184 results found
Cohen PA, Powell A, Böhm S, et al., 2019, Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: a systematic review and meta-analysis of individual patient data, Gynecologic Oncology, ISSN: 0090-8258
ObjectiveThere is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT.MethodsWe established an international collaboration to conduct a systematic review and meta-analysis, pooling individual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3–4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS).Results877 patients were included from published and unpublished studies. Median PFS and OS were 15 months (IQR 5–65) and 28 months (IQR 7–92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0·55 (95% CI, 0·45–0·66; P < 0·001) and 0·65 (95% CI 0·50–0·85, P = 0·002) respectively; no heterogeneity was identified (PFS: Q = 6·42, P = 0·698, I2 = 0·0%; OS: Q = 6·89, P = 0·648, I2 = 0·0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (n = 80) were more likely to achieve CRS3 (P = 0·027).ConclusionsCRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical
Colombo N, Sessa C, du Bois A, et al., ESMO-ESGO consensus conference recommendations on ovarian cancer: Pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease, Annals of Oncology, ISSN: 0923-7534
The development of guidelines is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically-relevant and evidence-based guidelines in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO-ESGO consensus conference on ovarian cancer was held on 12-14 April 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO-ESGO consensus conference, together with a summary of evidence supporting each recommendation.
Goranova T, Ennis D, Piskorz AM, et al., 2019, Correction: Safety and utility of image-guided research biopsies in relapsed high-grade serous ovarian carcinoma-experience of the BriTROC consortium., British Journal of Cancer, Vol: 120, ISSN: 0007-0920
This article was originally published under a CC BY NC SA License, but has now been made available under a CC BY 4.0 License.
Bagnoli M, Shi TY, Gourley C, et al., 2019, Gynecological cancers translational, research implementation, and harmonization: Gynecologic Cancer InterGroup consensus and still open questions, Cells, Vol: 8, ISSN: 2073-4409
In the era of personalized medicine, the introduction of translational studies in clinical trials has substantially increased their costs, but provides the possibility of improving the productivity of trials with a better selection of recruited patients. With the overall goal of creating a roadmap to improve translational design for future gynecological cancer trials and of defining translational goals, a main discussion was held during a brainstorming day of the Gynecologic Cancer InterGroup (GCIG) Translational Research Committee and overall conclusions are here reported. A particular emphasis was dedicated to the new frontier of the immunoprofiling of gynecological cancers. The discussion pointed out that to maximize patients’ benefit, translational studies should be integral to clinical trial design with standardization and optimization of procedures including a harmonization program of Standard Operating Procedures. Pathology-reviewed sample collection should be mandatory and ensured by dedicated funding. Biomarker validation and development should be made public and transparent to ensure rapid progresses with positive outcomes for patients. Guidelines/templates for patients’ informed consent are needed. Importantly for the public, recognized goals are to increase the involvement of advocates and to improve the reporting of translational data in a forum accessible to patients.
Yang Y, Wu L, Shu X, et al., 2019, Genetic data from nearly 63,000 women of European descent predicts DNA methylation biomarkers and epithelial ovarian cancer risk, Cancer Research, Vol: 79, Pages: 505-517, ISSN: 1538-7445
DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N=1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P<7.94×10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27 and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression.
Macintyre G, Piskorz A, Ross E, et al., 2018, frenchFISH: Poisson models for quantifying DNA copy-number from fluorescence in situ hybridisation of tissue sections
Chromosomal aberration and DNA copy number change are robust hallmarks of cancer. Imaging of spots generated using fluorescence in situ hybridisation (FISH) of locus specific probes is routinely used to detect copy number changes in tumour nuclei. However, it often does not perform well on solid tumour tissue sections, where partially represented or overlapping nuclei are common. To overcome these challenges, we have developed a computational approach called FrenchFISH, which comprises a nuclear volume correction method coupled with two types of Poisson models: either a Poisson model for improved manual spot counting without the need for control probes; or a homogenous Poisson Point Process model for automated spot counting. We benchmarked the performance of FrenchFISH against previous approaches in a controlled simulation scenario and exemplify its use in 12 ovarian cancer FFPE-tissue sections, for which we assess copy number alterations in three loci (c-Myc, hTERC and SE7). We show that FrenchFISH outperforms standard spot counting approaches and that the automated spot counting is significantly faster than manual without loss of performance. FrenchFISH is a general approach that can be used to enhance clinical diagnosis on sections of any tissue.
Sierra Gonzalez P, OPrey J, Cardaci S, et al., 2018, Mannose impairs tumour growth and enhances chemotherapy, Nature, Vol: 563, Pages: 719-723, ISSN: 0028-0836
It is now well established that tumours undergo changes in cellular metabolism1. As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake2, we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose3 but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types.
