Metabolic Changes in Ovarian Cancer最新文献

{"title":"Abstract A16: COL11A1 confers cisplatin resistance through fatty acid oxidation in ovarian cancer cells","authors":"M. Rada, Jennifer Cha, Jessica M. Sage, Bo Zhou, Wei Yang, S. Orsulic, Dong-Joo Cheon","doi":"10.1158/1557-3265.OVCA17-A16","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A16","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"158 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79995765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A22: Functional analysis of PGE2 pathway members EP4 and MRP4 in ovarian cancer","authors":"M. Ching, Conghong Fan, D. Roque, Gautam G. Rao, Paul N. Staats, A. Fulton, J. Reader","doi":"10.1158/1557-3265.OVCA17-A22","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A22","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91079109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PR03: Arginine deprivation as a potential targeted therapy for clear cell ovarian carcinoma","authors":"J. Ji, D. Cochrane, B. Tessier-Cloutier, L. Hoang, Yikan Wang, A. Cheung, C. Chow, Shane Colborne, Christopher J. Hughes, G. Morin, D. Huntsman","doi":"10.1158/1557-3265.OVCA17-PR03","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-PR03","url":null,"abstract":"In this study, we explored the metabolic pathways of clear cell ovarian carcinoma (CCOC) and the therapeutic importance of aberrant arginine metabolism in this cancer. In 2017, an estimated 22,440 women will be diagnosed with epithelial ovarian carcinoma (EOC) in the United States. EOC is divided into subtypes based on histology and prognosis. Among them, CCOC is truly a unique entity. Histologically, CCOC is characterized by clear cytoplasm, which stains PAS positive, indicating aberrant cellular glycogen storage. Genomic studies in CCOC have identified recurrent mutations in the ARID1A and PIK3CA genes, both encoding proteins with crucial roles in cellular metabolism, which further supports CCOC being a metabolism-dependent malignancy. At late stage, CCOC is more aggressive and refractory to conventional platinum-based therapy, compared to other EOC subtypes. Despite the lack of efficacy, platinum-based chemotherapy is still the gold standard for treating all EOC subtypes. The lack of targeted therapy for CCOC paints a grim picture for the patients as they inevitably relapse. Using a mass spectrometry-based study, we characterized the whole proteome of 17 formalin-fixed, paraffin-embedded (FFPE) patient CCOC tumors. The CCOC cases separated into 2 distinct subgroups based on unsupervised hierarchical clustering. We identified the top 250 most differentially expressed proteins between these 2 groups using Protein Expression Control Analysis (PECA) and subsequent pathway analysis through KEGG. Of these 250 proteins, 56 were metabolism-related, including Argininosuccinate Synthase 1 (ASS1). ASS1 is a crucial enzyme in the cellular synthesis of arginine; a deficiency in the enzyme makes cancer cells dependent on extracellular arginine for survival. In ASS-1 deficient sarcomas, targeted small-molecule therapy depriving extracellular arginine results in cell death and sensitization to conventional chemotherapy. In transcriptomic analysis of 55 patient CCOC tumors and cell lines, 13 cases had low ASS1 RNA expression compared to others. Subsequently, we collected 97 CCOC cases from a local tissue bank and studied ASS1 protein expression using immunohistochemistry. In these cases, ASS1 expression ranges from strong to diffusely weak to null, confirming the differential expression discovered in the proteomic and transcriptomic study. To this end, ASS1 levels were assessed in CCOC, endometrioid, and high-grade serous cell lines. ASS1 was not expressed in a subset of CCOC cell lines and was low in others. We further demonstrate that a subset of CCOC cell lines are sensitive to arginine deprivation, indicating that there may be some CCOC tumors that would benefit from combined arginine deprivation in conjunction with the gold standard platinum-based therapy. This abstract is also being presented as Poster A13. Citation Format: Jennifer Xiao Ye Ji, Dawn R. Cochrane, Basile Tessier-Cloutier, Lien N. Hoang, Yikan Wang, Angela Cheung, Christine Chow, Shane Colb","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84730350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A33: Patient-specific evaluation of chemoresistance and tumor recurrence using ovarian cancer stem cell spheroids","authors":"Shreya A Raghavan, P. Mehta, Michael Bregenzer, Maria R. Ward Rashidi, Elyse M. Fleck, L. Tan, K. McLean, R. Buckanovich, G. Mehta","doi":"10.1158/1557-3265.OVCA17-A33","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A33","url":null,"abstract":"Ovarian cancers grow in suspension in the ascites fluid, and contain a small population of ovarian cancer stem cells (OvCSC), which are resistant to therapy. Due to the rarity of OvCSCs, we developed a 3D hanging drop platform, in which as few as one ALDH+ CD133+ cell (isolated from primary malignant ascites) can be stably incorporated into 3D spheroids. Our platform can be utilized to quantify drug sensitivity of chemotherapeutic agents in the context of OvCSCs, distinguish drug responses for the same drugs between several patient samples, and model patient-specific tumor re-emergence, making it uniquely suited for the development