bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 320: New metastatic murine prostate cancer cell lines and preclinical model of human prostate cancer.
Authors: Ju Xiaoming , Pestell Richard G. 
Published: August 2014

Abstract
Defining oncogene-specific molecular pathways required for the induction and maintenance of prostate cancer is essential for the rational design of new therapies. Identifying molecular predictors of prostate cancer patient survival is important for patient therapeutic substratification.
We generated murine prostate cancer cell lines via selective transduction with a single oncogene (c-Myc, Ha-Ras, NeuT, and v-Src). These cell lines demonstrate contact-independent growth characteristics in soft agar, and have the substantial growth advantage over primary prostate epithelial cells. Each of the prostate lines grew tumor in immune competent mice after subcutaneous injection, and develop lung metastasis in c-Myc, Ha-Ras, and v-Src cell line groups. RNA samples were prepared from the these cell lines, Microarray analysis identified a total of 2635 out of 22115 genes that were significantly altered in expression (at least two-fold change) in oncogene over-expressing cell lines when compared with prostate epithelial cell control samples. The distinct oncogene expression signature was compared to gene signatures obtained from other published databases to identify similarities to human prostate cancer phenotypes. Comparisons were performed against gene signatures representative of differential expression in advanced state vs. early stage prostate cancer, high grade vs low grade prostate cancer, recurrent vs. nonrecurrent, the results indicate a significant degree of similarity between the prostate oncogene expression signature and high-grade disease; between the oncogene expression signature and the advanced stage disease phenotype. Interrogation of two distinct cohorts of Prostate cancer patient samples using the oncogene signature demonstrated an ability to distinguish tumor from normal prostate with a predictive value for prostate cancer of 98 - 99%. The signature provided in blinded study independent substratification of reduced recurrence free survival by Kaplan-Meier analysis.
The generation of new oncogene-specific prostate cancer cell lines that recapitulate human prostate cancer gene expression, that metastasize in immune-competent mice, are a valuable new resource for testing targeted therapy. The molecular signatures identified herein provide further value over current markers of prediction and outcome.
Citation Format: Xiaoming Ju, Richard G. Pestell. New metastatic murine prostate cancer cell lines and preclinical model of human prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 320. doi:10.1158/1538-7445.AM2013-320
Abstract 322: Dual targeting of the PI3K/mTOR pathways by PF-04691502 or PF-05212384 exhibits therapeutic effects against the metastatic disease progression in the Ovcar 3 disseminated model.
Authors: Yan Zhengming , Fang Douglas , Simmons Brett , Yuan Jing , Kan Julie , Zhang Cathy C. 
Published: August 2014

Abstract
Ovarian cancer has the highest mortality rate of all gynecological cancers primarily due to the high incidence of metastatic spread prior to diagnosis. Understanding the biology of this malignancy and developing models that reflect the patient disease phenotype will create better pre-clinical opportunities for testing targeted therapy. We used the Ovcar 3 cell line to establish a metastasis model through serial in vivo passage. The dual PI3K/mTOR inhibitors PF-04691502 and PF-05212384 were then investigated in this model for their therapeutic effect against metastatic disease progression. Notably, the stromal environment and tumor initiating subpopulation play critical roles on the Ovcar 3MET disease invasiveness and progression. Based on the molecular profile, these invasive Ovcar 3MET cells exhibited a more EMT phenotype when compared to parental cells. Impairing PI3K/mTOR pathway with the dual PI3K/mTOR inhibitors resulted in significant anti-metastatic activity and increased survival in the Ovcar 3MET model. Serum CA125 level, which is a validated clinical marker, correlated with anatomic measurement of tumor burdens via BLI and mouse survival time in these studies, providing means for longitudinal monitoring of disease progression and response to therapy. In addition, using ex vivo tumorsphere analysis under serum-free condition, both PF-04691502 and PF-05212384 demonstrated robust activity against the self-renewal ability of Ovcar 3 tumor cells. In summary, this translational tumor model may serve as a valuable tool for testing targeted therapies such as PI3K/mTOR inhibitors for their ability to impact progression of metastatic ovarian disease.
Citation Format: Zhengming Yan, Douglas Fang, Brett Simmons, Jing Yuan, Julie Kan, Cathy C. Zhang. Dual targeting of the PI3K/mTOR pathways by PF-04691502 or PF-05212384 exhibits therapeutic effects against the metastatic disease progression in the Ovcar 3 disseminated model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 322. doi:10.1158/1538-7445.AM2013-322
Abstract 3223: Metabolomic study reveals smokers’ characteristic profile.
Authors: Hsu Ping-Ching , Zhou Bin , Ressom Habtom W. , Cheema Amrita , Loffredo Christopher A. , Pickworth Wallace , Shields Peter G. 
Published: August 2014