Lin KK, Harrell MI, Oza AM, et al., BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma, Cancer Discovery, ISSN: 2159-8274
A key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in BRCA-mutant cancers is the acquisition of BRCA reversion mutations that restore protein function. To estimate the prevalence of BRCA reversion mutations in high-grade ovarian carcinoma (HGOC), we performed targeted next-generation sequencing of circulating cell-free DNA (cfDNA) extracted from pretreatment and postprogression plasma in patients with deleterious germline or somatic BRCA mutations treated with the PARP inhibitor rucaparib. BRCA reversion mutations were identified in pretreatment cfDNA from 18% (2/11) of platinum-refractory and 13% (5/38) of platinum-resistant cancers, compared to 2% (1/48) of platinum-sensitive cancers (P = 0.049). Patients without BRCA reversion mutations detected in pretreatment cfDNA had significantly longer rucaparib progression-free survival than those with reversion mutations (median, 9.0 vs. 1.8 months; HR, 0.12; P < 0.0001). To study acquired resistance, we sequenced 78 postprogression cfDNA, identifying eight additional patients with BRCA reversion mutations not found in pretreatment cfDNA.
Mcneish IA, Lin KK, Radke MR, et al., 2018, BRCA reversion mutations in circulating cell-free tumour DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma (HGOC), 30th EORTC-NCI-AACR Symposium, Publisher: ELSEVIER SCI LTD, Pages: E28-E28, ISSN: 0959-8049
Clamp AR, McNeish IA, Dean A, et al., 2018, Response to neoadjuvant chemotherapy in ICON8: A GCIG phase III randomised trial evaluating weekly dose-dense chemotherapy integration in first-line epithelial ovarian/fallopian tube/primary peritoneal carcinoma (EOC) treatment, 43rd ESMO Congress (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 336-336, ISSN: 0923-7534
Leary A, Ledermann JA, Oaknin A, et al., 2018, Use of the Poly (ADP-Ribose) Polymerase Inhibitor Rucaparib in Women with Recurrent Ovarian Carcinoma with Endometrioid and Other Nonserous Histopathologic Subtypes, Publisher: BMJ PUBLISHING GROUP, Pages: 200-201, ISSN: 1048-891X
Ennis D, Cooke S, Evers L, et al., 2018, The driver mutational landscape of ovarian squamous cell carcinomas arising in mature cystic teratoma, Publisher: BMJ PUBLISHING GROUP, Pages: 56-56, ISSN: 1048-891X
Rust K, Spiliopoulou P, Tang CY, et al., 2018, Routine germline BRCA1 and BRCA2 testing in ovarian carcinoma patients: analysis of the Scottish real life experience, BJOG: An International Journal of Obstetrics and Gynaecology, Vol: 125, Pages: 1451-1548, ISSN: 1470-0328
Objective:To determine the rate of germline BRCA1 and BRCA2 mutations in Scottish ovarian cancer patients before and after a change in testing policy.Design:Retrospective cohort study.Setting:Four cancer/genetics centres in Scotland.Population:Ovarian cancer patients undergoing germline BRCA1 and BRCA2 (gBRCA1/2) gene sequencing before 2013 (‘old criteria’; selection based solely on family history), after 2013 (‘new criteria’; sequencing offered to newly presenting non-mucinous ovarian cancer patients) and the ‘prevalent population’ (who presented before 2013, were not eligible for sequencing under the old criteria but were sequenced under the new criteria).Methods:Clinicopathological and sequence data were collected before and for 18 months after this change in selection criteria.Main Outcome Measures:Frequency of germline BRCA1, BRCA2, RAD51C and RAD51D mutations.Results:Of 599 patients sequenced, 205, 236 and 158 were in the ‘old criteria’, ‘new criteria’ and ‘prevalent’ populations respectively. The frequency of gBRCA1/2 mutations was 30.7%, 13.1% and 12.7% respectively. The annual rate of gBRCA1/2 mutation detection was 4.2 before and 20.7 after the policy change. 48% (15/31) ‘new criteria’ patients with gBRCA1/2 mutations had a Manchester score <15 and would not have been offered sequencing based on family history criteria. In addition, 20 gBRCA1/2 patients were identified in the prevalent population. The prevalence of gBRCA1/2 mutations in patients >70 years was 8.2%.Conclusions:Sequencing all non-mucinous ovarian cancer patients produces much higher annual gBRCA1/2 mutation detection with the frequency of positive tests still exceeding the 10% threshold upon which many family history based models operate.
