المؤلفون: Leslie, Kimberly K, Filiaci, Virginia L, Mallen, Adrianne R, Thiel, Kristina W, Devor, Eric J, Moxley, Katherine, Richardson, Debra, Mutch, David, Secord, Angeles Alvarez, Tewari, Krishnansu S, McDonald, Megan E, Mathews, Cara, Cosgrove, Casey, Dewdney, Summer, Casablanca, Yovanni, Jackson, Amanda, Rose, Peter G, Zhou, XunClare, McHale, Michael, Lankes, Heather, Levine, Douglas A, Aghajanian, Carol

المصدر: Gynecologic Oncology. 161(1)

مصطلحات موضوعية: Clinical Research, Genetics, Uterine Cancer, Cancer, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Angiogenesis Inhibitors, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Carboplatin, Clinical Trials, Phase II as Topic, Endometrial Neoplasms, Epothilones, Female, Genes, p53, Humans, Mutation, Neoplasm Recurrence, Local, Neoplasm Staging, Paclitaxel, Progression-Free Survival, Randomized Controlled Trials as Topic, Sirolimus, Survival Rate, Treatment Outcome, Tumor Suppressor Protein p53, Endometrial cancer, Chemotherapy, p53, Oncology and Carcinogenesis, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis

الوصف: BackgroundSuccessfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P.MethodsTP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P.ResultsMutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53.ConclusionsThis exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov: NCT00977574.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9dj65803Test

المؤلفون: Dixit, Garima, Gonzalez‐Bosquet, Jesus, Skurski, Joseph, Devor, Eric J., Dickerson, Erin B., Nothnick, Warren B., Issuree, Priya D., Leslie, Kimberly K., Maretzky, Thorsten

المساهمون: American Cancer Society, U.S. Department of Defense, National Institutes of Health

المصدر: Clinical and Translational Medicine ; volume 13, issue 5 ; ISSN 2001-1326 2001-1326

الوصف: Background Mutations in the receptor tyrosine kinase gene fibroblast growth factor receptor 2 ( FGFR2 ) occur at a high frequency in endometrial cancer (EC) and have been linked to advanced and recurrent disease. However, little is known about how these mutations drive carcinogenesis. Methods Differential transcriptomic analysis and two‐step quantitative real‐time PCR (qRT‐PCR) assays were applied to identify genes differentially expressed in two cohorts of EC patients carrying mutations in the FGFR2 gene as well as in EC cells harbouring mutations in the FGFR2 . Candidate genes and target signalling pathways were investigated by qRT‐PCR assays, immunohistochemistry and bioinformatics analysis. The functional roles of differently regulated genes were analysed using in vitro and in vivo experiments, including 3D‐orthotypic co‐culture systems, cell proliferation and migration protocols, as well as colony and focus formation assays together with murine xenograft tumour models. The molecular mechanisms were examined using CRISPR / Cas9‐based loss‐of‐function and pharmacological approaches as well as luciferase reporter techniques, cell‐based ectodomain shedding assays and bioinformatics analysis. Results We show that common FGFR2 mutations significantly enhance the sensitivity to FGF7‐mediated activation of a disintegrin and metalloprotease (ADAM)17 and subsequent transactivation of the epidermal growth factor receptor (EGFR). We further show that FGFR2 mutants trigger the activation of ADAM10‐mediated Notch signalling in an ADAM17‐dependent manner, highlighting for the first time an intimate cooperation between EGFR and Notch pathways in EC. Differential transcriptomic analysis in EC cells in a cohort of patients carrying mutations in the FGFR2 gene identified a strong association between FGFR2 mutations and increased expression of members of the Notch pathway and ErbB receptor family. Notably, FGFR2 mutants are not constitutively active but require FGF7 stimulation to reprogram Notch and EGFR pathway ...

الإتاحة: https://doi.org/10.1002/ctm2.1223Test

المؤلفون: Thiel, Kristina W., Newtson, Andreea M., Devor, Eric J., Zhang, Yuping, Malmrose, Paige K., Bi, Jianling, Losh, Haley A., Davies, Suzy, Smith, Lane E., Padilla, Jamie, Leiva, Stephanie M., Grueter, Chad E., Breheny, Patrick, Hagan, Christy R., Pufall, Miles A., Gertz, Jason, Guo, Yan, Leslie, Kimberly K.

