiara Battelli ◽  
Jacqueline Watson ◽  
Joyce Liu ◽  
Jennifer Curtis ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Sublethal Concentrations

scholarly journals Pharmacologic induction of innate immune signaling directly drives homologous recombination deficiency

2020 ◽  
Vol 117 (30) ◽  
pp. 17785-17795
Author(s):  
Lena J. McLaughlin ◽  
Lora Stojanovic ◽  
Aksinija A. Kogan ◽  
Julia L. Rutherford ◽  
Eun Yong Choi ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Dna Methyltransferase ◽  
Innate Immune ◽  
The Cancer Genome Atlas ◽  
Epigenetic Therapy ◽  
Brca Mutations ◽  
Cancer Subtypes ◽  
Dna Methyltransferase Inhibitors ◽  
Repair Mechanisms

Poly(ADP ribose) polymerase inhibitors (PARPi) have efficacy in triple negative breast (TNBC) and ovarian cancers (OCs) harboring BRCA mutations, generating homologous recombination deficiencies (HRDs). DNA methyltransferase inhibitors (DNMTi) increase PARP trapping and reprogram the DNA damage response to generate HRD, sensitizing BRCA-proficient cancers to PARPi. We now define the mechanisms through which HRD is induced in BRCA-proficient TNBC and OC. DNMTi in combination with PARPi up-regulate broad innate immune and inflammasome-like signaling events, driven in part by stimulator of interferon genes (STING), to unexpectedly directly generate HRD. This inverse relationship between inflammation and DNA repair is critical, not only for the induced phenotype, but also appears as a widespread occurrence in The Cancer Genome Atlas datasets and cancer subtypes. These discerned interactions between inflammation signaling and DNA repair mechanisms now elucidate how epigenetic therapy enhances PARPi efficacy in the setting of BRCA-proficient cancer. This paradigm will be tested in a phase I/II TNBC clinical trial.

scholarly journals Advanced Ovarian Cancer Displays Functional Intratumor Heterogeneity That Correlates to Ex Vivo Drug Sensitivity

2016 ◽  
Vol 26 (6) ◽  
pp. 1004-1011 ◽  
Author(s):  
Rachel L. O’Donnell ◽  
Angelika Kaufmann ◽  
Laura Woodhouse ◽  
Aiste McCormick ◽  
Paul A. Cross ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Epithelial Ovarian Cancer ◽  
Solid Tumor ◽  
Ex Vivo ◽  
Primary Cultures ◽  
Advanced Ovarian Cancer ◽  
Antigen Expression ◽  
Intratumor Heterogeneity ◽  
Protein Markers

IntroductionEpithelial ovarian cancer is recognized to be heterogeneous but is currently treated with a single treatment strategy. Successful patient stratification of emerging chemotherapy agents is dependent upon the availability of reliable biomarkers indicative of the entire tumor.AimThe aim of this study was to evaluate intertumor and intratumor heterogeneity within a series of epithelial ovarian cancer using homologous recombination (HR) DNA repair status.MethodsPrimary cultures generated from ascites and solid tumor from multiple intra-abdominal sites were characterized by their morphology and expression of protein markers. Results were compared with Formalin fixed paraffin embedded tissue pathology.Homologous recombination function was determined by quantification of nuclear Rad51 foci. Growth inhibition (sulforhodamine B) assays were used to calculate the GI50 for cisplatin and rucaparib.ResultsAscites with matched solid tumor were cultured from 25 patients.Concordance in functional HR status between ascites and solid tumor subcultures was seen in only 13 (52%) of 25 patients. Heterogeneity in HR status was seen even in patients with homogeneous histological subtype. Homologous recombination defective cultures were significantly more sensitive to cisplatin and rucaparib.Additionally, intertumor and intratumor heterogeneity was seen between the expression of epithelial and ovarian markers (EpCAM, cytokeratin, CA125, MOC-31, and vimentin). There was no relationship between heterogeneity of HR functional status and antigen expression.ConclusionsIntertumor and intratumor functional HR heterogeneity exists that cannot be detected using histological classification. This has implications for biomarker-directed treatment.