of personalized therapeutics. Three patient samples (Pt259, Pt224, Pt152) were evaluated and robust proliferation rates were observed in spheroids, ranging from 5.3 fold to 8.4 fold. By Day 7, ALDH+ CD133+ cells had differentiated within spheroids to form progeny of ALDH- CD133-, ALDH+ CD133-, and CD133+ ALDH- cells while maintaining an ALDH+ CD133+ population. Each patient-derived spheroid demonstrated a different composition of these progeny, which were similar to those observed in the patient samples. OvCSC spheroids had differing responses to drug treatments (cisplatin, ALDH targeting compound 673A, and JAK1/2 inhibitor ruxolitinib). Combination of cisplatin/673A targeted ALDH+ and CD133+ in all patient samples. Pt259 samples were maximally sensitive to cisplatin/673A, while Pt224 and Pt152 were more resistant (20-40% higher viability). Combination dose of cisplatin/ruxolitinib targeted CD133+ populations. By isolating cells that escaped chemotherapy, we created a spheroid model to study tumor re-emergence. ALDH+ populations re-emerged to a lower extent compared to original OvCSC spheroids, while CD133+ populations did not recover at all. Spheroids formed from the most platinum-sensitive cells (Pt259) and the most platinum-resistant cells (Pt152) following cisplatin/673A treatment were also serially passaged over 7 cycles in 7 weeks to characterize CD133+ and ALDH+ populations and evaluate their ability to reform spheroids, effectively modeling tumor re-emergence in vitro. ALDH+ OvCSC progeny reliably repopulated within these spheroids despite initial depletion following treatment. Over six serial passages, ALDH+, CD133+, and ALDH+ CD133+ populations gradually returned to original and even higher than levels seen in original patient samples. Lastly, OvCSC spheroids initiated tumors in immunodeficient mice at 100% success with only 10 spheroids injected. These tumors demonstrated a distinct response to therapy that corresponds with responses seen in spheroids, indicating that our model may be a means to screen tumors for personalized drug selection. Our patient-derived low-cell-number OvCSC spheroid platform can be utilized to study tumor biology, to model tumor re-emergence after primary chemotherapy, and to identify new targeted therapeutics from a personalized medicine standpoint. Citation Format: Shreya Raghavan","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82902443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A42: TR3/NR4A1 as a therapeutic target for ovarian cancer","authors":"A. Beeghly-Fadiel, D. Chase, J. Cooks, M. Crispens, D. Khabele, Andrew J. Wilson","doi":"10.1158/1557-3265.OVCA17-A42","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A42","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88038621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A58: Transcription factor SREBP2 mediates ovarian cancer drug resistance and recurrence","authors":"G. Karashchuk, A. Brodsky","doi":"10.1158/1557-3265.ovca17-a58","DOIUrl":"https://doi.org/10.1158/1557-3265.ovca17-a58","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86210321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A17: NUAK1 acts as a growth suppressor in epithelial ovarian cancer","authors":"Parima Saxena, O. Collins, Yudith Ramos Valdés, Adrian V Buensuceso, K. Francis, K. Brown, K. Colwill, A. Gingras, R. Rottapel, G. DiMattia, T. Shepherd","doi":"10.1158/1557-3265.OVCA17-A17","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A17","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86797820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A46: Hsp90 regulates Twist1 expression through STAT3 to induce epithelial-mesenchymal transition in ovarian cancer","authors":"K. Chong, Francesca Garofalo, Oluwagbemisola Madarikan, Nicholas Pitruzzello, Cheng-Hsiu Tsai, Jamie Bingham, Yang Yang-Hartwich","doi":"10.1158/1557-3265.OVCA17-A46","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A46","url":null,"abstract":"Background: Metastatic disease is the leading cause of death from ovarian cancer and its underlying mechanisms are poorly understood. Twist1 is a key driver of epithelial-mesenchymal transition (EMT) and metastasis. Understanding the function and regulation of Twist1 is a vital step in the development of effective treatments for metastatic ovarian cancer. Heat shock protein 90 (Hsp90) is a molecular chaperone that modulates multiple signaling networks, and recent studies have highlighted the roles of extracellular Hsp90 in promoting metastasis in cancer. The roles of Hsp90 in regulating intracellular pathways leading to EMT and metastasis remain largely unknown. Objective: In our study, we tested the hypothesis that Hsp90 promotes EMT in ovarian cancer through the regulation of Twist1 at the transcriptional level. Methods: We treated A2780 and SKOV3 with a Hsp90-specific inhibitor, 17-allylamino-17 demethoxygeldanamycin (17-AAG). The effects of Hsp90 inhibition on Twist1 mRNA expression and promoter activity were measured using quantitative PCR and luciferase reporter assays, respectively. Proximity ligation assays were performed to visualize the effects of 17-AAG on the interaction between Hsp90 and transcription factors, followed by chromatin immunoprecipitation to measure the binding of transcription factors to the Twist1 promoter. Results: Treatment with 17-AAG significantly downregulated