المصدر: The Journal of Steroid Biochemistry and Molecular Biology ; volume 234, page 106399 ; ISSN 0960-0760

مصطلحات موضوعية: Cell Biology, Clinical Biochemistry, Endocrinology, Molecular Biology, Molecular Medicine, Biochemistry, Endocrinology, Diabetes and Metabolism

الإتاحة: https://doi.org/10.1016/j.jsbmb.2023.106399Test
https://api.elsevier.com/content/article/PII:S0960076023001541?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0960076023001541?httpAccept=text/plainTest

المؤلفون: Reyes, Henry D, Miecznikowski, Jeffrey, Gonzalez-Bosquet, Jesus, Devor, Eric J, Zhang, Yuping, Thiel, Kristina W, Samuelson, Megan I, McDonald, Megan, Stephan, Jean-Marie, Hanjani, Parviz, Guntupalli, Saketh, Tewari, Krishnansu S, Backes, Floor, Ramirez, Nilsa, Fleming, Gini F, Filiaci, Virginia, Birrer, Michael J, Leslie, Kimberly K

المصدر: Gynecologic Oncology. 146(2)

مصطلحات موضوعية: Uterine Cancer, Cancer, Aged, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Carcinoma, Endometrioid, Chemotherapy, Adjuvant, Cisplatin, Disease-Free Survival, Doxorubicin, Endometrial Neoplasms, Female, Humans, Hysterectomy, Immunohistochemistry, Middle Aged, Neoplasm Staging, Paclitaxel, Piperidines, Prognosis, Retrospective Studies, Stathmin, Survival Rate, Endometrial cancer, Oncology and Carcinogenesis, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis

الوصف: ObjectiveGynecologic Oncology Group (GOG) 177 demonstrated that addition of paclitaxel to a backbone of adriamycin/cisplatin improves overall survival (OS) and progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer. Using patient specimens from GOG-177, our objective was to identify potential mechanisms underlying the improved clinical response to taxanes. Stathmin (STMN1) is a recognized poor prognostic marker in endometrial cancer that functions as a microtubule depolymerizing protein, allowing cells to transit rapidly through mitosis. Therefore, we hypothesized that one possible mechanism underlying the beneficial effects of paclitaxel could be to counter the impact of stathmin.MethodsWe analyzed the expression of stathmin by immunohistochemistry (IHC) in 69 specimens from patients enrolled on GOG-177. We also determined the correlation between stathmin mRNA expression and clinical outcomes in The Cancer Genome Atlas (TCGA) dataset for endometrial cancer.ResultsWe first established that stathmin expression was significantly associated with shorter PFS and OS for all analyzed cases in both GOG-177 and TCGA. However, subgroup analysis from GOG-177 revealed that high stathmin correlated with poor PFS and OS particularly in patients who received adriamycin/cisplatin only. In contrast, there was no statistically significant association between stathmin expression and OS or PFS in patients treated with paclitaxel/adriamycin/cisplatin.ConclusionsOur findings demonstrate that high stathmin expression is a poor prognostic marker in endometrial cancer. Paclitaxel may help to negate the impact of stathmin overexpression when treating high risk endometrial cancer cases.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5hp2v0d7Test

المؤلفون: Gai, Xiaochun, Feng, Yue, Flores, Tessa M, Kang, Huining, Yu, Hui, Leslie, Kimberly K, Zhu, Yiliang, Doherty, Jennifer A, Guo, Yan, Belinsky, Steven A, Cook, Linda S, Leng, Shuguang

المصدر: Thorax ; ISSN:1468-3296

مصطلحات موضوعية: COPD epidemiology, Emphysema, Lung Cancer, Smoking, Tobacco and the lung

الوصف: Early natural menopause (early-M; <45 years of age) increases the risk of lung morbidities and mortalities in smokers. However, it is largely unknown whether early-M due to surgery demonstrates similar effects and whether menopausal hormone therapy (MHT) is protective against lung diseases.

العلاقة: https://doi.org/10.1136/thorax-2023-220956Test; https://pubmed.ncbi.nlm.nih.gov/38871464Test

الإتاحة: https://doi.org/10.1136/thorax-2023-220956Test
https://pubmed.ncbi.nlm.nih.gov/38871464Test

المؤلفون: Rasmussen, Laura L., Leslie, Kimberly K., Santillan, Donna A., Santillan, Mark K.

