359 research outputs found
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No full textRaw data for Figure 4 of the following paper:Nanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancerRuogu Qi, Yongheng Wang, Peter M. Bruno, Haihua Xiao, Yingjie Yu, Ting Li, Sam Lauffer, Wei Wei, Qixian Chen, Xiang Kang, Haiqin Song, Xi Yang, Xing Huang, Alexandre Detappe, Ursula Matulonis, David Pepin, Michael T. Hemann, Michael J. Birrer & P. Peter Ghoroghchian Nature Communications volume 8, Article number: 2166 (2017) Published: 18 December 2017</div
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Current status and evolution of preclinical drug development models of epithelial ovarian cancer
No full textEpithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and the fifth most common cause of female cancer death in the United States. Although important advances in surgical and chemotherapeutic strategies over the last three decades have significantly improved the median survival of EOC patients, the plateau of the survival curve has not changed appreciably. Given that EOC is a genetically and biologically heterogeneous disease, identification of specific molecular abnormalities that can be targeted in each individual ovarian cancer on the basis of predictive biomarkers promises to be an effective strategy to improve outcome in this disease. However, for this promise to materialize, appropriate preclinical experimental platforms that recapitulate the complexity of these neoplasms and reliably predict antitumor activity in the clinic are critically important. In this review, we will present the current status and evolution of preclinical models of EOC, including cell lines, immortalized normal cells, xenograft models, patient-derived xenografts and animal models, and will discuss their potential for oncology drug development
Bevacizumab and its use in epithelial ovarian cancer
No full text Bevacizumab is a monoclonal antibody that binds to VEGF, a circulating protein involved in the promotion of angiogenesis and probably tumor growth and progression. Bevacizumab has demonstrated anticancer activity in several cancers, either combined with chemotherapy or when used as a single agent, and has been approved by the US FDA as a treatment for several cancers. As VEGF has been implicated in ovarian cancer progression and ascites formation, and high levels of VEGF have been found in plasma and ascites in women with ovarian cancer, bevacizumab has been tested as an anticancer therapy in ovarian cancer. Documented single-agent activity of bevacizumab in recurrent ovarian cancer has led to combination studies with both biologic agents as well as other chemotherapy agents in both recurrent and newly diagnosed cancer. One trial in patients with recurrent, heavily pretreated ovarian cancer demonstrated a higher than predicted risk of gastrointestinal perforation, and although a lower incidence of gastrointestinal perforation has been reported in less heavily pretreated patients, patients and their physicians must be aware of this risk. Upfront studies testing the impact of adding bevacizumab to carboplatin and paclitaxel chemotherapy for the treatment of newly diagnosed cancer are currently underway, and one Phase III randomized study (Gynecologic Oncology Group study 218) was recently presented and will be discussed in this article. </jats:p
Abstract LB-329: MicroRNA profiling to identify novel determinants of platinum resistance in BRCA1/2-mutated high-grade serous ovarian cancer
No full textAbstract
Ovarian cancer is the fifth leading cause of mortality in women and the most lethal of all gynecologic tumors. Patients with high grade serous ovarian carcinoma (HGSOC) have poor prognosis due to a combination of factors including lack of early detection and failure of therapeutic regimens. Approximately 50% of all ovarian tumors have germline/somatic mutations or epigenetic alterations in genes making up the homologous recombination (HR) pathway. The resultant “BRCAness” phenotype pre-disposes these tumors to an improved response from current ovarian cancer therapies i.e. platinum therapy and PARP inhibitors. Despite the predicted synthetic lethality, a majority of patients with recurrent ovarian cancer eventually develop resistance. A detailed understanding of clinically relevant mechanisms of chemotherapy resistance is an important step in improving disease outcomes.
To systematically identify microRNA (miRNA) mediators of chemo-resistance in HGSOC, we performed small RNA sequencing of 38 BRCA mutated tumors with known response to platinum chemotherapy and identified three miRNA’s: miR-139-5p, miR-493-5p and miR-494-3p that were significantly overexpressed in platinum resistant compared to the platinum sensitive tumors. Overexpression of these candidate miRNA’s was associated with worse overall outcome among BRCA1/2-mutated tumors in the TCGA dataset. Interestingly, overexpression of miR-493-5p only correlated with poor progression free survival in BRCA2 mutant tumors and not BRCA1 mutant tumors. Importantly, overexpression of miR-493-5p was also identified in 13 out of 40 olaparib resistant tumors in KB2P BRCA2 deficient mouse models. Additionally, overexpression of miR-493-5p in BRCA2 mutated HGSOC cell-lines induced resistance to cisplatin and olaparib in vitro. Mechanistically, resistance mediated by miR-493-5p was not associated with restoration of HR (as evaluated by restoration of Rad51 foci) but was rather related to replication fork stabilization. Identification of specific targets of miR-493-5p is currently underway. In summary, overexpression of miR-493-5p may be a novel mechanism of resistance to platinum and PARP-inhibitors in BRCA2-mutated ovarian cancers and may serve as a biomarker of response to these agents in BRCA2 mutated ovarian tumors. Inhibition of miR-493-5p may be a novel strategy to resensitize chemo-resistant BRCA2 mutated tumors to platinum therapy and PARP-inhibitors.
