Browsing by Subject "Ovarian cancer"

Now showing 1 - 10 of 65
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    A Phase 2 Study of Dasatinib in Recurrent Clear Cell Carcinoma of the Ovary, Fallopian Tube, Peritoneum or Endometrium: NRG Oncology/Gynecologic Oncology Group Study 0283
    (Elsevier, 2023) O’Cearbhaill, Roisin E.; Miller, Austin; Soslow, Robert A.; Lankes, Heather A.; DeLair, Deborah; Segura, Sheila; Chavan, Shweta; Zamarin, Dmitriy; DeBernardo, Robert; Moore, Kathleen; Moroney, John; Shahin, Mark; Thaker, Premal H.; Wahner-Hendrickson, Andrea E.; Aghajanian, Carol; Pathology and Laboratory Medicine, School of Medicine
    Objective: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma. Methods: We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes. Results: Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors. Conclusions: Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype.
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    A Systematic Review and Meta-Analysis on the Prognostic Value of BRCA Mutations, Homologous Recombination Gene Mutations, and Homologous Recombination Deficiencies in Cancer
    (Hindawi, 2022-07-20) Shao, Changxia; Chang, Michael S.; Lam, Fred C.; Marley, Andrew R.; Tang, Huilin; Song, Yiqing; Miller, Chelsey; Brown, Madeline; Wan, Isabella; Han, Jiali; Adeboyeje, Gboyega; Epidemiology, Richard M. Fairbanks School of Public Health
    Patients with BRCA1/2 mutations (BRCAm), loss-of-function mutations in other homologous recombination repair (HRRm) genes, or tumors that are homologous recombination deficiency positivity (HRD+) demonstrate a robust response to PARPi therapy. We conducted a systematic literature review and meta-analysis to evaluate the prognostic value of BRCAm, HRRm, and HRD+ on overall survival (OS) among those treated by chemotherapy or targeted therapy other than PARPi across tumor types. A total of 135 eligible studies were included. Breast cancer (BC) patients with BRCA1/2m had a similar overall survival (OS) to those with wild-type BRCA1/2 (BRCA1/2 wt) across 18 studies. Ovarian cancer (OC) patients with BRCA1/2m had a significantly longer OS than those with BRCA1/2 wt across 24 studies reporting BRCA1m and BRCA2m, with an HR of 0.7 (0.6-0.8). Less OS data were reported for other tumors: 6 studies for BRCA2m compared with BRCA2 wt in prostate cancer with an HR of 1.9 (1.1-3.2) and 2 studies for BRCA1/2m compared with BRCA1/2 wt in pancreatic cancer with an HR of 1.5 (0.8-3.1). Only 4 studies reported HRD+ by either BRCA m or genomic instability score (GIS) ≥ 42 and OS by HRD status. The HR was 0.67 (0.43-1.02) for OS with HRD+ vs. HRD-. A total of 15 studies reported the association between HRRm and OS of cancers in which one or more HRR genes were examined. The HR was 1.0 (0.7-1.4) comparing patients with HRRm to those with HRR wild-type across tumors. Our findings are useful in improving the precision and efficacy of treatment selection in clinical oncology.
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    Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice
    (Springer Nature, 2020-12-10) Levy, Karen; Natarajan, Suchitra; Wang, Jinghui; Chow, Stephanie; Eggold, Joshua T.; Loo, Phoebe E.; Manjappa, Rakesh; Melemenidis, Stavros; Lartey, Frederick M.; Schüler, Emil; Skinner, Lawrie; Rafat, Marjan; Ko, Ryan; Kim, Anna; Al-Rawi, Duaa H.; von Eyben, Rie; Dorigo, Oliver; Casey, Kerriann M.; Graves, Edward E.; Bush, Karl; Yu, Amy S.; Koong, Albert C.; Maxim, Peter G.; Loo, Billy W., Jr.; Rankin, Erinn B.; Radiation Oncology, School of Medicine
    Radiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.
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    ARID3B increases ovarian tumor burden and is associated with a cancer stem cell gene signature
    (Impact Journals, 2014-09-30) Roy, Lynn; Samyesudhas, Serene J.; Carrasco, Martin; Joseph, Stancy; Dahl, Richard; Cowden Dahl, Karen D.; Biochemistry & Molecular Biology, School of Medicine
    Ovarian cancer is the most deadly gynecological malignancy since most patients have metastatic disease at the time of diagnosis. Therefore, identification of critical pathways that contribute to ovarian cancer progression is necessary to yield novel therapeutic targets. Recently we reported that the DNA binding protein ARID3B is overexpressed in human ovarian tumors. To determine if ARID3B has oncogenic functions in vivo, ovarian cancer cell lines stably expressing ARID3B were injected intraperitoneally into nude mice. Overexpression of ARID3B increased tumor burden and decreased survival. To assess how ARID3B contributes to the increased tumor growth in vivo, we identified ARID3B induced genes in tumor ascites cells. ARID3B induced expression of genes associated with metastasis and cancer stem cells (CD44, LGR5, PROM1 (CD133), and Notch2). Moreover, ARID3B increased the number of CD133+ (a cancer stem cell marker) cells compared to control cells. The increase in CD133+ cells resulting from ARID3B expression was accompanied by enhanced paclitaxel resistance. Our data demonstrate that ARID3B boosts production CD133+ cells and increases ovarian cancer progression in vivo.