scholarly journals Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy

2019 ◽  
Vol 116 (18) ◽  
pp. 9008-9013 ◽  
Author(s):  
Raffit Hassan ◽  
Betsy Morrow ◽  
Anish Thomas ◽  
Tom Walsh ◽  
Ming K. Lee ◽  
...  
Keyword(s):  
Overall Survival ◽  
Dna Repair ◽  
Tumor Suppressor ◽  
Malignant Mesothelioma ◽  
Tumor Suppressor Genes ◽  
Pleural Mesothelioma ◽  
Loss Of Function ◽  
Suppressor Genes ◽  
Inherited Mutations ◽  
Platinum Chemotherapy

Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation (P = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, P = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, P = 0.47). Effect of patient genotype on overall survival, measured at 3 y, remained independently significant after adjusting for gender and age at diagnosis, two other known prognostic factors. Patients with pleural mesothelioma with inherited mutations in DNA repair and other tumor suppressor genes appear to particularly benefit from platinum chemotherapy compared with patients without inherited mutations. These patients may also benefit from other DNA repair targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.

scholarly journals Clinico-pathological correlation of homologous recombination status in epithelial ovarian cancer: Surgeon’s perspective

2016 ◽  
Author(s):  
Asima Mukhopadhyay ◽  
Nicola Curtin ◽  
Richard Edmondson
Keyword(s):  
Homologous Recombination ◽  
Ex Vivo ◽  
Parp Inhibitor ◽  
Primary Cultures ◽  
Functional Assay ◽  
Primary Surgery ◽  
Ovarian Cancers ◽  
Surgical Expertise ◽  
Hyperthermic Treatment ◽  
Ascetic Fluid

Background: TCGA data using expensive multi-modality diagnostic platforms have shown that 50% epithelial ovarian cancers (EOCs) are estimated to be homologous recombination (HR) deficient (HRD). We developed a functional assay for HR using gamma H2AX-Rad51 immunofluoresence.[1] Methods: Primary cultures were developed in 50 consecutive EOCs from ascetic fluid and HR assay was performed. Results: 50% patients were HRD based on the functional assay and show improved ex-vivo chemosensitivity to PARP inhibitor (PARPi) (PPV = 92%, NPV = 100%). HRD patients showed improved platinum sensitivity (53.8% vs 16.7%), survival (12 month OS - 41.7% vs. 11.5%) and optimal cytoreduction (80% vs. 62%) rates compared to HR competent (HRC) tumours which are less responsive and represent an unmet clinical need. Conclusions: Personalised surgical and chemotherapeutic strategies may be developed for HR stratified EOCs. Primary surgery may be the preferred approach in HRC due to poor chemoresponse; surgical expertise/environment should be optimised to ensure optimal surgical outcome. Intra-operative hyperthermic treatment and selective HR inhibitors may improve subsequent chemoresponse in HRC and are currently being investigated.

Concurrent BRAFV600E and BRCA mutations in microsatellite stable (MSS) metastatic colorectal cancer (mCRC): Prevalence and case series of mCRC (pts) with prolonged overall survival (OS).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3561-3561
Author(s):  
Timothy Lewis Cannon ◽  
Jamie Randall ◽  
Ethan Sokol ◽  
Sonja Alexander ◽  
Raymond Couric Wadlow ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Homologous Recombination ◽  
Targeted Therapies ◽  
Brca2 Mutation ◽  
Cohort Analysis ◽  
Braf V600e ◽  
Tumor Board ◽  
Brca Mutations ◽  
Molecular Tumor Board