Citation Format: Khyati Meghani, Ewa Gogola, Sven Rottenberg, Jos Jonkers, Ursula Matulonis, Elizabeth Swisher, Panagiotis Konstantinopoulos, Dipanjan Chowdhury. MicroRNA profiling to identify novel determinants of platinum resistance in BRCA1/2-mutated high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-329. doi:10.1158/1538-7445.AM2017-LB-329</jats:p
Abstract MIP-075: SOMATIC MUTATIONS AND COPY-NUMBER VARIATIONS IN OVARIAN CANCERS VIA TARGETED SEQUENCING OF EXONS OF 300 CANCER-ASSOCIATED GENES, INCLUDING MULTIPLE DNA DAMAGE REPAIR GENES
No full textAbstract
INTRODUCTION: Recent studies demonstrated frequent alterations in DNA damage repair (DDR) genes in ovarian cancer, from well-established variants in BRCA1/2 to rarely altered genes in various DDR pathways that may be clinically relevant. Here we summarize somatic alterations in DDR related genes identified by targeted sequencing of several hundred ovarian cancers.
EXPERIMENTAL PROCEDURES: Targeted next-generation sequencing was performed on formalin-fixed tumor tissues from &gt;500 patients with ovarian cancer enrolled in an IRB-approved protocol at Dana-Farber Cancer Institute (DFCI). The current dataset includes 269 patients whose tumors underwent gynecologic pathology review. Targeted sequencing via hybrid capture was performed for exons of 300 cancer-associated genes. Sequence data was analyzed at Brigham and Women's Hospital to identify single-nucleotide variants (SNVs) and insertions/deletions (indels). Putative copy number variants (CNVs) were computationally inferred from sequencing coverage in a subset of patients (n=219). Germline analysis was not performed in this study, but SNVs were filtered against variant databases. Corresponding clinical data is undergoing analysis.
RESULTS: In the 269-patient cohort, 67% of samples were primary tumors, 25% metastatic recurrences, and 3% local recurrences. Histologies included high-grade serous (34%), endometrioid (12%), clear cell (9%), malignant mixed mesodermal tumor (MMMT, carcinosarcoma) (9%), low-grade serous (7%), granulosa cell (7%), mucinous (3%), and borderline variants (6%). We focused upon alterations in DDR related genes in the targeted panel. Of the 269 patients, ~9% harbored BRCA1 variants and ~13% harbored BRCA2 variants; frameshift and nonsense mutations were frequent. Copy losses in BRCA1 or BRCA2 were predicted in up to 1/3 of patients, some of whom also carried SNVs/indels in the same gene. BRCA1/2 alterations were more frequent in high-grade serous cancers, but were also observed in other histologic subtypes. SNVs/indels in ATM were common, present in ~9% of patients. Another ~10% of patients had a variant in one of the Fanconi Anemia (FA) genes (FANCA,B,C,D2,E,F,G,I) or BRIP1. Alterations in MMR genes (MLH1, MSH2, MSH6, PMS2) were present in ~12%. SNVs in genes encoding DDR associated helicases BLM or WRN were observed in ~8%. PRKDC, encoding the DNA-PK catalytic subunit involved in non-homologous end joining, was altered in up to 7%. The SNVs in these DDR genes were observed in all histologic subtypes at varying frequencies. CNVs in DDR related genes were common, including predicted amplifications of CCNE1 and 2-copy deletions in several FA genes. Several limitations of this dataset may result in overestimates of the frequency of clinically significant alterations, e.g. some SNVs may represent benign variants (specific mutations are undergoing more detailed analysis to eliminate these); some patients harbor multiple mutations; and CNVs are predicted but need to be confirmed by orthogonal methods.
CONCLUSIONS: Targeted sequencing data from a large cohort of ovarian cancer patients collectively support previous work indicating a significant frequency of alterations in DDR related genes in ovarian cancer, across multiple histologic subtypes. Further analysis of specific mutations and clinical correlations with DDR gene alterations are ongoing. Identifying alterations in DDR genes in ovarian cancer patients is feasible and may have clinical relevance, particularly regarding DNA repair targeted agents and chemotherapeutics.
Citation Format: Elizabeth Stover, Brooke Howitt, Levi Garraway, Ursula Matulonis. SOMATIC MUTATIONS AND COPY-NUMBER VARIATIONS IN OVARIAN CANCERS VIA TARGETED SEQUENCING OF EXONS OF 300 CANCER-ASSOCIATED GENES, INCLUDING MULTIPLE DNA DAMAGE REPAIR GENES [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-075.</jats:p
Abstract IA01: PARP inhibitors as single agents and in combinations for ovarian cancer: What lies ahead?
No full text
PARP Inhibitors in Ovarian Cancer: A Trailblazing and Transformative Journey
No full textAbstract
PARP inhibitors have transformed treatment for ovarian cancer, a cancer notable for homologous recombination (HR) deficiencies and aberrant DNA repair, especially in the high-grade serous subtype. PARP inhibitors are now approved for recurrent ovarian cancer as maintenance following response to platinum chemotherapy and BRCA-mutated (BRCAm) cancer treatment. Clin Cancer Res; 24(17); 4062–5. ©2018 AACR.
See related article by Ison et al., p. 4066</jats:p
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