McNeish IA, Kondrashova O, Topp M, et al., 2018, Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma, Nature Communications, Vol: 9, ISSN: 2041-1723
Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naïve BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit and facilitate tailoring of PARPi therapy.
Kelemen LE, Earp M, Fridley BL, et al., 2018, rs495139 in the TYMS-ENOSF1 region and risk of Ovarian carcinoma of mucinous histologo, International Journal of Molecular Sciences, Vol: 19, ISSN: 1422-0067
Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
Macintyre G, Goranova TE, De Silva D, et al., 2018, Copy-number signatures and mutational processes in ovarian carcinoma, Nature Genetics, Vol: 50, Pages: 1262-1270, ISSN: 1061-4036
The genomic complexity of profound copy-number aberration has prevented effective molecular stratification of ovarian cancers. To decode this complexity, we derived copy-number signatures from shallow whole genome sequencing of 117 high-grade serous ovarian cancer (HGSOC) cases, which were validated on 527 independent cases. We show that HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in known patterns of genomic aberration. Copy-number signature exposures at diagnosis predict both overall survival and the probability of platinum-resistant relapse. Measuring signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes.
Ennis D, Cooke SL, Evers L, et al., 2018, The driver mutational landscape of ovarian squamous cell carcinomas arising in mature cystic teratoma., AACR Special Conference on Addressing Critical Questions in Ovarian Cancer Research and Treatment, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 34-+, ISSN: 1078-0432
Leung EYL, Ennis DP, Athineos D, et al., 2018, Oncolytic adenovirus infection leads to contact-dependent activation of natural killer cells and augments virotherapy effectiveness for ovarian cancer., AACR Special Conference on Addressing Critical Questions in Ovarian Cancer Research and Treatment, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 97-98, ISSN: 1078-0432
McNeish IA, A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk, Cancer Research, ISSN: 1538-7445
Lu Y, Beeghly-Fadiel A, Wu L, et al., 2018, A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk, Cancer Research, ISSN: 1538-7445
Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in non-coding regions, and causal genes underlying these associations remain largely unknown. Here we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian-tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P<2.2×10-6, we identified 35 genes including FZD4 at 11q14.2 (Z=5.08, P=3.83×10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly-associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and 3 genes remained (P<1.47 x 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.
McNeish IA, 2018, Neoantigens in ovarian cancer: embarrassment of riches or needles in a haystack?, Clinical Cancer Research, ISSN: 1078-0432
Comprehensive genomic and transcriptomic analysis demonstrates that tumor-infiltrating T lymphocytes that react to mutated neo-epitopes could be identified in recurrent ovarian cancer. Two of these T cell populations reacted against TP53 hotspot missense mutations that are present in a wide variety of malignancies.
Earp M, Tyrer JP, Winham SJ, et al., 2018, Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility, PLoS ONE, Vol: 13, Pages: 1-13, ISSN: 1932-6203
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR=1.33, p=4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR=1.07, p=0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR=0.90, p=0.00033; rs927062, OR =0.94, p=0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.
Walton JB, Farquharson M, Mason S, et al., 2018, Author correction: CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity, Scientific Reports, Vol: 8, ISSN: 2045-2322
Nesic K, Wakefield M, Kondrashova O, et al., 2018, Targeting DNA repair: the genome as a potential biomarker, Journal of Pathology, Vol: 244, Pages: 586-597, ISSN: 0022-3417
Genomic instability and mutations are fundamental aspects of human malignancies, leading to progressive accumulation of the hallmarks of cancer. For some time, it has been clear that key mutations may be used both as prognostic and predictive biomarkers, the best-known examples being the presence of germline BRCA1 or BRCA2 mutations, which are not only associated with improved prognosis in ovarian cancer, but are also predictive of response to poly(ADP-ribose) polymerase (PARP) inhibitors. Although biomarkers as specific and powerful as these are rare in human malignancies, next generation sequencing and improved bioinformatic analyses are revealing mutational signatures, broader patterns of alterations in the cancer genome that have the power to reveal information about underlying driver mutational processes. Thus, the cancer genome can act as a stratification factor in clinical trials and, ultimately, will be used to drive personalised treatment decisions. In this review, we will use ovarian high grade serous carcinoma (HGSC) as an example of a disease of extreme genomic complexity that is marked by widespread copy number alterations, but which lacks powerful driver oncogene mutations. Understanding of the genomics of HGSC has led to the routine introduction of germline and somatic BRCA1/2 testing, as well as testing of mutations in other homologous recombination genes, widening the range of patients who may benefit from PARP inhibitors. We will discuss how whole genome-wide analyses, including loss of heterozygosity quantification and whole genome sequencing, may extend this paradigm to allow all patients to benefit from effective targeted therapies.