Abstract
Given recent FDA legislation to mandate cigarette performance standards and evaluate health claims for modified tobacco products, and separately the fact that most persons with lung cancer are former smokers, biomarkers of lung cancer risk are needed. Yet, today there are only a few biomarkers of exposure and none that are validated for lung cancer risk. This study identified putative biomarkers of exposure and harm through metabolomics, a powerful method to identify numerous metabolites and profiles. It utilized a previously conducted epidemiological study of well-characterized smokers. Using UPLC-QTOF-MS, we analyzed global metabolomic profiles of 160 smokers’ plasma totaling 613 repeated samples, and evaluated whether gender, race, number of cigarettes per day, nicotine metabolism, and type of cigarette is associated with smokers’ global metabolome. These subjects completed an extensive interview and smoked two cigarettes in a smoking laboratory. Blood and CO measurements were collected before and after each cigarette. Using subset analysis for the effect of gender on smokers’ metabolome, we were able to identify putative metabolites that are mostly steroid hormones or cholesterol derivatives, signifying the importance of sex-specific differences in metabolism. There was also significant discrimination in the metabolome of heavy and light smokers, of African-American and Caucasian smokers, and of menthol and non-menthol cigarette smokers. We also performed a paired analysis on menthol versus non-menthol smokers matched by race, gender, metabolizer status, and smoking status. Our result showed not only a significant discrimination between metabolomes of these two cigarette types, but also discriminated a cigarette brand with the lowest nicotine yield from the one with the highest yield. Putative metabolites were identified including several related to carcinogenesis and the inhibition of actin cytoskeleton activation. Further validation is needed to identify and characterize those metabolites.
In summary, we have shown that the potential biomarkers identified in this study are strongly related to other well established lung cancer risk factors including gender, race, and tobacco exposure variables, and therefore may be useful in cohort studies of persons at high risk for lung cancer.
Citation Format: Ping-Ching Hsu, Bin Zhou, Habtom W. Ressom, Amrita Cheema, Christopher A. Loffredo, Wallace Pickworth, Peter G. Shields. Metabolomic study reveals smokers’ characteristic profile. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3223. doi:10.1158/1538-7445.AM2013-3223
Abstract 323: High grade serous ovarian cancer cells spontaneously self-organize in vitro into multicellular irregular aggregates and highly organized spheroids.
Authors: Goyeneche Alicia A. 
Published: August 2014

Abstract
Ovarian cancer (OvCa) has the worst prognosis among gynecologic cancers because it is typically detected at an advanced stage. Accumulation of fluid inside the peritoneal cavity, and multicellular clusters featured within ascites are common manifestations of the disease. Patients undergo aggressive cytoreductive surgery followed by platinum-taxane therapy; yet in most cases, patients will relapse and die due to tumor progression. OvCa recurs as it presents, with growths within the peritoneal cavity, accumulation of ascites, but with a chemotherapy-resistant phenotype. Thus, understanding the dynamics of peritoneal metastases is of clear significance. This work provides evidences that OvCa cells derived from serous, treatment-resistant relapsed disease spontaneously develop multicellular anchorage-independent OvCa aggregates in vitro. The human serous ovarian adenocarcinoma PEO6 cells, while growing as adherent monolayer, spontaneously self-assemble into multicellular foci that float away off the adherent component of the culture. The floating phenotype is comprised of irregular cellular clusters and more organized spheroids with blastocyst-like morphology. Within each multicellular structure cells gather differently as evidenced by the distribution pattern of the cell junction adhesion molecule E-cadherin. Both types of non-adherent multicellular aggregates have live cells with no morphological features of apoptosis indicating their resistance to anoikis. Anchorage independent OvCa spheroids have the capacity to recreate the entire culture phenotype when placed in a new dish; the spheroids adhere upon transference and develop foci that grow upright irregular aggregates and more organized spheroids, ultimately leading to the generation of new non-adherent components. The floating PEO6 structures include clusters of cells expressing the cancer initiating antigen CD133 supporting their plasticity to perpetuate the anchorage-independent component of the culture. In summary, this study led to the characterization of an in vitro model of recurrent, treatment-resistant serous OvCa cells with intrinsic ability to gather in two types of clusters that survive in an anchorage-independent manner-a hallmark of transformation and critical factor in metastasis. The spontaneous in vitro development of OvCa multicellular irregular aggregates and spheroids at recurrence may represent a preclinical model to study the biology of selection and adaptation of disease malignancy and ways to interrupt its progression.
Citation Format: Alicia A. Goyeneche. High grade serous ovarian cancer cells spontaneously self-organize in vitro into multicellular irregular aggregates and highly organized spheroids. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 323. doi:10.1158/1538-7445.AM2013-323
Abstract 3252: A novel small molecule, LY5, selectively inhibits STAT3 phosphorylation and activities and exhibits potent growth suppressive activity in cancer cells.
Authors: Xiao Hui , Yu Wenying , Olson Veronica R. , Li Chenglong , Houghton Peter , Lin Jiayuh 
Published: August 2014