المصدر: Volume: 11 ; Issue: 1 ; JournalTitle: Proceedings in Obstetrics and Gynecology ; 2154-4751

وصف الملف: 1-1

العلاقة: https://doi.org/10.17077/2154-4751.31433Test; /article/id/31433/

الإتاحة: https://doi.org/10.17077/2154-4751.31433Test

المؤلفون: Gonzalez-Bosquet, Jesus, Cardillo, Nicholas D, Reyes, Henry D, Smith, Brian J, Leslie, Kimberly K, Bender, David P, Goodheart, Michael J, Devor, Eric J

المصدر: Department of Obstetrics and Gynecology Faculty Papers

مصطلحات موضوعية: Female, Humans, Fallopian Tube Neoplasms, Cystadenocarcinoma, Serous, Retrospective Studies, Pilot Projects, Fallopian Tubes, Ovarian Neoplasms, Medicine and Health Sciences, Obstetrics and Gynecology

الوصف: The preoperative diagnosis of pelvic masses has been elusive to date. Methods for characterization such as CA-125 have had limited specificity. We hypothesize that genomic variation can be used to create prediction models which accurately distinguish high grade serous ovarian cancer (HGSC) from benign tissue. Methods: In this retrospective, pilot study, we extracted DNA and RNA from HGSC specimens and from benign fallopian tubes. Then, we performed whole exome sequencing and RNA sequencing, and identified single nucleotide variants (SNV), copy number variants (CNV) and structural variants (SV). We used these variants to create prediction models to distinguish cancer from benign tissue. The models were then validated in independent datasets and with a machine learning platform. Results: The prediction model with SNV had an AUC of 1.00 (95% CI 1.00-1.00). The models with CNV and SV had AUC of 0.87 and 0.73, respectively. Validated models also had excellent performances. Conclusions: Genomic variation of HGSC can be used to create prediction models which accurately discriminate cancer from benign tissue. Further refining of these models (early-stage samples, other tumor types) has the potential to lead to detection of ovarian cancer in blood with cell free DNA, even in early stage.

وصف الملف: application/pdf

العلاقة: https://jdc.jefferson.edu/obgynfp/95Test; https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1098&context=obgynfpTest

الإتاحة: https://jdc.jefferson.edu/obgynfp/95Test
https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1098&context=obgynfpTest

المؤلفون: Bi, Jianling, Zhang, Yuping, Malmrose, Paige K., Losh, Haley A., Newtson, Andreea M., Devor, Eric J., Thiel, Kristina W., Leslie, Kimberly K.

المساهمون: U.S. Department of Health & Human Services | NIH | National Cancer Institute, United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs, U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences

المصدر: Cell Death & Disease ; volume 13, issue 1 ; ISSN 2041-4889

مصطلحات موضوعية: Cancer Research, Cell Biology, Cellular and Molecular Neuroscience, Immunology

الوصف: Histone deacetylase (HDAC) inhibitors and proteasome inhibitors have been approved by the FDA for the treatment of multiple myeloma and lymphoma, respectively, but have not achieved similar activity as single agents in solid tumors. Preclinical studies have demonstrated the activity of the combination of an HDAC inhibitor and a proteasome inhibitor in a variety of tumor models. However, the mechanisms underlying sensitivity and resistance to this combination are not well-understood. This study explores the role of autophagy in adaptive resistance to dual HDAC and proteasome inhibition. Studies focus on ovarian and endometrial gynecologic cancers, two diseases with high mortality and a need for novel treatment approaches. We found that nanomolar concentrations of the proteasome inhibitor ixazomib and HDAC inhibitor romidepsin synergistically induce cell death in the majority of gynecologic cancer cells and patient-derived organoid (PDO) models created using endometrial and ovarian patient tumor tissue. However, some models were not sensitive to this combination, and mechanistic studies implicated autophagy as the main mediator of cell survival in the context of dual HDAC and proteasome inhibition. Whereas the combination of ixazomib and romidepsin reduces autophagy in sensitive gynecologic cancer models, autophagy is induced following drug treatment of resistant cells. Pharmacologic or genetic inhibition of autophagy in resistant cells reverses drug resistance as evidenced by an enhanced anti-tumor response both in vitro and in vivo. Taken together, our findings demonstrate a role for autophagic-mediated cell survival in proteasome inhibitor and HDAC inhibitor-resistant gynecologic cancer cells. These data reveal a new approach to overcome drug resistance by inhibiting the autophagy pathway.