Twist1 expression at the mRNA level in A2780, SKOV3, and three ovarian cancer patient-derived cell lines. Hsp90 overexpression substantially induced Twist1 promoter activity while treatment with 17-AAG significantly decreased the activity. Western blotting and immunofluorescent staining revealed the presence of 4 transcription factors known to be clients of Hsp90 and regulators of Twist1, which are β-catenin, signal transducer and activator of transcription 3 (STAT3), hypoxia-inducible factor 1-alpha (HIF-1α), and HIF-1β. We identified that Hsp90 interacts with β-catenin, STAT3, and HIF-1α in our cell lines. We observed that 17-AAG treatment dramatically impaired Hsp90-STAT3 interaction and the binding of STAT3 to the Twist1 promoter. Inhibition of Hsp90 was also shown to block interleukin-6 (IL-6) and transforming growth factor beta (TGF-β)-induced EMT. Conclusion: Taken together, our findings reveal that STAT3 is dependent on Hsp90 to activate Twist1 expression. Hsp90 plays a critical role in enabling STAT3 to bind to the Twist1 promoter and promote Twist1 transcription leading to EMT. We uncovered a previously unrecognized role of Hsp90, which cooperates with STAT3 in the transcriptional regulation of Twist1 in ovarian cancer cells. Inhibiting Hsp90 using small-molecule inhibitors such as 17-AAG may have potential as a therapeutic strategy to prevent EMT and metastasis in ovarian cancer. Citation Format: Kay Yi Chong, Francesca Garofalo, Oluwagbemisola Madarikan, Nicholas Pitruzzello, Cheng-Hsiu Tsai, Jamie Bingham, Yang Yang-Hartwich. Hsp90 regulates Twi","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"193 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76952534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A14: TP53 missense mutations associate with different metabolic pathways","authors":"L. Kelemen, J. Brenton, D. Bowtell, B. Fridley","doi":"10.1158/1557-3265.OVCA17-A14","DOIUrl":"https://doi.org/10.1158/1557-3265.OVCA17-A14","url":null,"abstract":"Background: Deleterious TP53 mutations are found in 99% of patients with high-grade serous ovarian cancer (HGSOC). TP53 missense mutations, found in two-thirds of HGSOC tumors, endow the mutant protein with new gain-of-function (GOF) activities leading to altered expression of genes involved in maintaining controlled cellular metabolism and the development of drug resistance. Identification of specific altered pathways could be exploited therapeutically. We investigated whether all missense mutations alter the same metabolic pathways. Methods: We used publicly available data from The Cancer Genome Atlas (TCGA) and the Australia Ovarian Cancer Study (AOCS). TCGA and AOCS gene expression datasets were downloaded from the Curated Ovarian Data, a resource of uniformly prepared microarray data from 23 studies with curated and documented clinical metadata. We merged gene expression data from TCGA (Affymetrix HT_HG-U133A) and AOCS (Affymetrix HG-U133Plus2), subset to 12,211 features common to both datasets and included non-missing values of invasive HGSOC. TP53 mutations were downloaded from TCGA and obtained for AOCS and merged with the curated datasets. The final datasets consisted of 295 patients in TCGA (N=184 with missense mutations with putative GOF activity, and N=111 nonsense mutations with putative loss of function (LOF) activity and 21 wild-type) and 142 patients in AOCS (N=83 missense mutations with putative GOF activity, N=59 nonsense mutations with putative LOF activity and N=13 wild-type). Gene expression values were normalized in each dataset separately by subtracting the mean value of each gene and dividing by the standard deviation. Mutations were categorized according to missense vs nonsense mutation class and also according to specific mutations. We evaluated all gene sets in KEGG but focused a priori on the association of Oxidative Phosphorylation (OXPHOS), Fatty Acid Metabolism (FA), Glycolysis and Gluconeogenesis (GLY), and the P53 pathway with overall (OS) and progression-free survival (PFS) using Cox regression models stratified by mutation class and adjusted for age and stage. Results: There were no significant differences between TP53 missense vs nonsense mutation class for gene set expressions for a priori pathways of interest in TCGA, and a nominal difference for the P53 gene set expression (P=0.07) in AOCS. Comparing TCGA, AOCS, and the combined datasets, differential gene set expressions by TP53 mutation class were observed in all three datasets at P Conclusions: Specific TP53 missense mutations are associated with different metabolic pathways and may lead to differences in survival. Citation Format: Linda E. Kelemen, James D. Brenton, David D. Bowtell, Brooke L. Fridley. TP53 missense mutations associate with different metabolic pathways. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Ca","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79944786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract IA06: Stromal regulation of metastasis","authors":"E. Lengyel, Mark A. Eckert, Iris L. Romero, H. Kenny","doi":"10.1158/1557-3265.ovca17-ia06","DOIUrl":"https://doi.org/10.1158/1557-3265.ovca17-ia06","url":null,"abstract":"","PeriodicalId":18646,"journal":{"name":"Metabolic Changes in Ovarian Cancer","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75921862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}