Abstract
In response to cytokines and growth factors, Signal Transducers and Activators of Transcription 3 (STAT3) signaling is activated which plays a critical role in oncogenesis, proliferation, survival, and invasion of various human cancers and cancer cell lines. Numerous evidences have demonstrated that inhibition of STAT3 signaling pathway results in decreased growth and apoptosis in human cancer cells. This makes STAT3 an excellent molecular target for cancer therapy. In this study, we investigated a novel non-peptide, cell-permeable, small molecule, named as LY5, which selectively targets STAT3. LY5 inhibited constitutive STAT3 activation in various human pediatric sarcoma and medulloblastoma cell lines expressing elevated levels of STAT3 phosphorylation. LY5 also blocked STAT3 phosphorylation induced by Interleukin-6, IGF-1, and OSM in SJSA human osteosarcoma cells, but did not inhibit STAT1, STAT2, STAT4, and STAT6 phosphorylation stimulated by interferon (IFN)-γ,IFN-α, and IL-4, respectively. Furthermore, LY5 suppressed the induction of STAT3 nuclear localization by IL-6, which could prevent STAT3 function as a transcription factor, but not STAT1 nuclear localization induced by IFN-γ. In addition, LY5 induced apoptosis in sarcoma and medulloblastoma cells as indicated by the increases of cleaved caspase-3, but LY5 did not induce apoptosis in normal primary human cells. The inhibition of STAT3 signaling by LY5 was further confirmed by down-regulating the expression of the downstream targets of STAT3, including cyclin D1, Bcl-XL, and survivin. Taken together, these findings indicated LY5 selectively inhibited constitutive STAT3 activation and suggested that LY5 is a promising therapeutic candidate for pediatric sarcoma and medulloblastoma through inhibiting STAT3 signaling.
Citation Format: Hui Xiao, Wenying Yu, Veronica R. Olson, Chenglong Li, Peter Houghton, Jiayuh Lin. A novel small molecule, LY5, selectively inhibits STAT3 phosphorylation and activities and exhibits potent growth suppressive activity in cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3252. doi:10.1158/1538-7445.AM2013-3252
Abstract 327: Establishment of patient primary ovarian cancer xenograft models for test of anticancer agents.
Authors: Liu Changnian , Xu Chunping , Li Wenwei , Zhou Wen , Liu Yong , Zhou Rui , Zhang Ning 
Published: August 2014

Abstract
BACKGROUND Human xenograft tumor models established by transplantation of human tumor cell lines into immunodifficient mice have been routinely used for preclinical test of anticancer agents. But tumor cell lines have a relatively low transplantability, which resulted in a limited number of tumor models available for selection of right tumor modes for test of targeted therapeutics. Recently, we have developed a large number of patient primary ovarian tumor xenograft models by transplanting human fresh ovarian tumor tissues into nude mice, which have been employed for preclinical test of clinically used drugs and novel anticancer agents for their chemosensitivity screening. METHODS The fresh ovarian tumor samples were collected from local hospitals. The tumor fragments of 2-3 mm were subcutaneously implanted in the flanks of nude mice by trocar needle. Sixteen tumor fragments were grafted into four mice from one patient tumor tissue (passage 0). The clinically used drugs included cisplatin, carboplatin, paclitaxel, and docetaxel. The histology and gene sequence of the established primary tumor models were analyzed and compared with patients’ original tumors. RESULTS A total of 77 patients’ ovarian tumor samples were implanted into nude mice; and 38 primary tumor models have been established with a tumor taking rates of 49% for the first passage. The tumor taking rates were higher in the later passages ranged from approximately 85-100%. The therapeutic efficacy of the test anticancer drugs was consistent with their clinical findings. The patients’ primary ovarian tumor xenografts from all 5 passages retained a similarity in architecture, histopathological morphology, and genomic mutation status to their patients’ original tumors. CONCLUSIONS The patient primary tumor model system can provide a larger number of models for selection of right models for preclinical testing novel agents based on their anticancer mechanism. The primary tumor models retain a similarity in histology and genomic mutation status to their patients’ original tumors. They may predict more relevant clinical response rate and higher correlation with clinical findings than use of traditional xenograft models established from long-term cultured cancer cell lines. Especially, they have advantages for test of target-oriented therapeutics in new drugs development programs.
Citation Format: Changnian Liu, Chunping Xu, Wenwei Li, Wen Zhou, Yong Liu, Rui Zhou, Ning Zhang. Establishment of patient primary ovarian cancer xenograft models for test of anticancer agents. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 327. doi:10.1158/1538-7445.AM2013-327
Abstract 328: A p53 activating mutation accelerates the progression of high-grade serous ovarian cancer arising from the fallopian tube.
Authors: Kim Jaeyeon , Coffey Donna M. , Ma Lang , Matzuk Martin M. 
Published: August 2014