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    AUCTSP: an improved biomarker gene pair class predictor
    (BMC, 2018-06-26) Kagaris, Dimitri; Khamesipour, Alireza; Yiannoutsos, Constantin T.; Biostatistics, School of Public Health
    The Top Scoring Pair (TSP) classifier, based on the concept of relative ranking reversals in the expressions of pairs of genes, has been proposed as a simple, accurate, and easily interpretable decision rule for classification and class prediction of gene expression profiles. The idea that differences in gene expression ranking are associated with presence or absence of disease is compelling and has strong biological plausibility. Nevertheless, the TSP formulation ignores significant available information which can improve classification accuracy and is vulnerable to selecting genes which do not have differential expression in the two conditions ("pivot" genes). RESULTS: We introduce the AUCTSP classifier as an alternative rank-based estimator of the magnitude of the ranking reversals involved in the original TSP. The proposed estimator is based on the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) and as such, takes into account the separation of the entire distribution of gene expression levels in gene pairs under the conditions considered, as opposed to comparing gene rankings within individual subjects as in the original TSP formulation. Through extensive simulations and case studies involving classification in ovarian, leukemia, colon, breast and prostate cancers and diffuse large b-cell lymphoma, we show the superiority of the proposed approach in terms of improving classification accuracy, avoiding overfitting and being less prone to selecting non-informative (pivot) genes. CONCLUSIONS: The proposed AUCTSP is a simple yet reliable and robust rank-based classifier for gene expression classification. While the AUCTSP works by the same principle as TSP, its ability to determine the top scoring gene pair based on the relative rankings of two marker genes across all subjects as opposed to each individual subject results in significant performance gains in classification accuracy. In addition, the proposed method tends to avoid selection of non-informative (pivot) genes as members of the top-scoring pair.
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    Author Correction: CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity
    (Nature Publishing Group, 2018-04-13) Walton, Josephine B.; Farquharson, Malcolm; Mason, Susan; Port, Jennifer; Kruspig, Bjorn; Dowson, Suzanne; Stevenson, David; Murphy, Daniel; Matzuk, Martin; Kim, Jaeyeon; Coffelt, Seth; Blyth, Karen; McNeish, Iain A.; Biochemistry and Molecular Biology, School of Medicine
    A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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    BORIS expression in ovarian cancer precursor cells alters the CTCF cistrome and enhances invasiveness through GALNT14
    (American Association for Cancer Research, 2019-10) Hillman, Joanna C.; Pugacheva, Elena M.; Barger, Carter J.; Sribenja, Sirinapa; Rosario, Spencer; Albahrani, Mustafa; Truskinovsky, Alexander M.; Stablewski, Aimee; Liu, Song; Loukinov, Dmitri I.; Zentner, Gabriel E.; Lobanenkov, Victor V.; Karpf, Adam R.; Higgins, Michael J.; Medicine, School of Medicine
    High-grade serous carcinoma (HGSC) is the most aggressive and predominant form of epithelial ovarian cancer and the leading cause of gynecological cancer death. We have previously shown that CTCFL (also known as BORIS, Brother of the Regulator of Imprinted Sites) is expressed in most ovarian cancers, and is associated with global and promoter-specific DNA hypomethylation, advanced tumor stage, and poor prognosis. To explore its role in HGSC, we expressed BORIS in human fallopian tube secretory epithelial cells (FTSEC), the presumptive cells of origin for HGSC. BORIS-expressing cells exhibited increased motility and invasion, and BORIS expression was associated with alterations in several cancer-associated gene expression networks, including fatty acid metabolism, TNF signaling, cell migration, and ECM-receptor interactions. Importantly, GALNT14, a glycosyltransferase gene implicated in cancer cell migration and invasion, was highly induced by BORIS, and GALNT14 knockdown significantly abrogated BORIS-induced cell motility and invasion. In addition, in silico analyses provided evidence for BORIS and GALNT14 co-expression in several cancers. Finally, ChIP-seq demonstrated that expression of BORIS was associated with de novo and enhanced binding of CTCF at hundreds of loci, many of which correlated with activation of transcription at target genes, including GALNT14. Taken together, our data indicate that BORIS may promote cell motility and invasion in HGSC via upregulation of GALNT14, and suggests BORIS as a potential therapeutic target in this malignancy.