3561 Background: BRAF V600E+, MSS mCRC patients comprise up to 10% of advanced CRC. They have a poor prognosis with median survivals typically <1 year. Despite use of multi-agent first-line chemotherapy regimens and combination targeted therapies, outcomes are still poor. In our Institutional Molecular Tumor Board database, we identified 3 consecutive mCRC pts with MSS/ BRAF V600E who also had a BRCA1 or BRCA2 co-mutation and had prolonged overall survival. Prior studies suggested that BRCA mutations are uncommon in CRC and we queried the Foundation Medicine (FM) genomic database to evaluate the prevalence of these cases as well as those with co-mutations in other homologous recombination genes. Methods: 36,966 CRC pts were sequenced by FMI using hybrid capture comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA) for pathogenic BRAF mutations and/or a mutation in BRCA1/2 or a co-mutation in other homologous recombination (HR) genes ( BARD1, CDK12, FANCL, PALB2, ATM, RAD54L, CHEK2, BRAF, BRIP1, RAD51D, RAD51C, RAD51B, CHEK1). Selected cohort analysis were BRAF V600E co-mutated with BRCA1 and BRCA2, separated into MSI-H and MSS cohorts. The clinicopathological features and genomic loss of heterozygosity (gLOH) of those with a BRAF V600E and a BRCA1/BRCA2 mutation are described along with 3 consecutive cases of CRC patients, identified through the Inova Schar Cancer Institute (ISCI) molecular tumor board (MTB) registry, whom had prolonged OS. Results: Of 36,966 colorectal cancer pts, 6.6% were BRAF V600E+ and 1.5% had any co-occurring HR gene mutation(s) with 0.6% having co-mutations of BRAF V600E and BRCA1/2. BRCA co-mutations were higher in MSI-High BRAF V600E, however 24.1% of these occurred in MSS BRAF V600E. BRCA1 co-mutated was more commonly associated with MSS BRAF V600E and was associated with a higher gLOH than MSI-H BRAF V600E (18.7% vs 2.8%; p <0.001 ). In our institutional MTB database, (3/241;1.2%) CRC patients were MSS, BRAF V600E+ with BRCA1 or BRCA2 co-mutations, one confirmed germline and 2 somatic in origin, and had average gLOH of 21.4% with overall survivals of 72+(alive), 17+(alive), and 30 months, respectively. Conclusions: Co-existence of BRAF V600E/ BRCA1/2 may represent a unique subset of advanced MSS CRC that may have a better prognosis and represent an opportunity to test novel targeted therapies. Larger prospective clinical validation trials in this subset is warranted.[Table: see text]

scholarly journals Down-Regulation of Rad51 and Decreased Homologous Recombination in Hypoxic Cancer Cells

2004 ◽  
Vol 24 (19) ◽  
pp. 8504-8518 ◽  
Author(s):  
Ranjit S. Bindra ◽  
Paul J. Schaffer ◽  
Alice Meng ◽  
Jennifer Woo ◽  
Kårstein Måseide ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Genetic Instability ◽  
Mammalian Cells ◽  
Hypoxic Exposure ◽  
Multiple Cancer ◽  
Down Regulation ◽  
Recombination Pathway

ABSTRACT There is an emerging concept that acquired genetic instability in cancer cells can arise from the dysregulation of critical DNA repair pathways due to cell stresses such as inflammation and hypoxia. Here we report that hypoxia specifically down-regulates the expression of RAD51, a key mediator of homologous recombination in mammalian cells. Decreased levels of Rad51 were observed in multiple cancer cell types during hypoxic exposure and were not associated with the cell cycle profile or with expression of hypoxia-inducible factor. Analyses of RAD51 gene promoter activity, as well as mRNA and protein stability, indicate that the hypoxia-mediated regulation of this gene occurs via transcriptional repression. Decreased expression of Rad51 was also observed to persist in posthypoxic cells for as long as 48 h following reoxygenation. Correspondingly, we found reduced levels of homologous recombination in both hypoxic and posthypoxic cells, suggesting that the hypoxia-associated reduction in Rad51 expression has functional consequences for DNA repair. In addition, hypoxia-mediated down-regulation of Rad51 was confirmed in vivo via immunofluorescent image analysis of experimental tumors in mice. Based on these findings, we propose a novel mechanism of genetic instability in the tumor microenvironment mediated by hypoxia-induced suppression of the homologous recombination pathway in cancer cells. The aberrant regulation of Rad51 expression may also create heterogeneity in the DNA damage response among cells within tumors, with implications for the response to cancer therapies.

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