Abstract
The tumor suppressor p53 is the most frequently mutated gene in high-grade serous ovarian cancer, the deadliest subtype responsible for 70% of all ovarian cancer deaths. Yet the precise role of p53 mutation in ovarian cancer remains unknown. To address this, we have incorporated a p53 activating mutation, p53R172H, into conditional Dicer-Pten double-knockout (DKO) mice, which develop metastatic high-grade serous carcinomas originating in the fallopian tube, to generate triple-mutant (TKO) mice (p53 LSL-R172H/+ Dicer flox/flox Pten flox/flox Amhr2 cre/+). Like DKO mice, these TKO mice develop high-grade serous carcinomas aggressively metastasizing throughout the abdominal cavity, inducing ascites and causing death. These TKO mice, however, die significantly earlier than DKO mice (average survival: 7.3 (n=31) for the TKO mice vs. 9.4 (n=24) months for the DKO mice; p&lt;0.0001). Despite the overall similar extent of tumor burden and metastasis, TKO tumors appear to spread faster than DKO tumors. In TKO mice, tumor cells originating in the fallopian tube acutely penetrate the ovary, as marked by fallopian tube-specific epithelial markers, cytokeratin 14 and 17. In contrast, the ovary of DKO mice remains intact, largely free of metastasis during tumor progression. Moreover, unlike DKO ovaries, which alone fail to develop any tumors, TKO ovaries are able to initiate and develop metastatic ovarian tumors even after the fallopian tubes are removed, suggesting a tumor-initiating role of p53 mutation in the ovary. Collectively, these results thus reveal the critical role of p53 mutation in initiation and progression of ovarian cancer (Grant support: Ovarian Cancer Research Fund (OCRF); F32 National Research Service Award (NRSA)).
Citation Format: Jaeyeon Kim, Donna M. Coffey, Lang Ma, Martin M. Matzuk. A p53 activating mutation accelerates the progression of high-grade serous ovarian cancer arising from the fallopian tube. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 328. doi:10.1158/1538-7445.AM2013-328
Abstract 3293: Co-administration of lapatinib increases exposure to docetaxel but not doxorubicin in the small intestine of mice.
Authors: Hudachek Susan F. , Gustafson Daniel 
Published: August 2014

Abstract
Combination therapy is increasingly utilized for the treatment of metastatic breast cancer. However, co-administration of drugs, particularly agents that are substrates for or inhibitors of p-glycoprotein, can result in increased tissue toxicity. Unfortunately, determining levels of chemotherapeutics in human tissues is challenging and plasma drug concentrations are not always indicative of tissue toxicokinetics or toxicodynamics, especially when tissue penetration is altered.
The aim of the work presented herein was to determine if concomitant administration of compounds currently being combined in clinical trials for metastatic breast cancer treatment alters plasma and tissue pharmacokinetics in mice if both agents are p-glycoprotein substrates and/or inhibitors. Accordingly, we investigated the pharmacokinetic interactions of the classic cytotoxics and p-glycoprotein substrates docetaxel and doxorubicin when given concurrently with the targeted agent and p-glycoprotein inhibitor lapatinib.
Our time course plasma and tissue distribution studies showed that co-administration of lapatinib with doxorubicin did not appreciably alter the pharmacokinetics of this anthracycline in the plasma or six tissues evaluated in mice, presumably because, at doses relevant to human exposure, lapatinib inhibition of p-glycoprotein did not significantly alter doxorubicin transport out of these tissue compartments. However, combining lapatinib with docetaxel dramatically increased intestinal exposure to this chemotherapeutic, which has clinical implications for enhancing gastrointestinal toxicity. The significant lapatinib-docetaxel interaction is likely CYP3A4-mediated and thus, our study suggests that caution should be taken when this combination is administered, particularly to patients with compromised CYP3A activity, and recipients should be closely monitored for enhanced toxicity, particularly for adverse effects on the intestine.
Citation Format: Susan F. Hudachek, Daniel Gustafson. Co-administration of lapatinib increases exposure to docetaxel but not doxorubicin in the small intestine of mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3293. doi:10.1158/1538-7445.AM2013-3293