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    Cancer associated fibroblasts serve as an ovarian cancer stem cell niche through noncanonical Wnt5a signaling
    (Springer Nature, 2024-01-08) Fang, Yiming; Xiao, Xue; Wang, Ji; Dasari, Subramanyam; Pepin, David; Nephew, Kenneth P.; Zamarin, Dmitriy; Mitra, Anirban K.; Medicine, School of Medicine
    Frequent relapse and chemoresistance cause poor outcome in ovarian cancer (OC) and cancer stem cells (CSCs) are important contributors. While most studies focus exclusively on CSCs, the role of the microenvironment in providing optimal conditions to maintain their tumor-initiating potential remains poorly understood. Cancer associated fibroblasts (CAFs) are a major constituent of the OC tumor microenvironment and we show that CAFs and CSCs are enriched following chemotherapy in patient tumors. CAFs significantly increase OC cell resistance to carboplatin. Using heterotypic CAF-OC cocultures and in vivo limiting dilution assay, we confirm that the CAFs act by enriching the CSC population. CAFs increase the symmetric division of CSCs as well as the dedifferentiation of bulk OC cells into CSCs. The effect of CAFs is limited to OC cells in their immediate neighborhood, which can be prevented by inhibiting Wnt. Analysis of single cell RNA-seq data from OC patients reveal Wnt5a as the highest expressed Wnt in CAFs and that certain subpopulations of CAFs express higher levels of Wnt5a. Our findings demonstrate that Wnt5a from CAFs activate a noncanonical Wnt signaling pathway involving the ROR2/PKC/CREB1 axis in the neighboring CSCs. While canonical Wnt signaling is found to be predominant in interactions between cancer cells in patients, non-canonical Wnt pathway is activated by the CAF-OC crosstalk. Treatment with a Wnt5a inhibitor sensitizes tumors to carboplatin in vivo. Together, our results demonstrate a novel mechanism of CSC maintenance by signals from the microenvironmental CAFs, which can be targeted to treat OC chemoresistance and relapse.
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    Cancer Associated Fibroblasts: Naughty Neighbors That Drive Ovarian Cancer Progression
    (MDPI, 2018-10-29) Dasari, Subramanyam; Fang, Yiming; Mitra, Anirban K.; Medical and Molecular Genetics, School of Medicine
    Ovarian cancer is the most lethal gynecologic malignancy, and patient prognosis has not improved significantly over the last several decades. In order to improve therapeutic approaches and patient outcomes, there is a critical need for focused research towards better understanding of the disease. Recent findings have revealed that the tumor microenvironment plays an essential role in promoting cancer progression and metastasis. The tumor microenvironment consists of cancer cells and several different types of normal cells recruited and reprogrammed by the cancer cells to produce factors beneficial to tumor growth and spread. These normal cells present within the tumor, along with the various extracellular matrix proteins and secreted factors, constitute the tumor stroma and can compose 10⁻60% of the tumor volume. Cancer associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment, and play a critical role in promoting many aspects of tumor function. This review will describe the various hypotheses about the origin of CAFs, their major functions in the tumor microenvironment in ovarian cancer, and will discuss the potential of targeting CAFs as a possible therapeutic approach.
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    CD133 Promotes Adhesion to the Ovarian Cancer Metastatic Niche
    (Libertas Academica, 2018-04-09) Roy, Lynn; Bobbs, Alexander; Sattler, Rachel; Kurkewich, Jeffrey L; Dausinas, Paige B.; Nallathamby, Prakash; Cowden Dahl, Karen D.; Biochemistry and Molecular Biology, School of Medicine
    Cancer stem cells (CSCs) are an attractive therapeutic target due to their predicted role in both metastasis and chemoresistance. One of the most commonly agreed on markers for ovarian CSCs is the cell surface protein CD133. CD133+ ovarian CSCs have increased tumorigenicity, resistance to chemotherapy, and increased metastasis. Therefore, we were interested in defining how CD133 is regulated and whether it has a role in tumor metastasis. Previously we found that overexpression of the transcription factor, ARID3B, increased the expression of PROM1 (CD133 gene) in ovarian cancer cells in vitro and in xenograft tumors. We report that ARID3B directly regulates PROM1 expression. Importantly, in a xenograft mouse model of ovarian cancer, knockdown of PROM1 in cells expressing exogenous ARID3B resulted in increased survival time compared with cells expressing ARID3B and a control short hairpin RNA. This indicated that ARID3B regulation of PROM1 is critical for tumor growth. Moreover, we hypothesized that CD133 may affect metastatic spread. Given that the peritoneal mesothelium is a major site of ovarian cancer metastasis, we explored the role of PROM1 in mesothelial attachment. PROM1 expression increased adhesion to mesothelium in vitro and ex vivo. Collectively, our work demonstrates that ARID3B regulates PROM1 adhesion to the ovarian cancer metastatic niche.