Ong J-S, Hwang L-D, Cuellar-Partida G, et al., 2018, Assessment of moderate coffee consumption and risk of epithelial ovarian cancer: a Mendelian randomization study, INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, Vol: 47, Pages: 450-459, ISSN: 0300-5771
McGivern N, El-Helali A, Mullan P, et al., 2018, Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer, Oncotarget, Vol: 9, Pages: 4722-4736, ISSN: 1949-2553
SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Using two complementary strategies; a targeted tumour suppressor gene siRNA screen, and a phospho-receptor tyrosine kinase array, we demonstrate that activation of MAPK signalling, via a reduction in NF1 (neurofibromin) expression or overexpression of HER2 and the insulin receptor, can drive resistance to AZD0530. Knockdown of NF1 in two ovarian cancer cell lines resulted in resistance to AZD0530, and was accompanied with activated MEK and ERK signalling. We also show that silencing of HER2 and the insulin receptor can partially resensitize AZD0530 resistant cells, which was associated with decreased phosphorylation of MEK and ERK. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials.
MacNab W, Glasspool RM, Shanbhag S, et al., 2018, Outcomes of women not receiving treatment for advanced ovarian cancer in the West of Scotland: a retrospective analysis, EUROPEAN JOURNAL OF GYNAECOLOGICAL ONCOLOGY, Vol: 39, Pages: 58-62, ISSN: 0392-2936
Oncolytic adenoviral mutants infect human malignant cells and replicate selectively within them. This induces direct cytotoxicity that can also trigger profound innate and adaptive immune responses. However, the mechanism by which adenoviruses produce cell death remains uncertain. We previously suggested that type 5 adenoviruses, including the E1A CR2 deletion mutant dl922-947, might induce a novel form of programmed death resembling necroptosis. Here we have investigated the roles of core necrosis proteins RIPK1, RIPK3 and MLKL in the cytotoxicity of dl922-947 and other adenovirus serotypes. By electron microscopy, we show that dl922-947 induces similar necrotic morphology as TSZ treatment (TNF-α, Smac mimetic, zVAD.fmk). However, dl922-947-mediated death is independent of TNF-α signalling, does not require RIPK1 and does not rely upon the presence of MLKL. However, inhibition of caspases, specifically caspase-8, induces necroptosis that is RIPK3 dependent and significantly enhances dl922-947 cytotoxicity. Moreover, using CRISPR/Cas9 gene editing, we demonstrate that the increase in cytotoxicity seen upon caspase inhibition is also MLKL dependent. Even in the absence of caspase inhibition, RIPK3 expression promotes dl922-947 and wild-type adenovirus type 5 efficacy both in vitro and in vivo. Together, these results suggest that adenovirus induces a form of programmed necrosis that differs from classical TSZ necroptosis.
Walton JB, Farquharson M, Mason S, et al., 2017, CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity., Scientific Reports, Vol: 7, ISSN: 2045-2322
Transplantable murine models of ovarian high grade serous carcinoma (HGSC) remain an important research tool. We previously showed that ID8, a widely-used syngeneic model of ovarian cancer, lacked any of the frequent mutations in HGSC, and used CRISPR/Cas9 gene editing to generate derivatives with deletions in Trp53 and Brca2. Here we have used one ID8 Trp53 -/- clone to generate further mutants, with additional mutations in Brca1, Pten and Nf1, all of which are frequently mutated or deleted in HGSC. We have also generated clones with triple deletions in Trp53, Brca2 and Pten. We show that ID8 Trp53 -/-;Brca1 -/- and Trp53 -/-;Brca2 -/- cells have defective homologous recombination and increased sensitivity to both platinum and PARP inhibitor chemotherapy compared to Trp53 -/-. By contrast, loss of Pten or Nf1 increases growth rate in vivo, and reduces survival following cisplatin chemotherapy in vivo. Finally, we have also targeted Trp53 in cells isolated from a previous transgenic murine fallopian tube carcinoma model, and confirmed that loss of p53 expression in this second model accelerates intraperitoneal growth. Together, these CRISPR-generated models represent a new and simple tool to investigate the biology of HGSC, and the ID8 cell lines are freely available to researchers.
Blagden SP, Cook A, Poole C, et al., 2017, QUALITY OF LIFE WITH WEEKLY, DOSE-DENSE VERSUS STANDARD CHEMOTHERAPY FOR OVARIAN CANCER IN THE ICON8 STUDY, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 1919-1919, ISSN: 1048-891X
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