الإتاحة: https://doi.org/10.1038/s41419-022-04508-2Test
https://www.nature.com/articles/s41419-022-04508-2.pdfTest
https://www.nature.com/articles/s41419-022-04508-2Test

المؤلفون: Rush, Craig M., Blanchard, Zannel, Polaski, Jacob T., Osborne, Kyle S., Osby, Krystle, Vahrenkamp, Jeffery M., Yang, Chieh-Hsiang, Lum, David H., Hagan, Christy R., Leslie, Kimberly K., Pufall, Miles A., Thiel, Kristina W., Gertz, Jason

المساهمون: National Human Genome Research Institute

المصدر: Scientific Reports ; volume 12, issue 1 ; ISSN 2045-2322

مصطلحات موضوعية: Multidisciplinary

الوصف: Most endometrial cancers express the hormone receptor estrogen receptor alpha (ER) and are driven by excess estrogen signaling. However, evaluation of the estrogen response in endometrial cancer cells has been limited by the availability of hormonally responsive in vitro models, with one cell line, Ishikawa, being used in most studies. Here, we describe a novel, adherent endometrioid endometrial cancer (EEC) cell line model, HCI-EC-23. We show that HCI-EC-23 retains ER expression and that ER functionally responds to estrogen induction over a range of passages. We also demonstrate that this cell line retains paradoxical activation of ER by tamoxifen, which is also observed in Ishikawa and is consistent with clinical data. The mutational landscape shows that HCI-EC-23 is mutated at many of the commonly altered genes in EEC, has relatively few copy-number alterations, and is microsatellite instable high (MSI-high). In vitro proliferation of HCI-EC-23 is strongly reduced upon combination estrogen and progesterone treatment. HCI-EC-23 exhibits strong estrogen dependence for tumor growth in vivo and tumor size is reduced by combination estrogen and progesterone treatment. Molecular characterization of estrogen induction in HCI-EC-23 revealed hundreds of estrogen-responsive genes that significantly overlapped with those regulated in Ishikawa. Analysis of ER genome binding identified similar patterns in HCI-EC-23 and Ishikawa, although ER exhibited more bound sites in Ishikawa. This study demonstrates that HCI-EC-23 is an estrogen- and progesterone-responsive cell line model that can be used to study the hormonal aspects of endometrial cancer.

الإتاحة: https://doi.org/10.1038/s41598-022-24211-8Test
https://www.nature.com/articles/s41598-022-24211-8.pdfTest
https://www.nature.com/articles/s41598-022-24211-8Test

المؤلفون: Gonzalez Bosquet, Jesus, Devor, Eric J., Newtson, Andreea M., Smith, Brian J., Bender, David P., Goodheart, Michael J., McDonald, Megan E., Braun, Terry A., Thiel, Kristina W., Leslie, Kimberly K.

المصدر: Scientific Reports ; volume 11, issue 1 ; ISSN 2045-2322

مصطلحات موضوعية: Multidisciplinary

الوصف: Nearly a third of patients with high-grade serous ovarian cancer (HGSC) do not respond to initial therapy and have an overall poor prognosis. However, there are no validated tools that accurately predict which patients will not respond. Our objective is to create and validate accurate models of prediction for treatment response in HGSC. This is a retrospective case–control study that integrates comprehensive clinical and genomic data from 88 patients with HGSC from a single institution. Responders were those patients with a progression-free survival of at least 6 months after treatment. Only patients with complete clinical information and frozen specimen at surgery were included. Gene, miRNA, exon, and long non-coding RNA (lncRNA) expression, gene copy number, genomic variation, and fusion-gene determination were extracted from RNA-sequencing data. DNA methylation analysis was performed. Initial selection of informative variables was performed with univariate ANOVA with cross-validation. Significant variables (p < 0.05) were included in multivariate lasso regression prediction models. Initial models included only one variable. Variables were then combined to create complex models. Model performance was measured with area under the curve (AUC). Validation of all models was performed using TCGA HGSC database. By integrating clinical and genomic variables, we achieved prediction performances of over 95% in AUC. Most performances in the validation set did not differ from the training set. Models with DNA methylation or lncRNA underperformed in the validation set. Integrating comprehensive clinical and genomic data from patients with HGSC results in accurate and robust prediction models of treatment response.

الإتاحة: https://doi.org/10.1038/s41598-021-85256-9Test
https://www.nature.com/articles/s41598-021-85256-9.pdfTest
https://www.nature.com/articles/s41598-021-85256-9Test