bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-257: c-Met: a new cancer stem cell marker and therapeutic target for pancreatic cancer
Authors: Li Chenwei , Hynes Mark , Dosch Joseph , Wu Jing-Jiang , Sarkar Bedabrata , di Magliano Marina Pasca , Simeone Diane M. 
Published: February 2011

Abstract
Pancreatic adenocarcinoma is a highly aggressive disease which is usually diagnosed in an advanced state and for which there are little/no effective therapies. The growth of many cancers depends on a subpopulation of self-renewing cells, termed cancer stem cells (CSC). We have previously identified such a CSC population in human pancreatic cancers which possess the cell surface marker phenotype CD44+CD24+ESA+. C-Met, a member of the receptor tyrosine kinases (RTKs) family and receptor for the hepatocyte growth factor (HGF) ligand, has been recently described as a marker of normal mouse pancreatic stem/progenitor cells. We hypothesized that c-Met may function as a cell surface marker and therapeutic target for human pancreatic CSCs. Studies were performed in low passage primary human pancreatic adenocarcinoma xenografts (n = 3) established in NOD-SCID mice. Self-renewal capacity of c-Methigh pancreatic cancer cells was assessed using in vitro sphere assays and in vivo tumorigenicity of c-Methigh pancreatic cancer cells was evaluated by cell implantation in NOD/SCID mice. In vitro studies demonstrated that c-Methigh cells formed spheres in non-adherent cultures, while c-Met− cells did not. Use of the c-Met inhibitor XL184 or c-Met knockdown with shRNA significantly inhibited tumor sphere formation. Pancreatic cancer cells expressing high c-Met had increased tumorigenic potential in vivo and cells expressing both CD44 and c-Methigh, representing 0.5-5% of pancreatic cancer cells, demonstrated the highest tumorigenic potential of all populations studied to date. C-Methigh CD44+ expressing pancreatic cancer cells demonstrated the capacity for self-renewal and production of differentiated progeny, properties that define CSCs. Further, c-Met inhibition of established primary human pancreatic tumors in NOD/SCID mice significantly inhibited tumor growth and depleted the pancreatic CSC population, when used alone or in combination with gemcitabine. Inhibition of c-Met also prevented the developmental of metastases using an intracardiac injection model. In this report, we define c-Met as a new marker for pancreatic CSC and define c-MethighCD44+ cells as a highly tumorigenic pancreatic CSC population. Our data also indicate that targeting c-Met may be useful in eradicating a CSC population and inhibiting the development of metastases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-257.
Abstract LB-26: Translational up-regulation of Aurora-A in EGFR-expressed cancer
Authors: Hung Liang-Yi 
Published: February 2011

Abstract
Abnormal expression of Aurora-A and EGFR is observed in different kinds of cancer and associated with poor prognosis in cancer patients. However, the relationship between Aurora-A and EGFR in tumor development was not clear. In previously report (Nucleic Acids Res, 2008, 36:4337-4351), we found EGFR translocates to nucleic to activate Aurora-A expression after EGF treatment in EGFR-overexpressed cells. However, we also observed that not all the EGFR-overexpressed cells have the nuclear EGFR pathway to mediate the Aurora-A expression. In this study, we demonstrated that EGF signaling increased the Aurora-A protein expression in EGFR-overexpressed colorectal cancer cell lines via increasing the translational efficiency. In addition, the overexpression of EGFR was also associated with higher expression of Aurora-A in clinical colorectal samples. Activation of the PI3K/Akt/mTOR and MEK/ERK pathways mediated the effect of EGF induced translational up-regulation. Besides, only the splicing variants containing exon 2 of Aurora-A mRNA showed increased interaction with the translational complex to synthesize Aurora-A protein under EGF stimulus. Besides, the exon 2 containing splicing variants were the major Aurora-A splicing form expressed in human colorectal cancers. Taken together, our results propose a novel regulatory mechanism for the abnormal expression of Aurora-A in EGFR-overexpressed cancers, and highlight the importance of alternative 5′-UTR splicing variants in regulating Aurora-A expression. Furthermore, the specific expression of exon 2 containing splicing variants in cancer tissues may serve as a potential target for cancer therapy in the future.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-26.
Abstract LB-261: Cancer stem cell characteristics exhibited by doxorubicin-selected drug-resistant breast cancer cells
Authors: Calcagno Anna Maria , Salcido Crystal D. , Gillet Jean-Pierre , Wu Chung-Pu , Fostel Jennifer M. , Mumau Melanie , Gottesman Michael M. , Varticovski Lyuba , Ambudkar Suresh V. 
Published: February 2011

Abstract
Background: Cancer stem cells (CSCs) are presumed to possess the virtually unlimited ability to proliferate while preserving self-renewal. These cells are also highly resistant to chemotherapeutics, a feature which correlates with overexpression of ATP-binding cassette (ABC) transporters. No reports to our knowledge have shown that prolonged continuous selection of cells for drug resistance enriches cancer stem-like cells.
Methods: We examined parental and drug-selected breast cancer cell lines to determine whether there is a relationship between drug resistance and the presence of cells with a CSC phenotype. MCF-7/ADR cells, generated from weakly tumorigenic parental MCF7 cells by continuous exposure to increasing concentrations of doxorubicin, were examined by microarray analysis, flow cytometry, invasion, in vivo tumorigenicity and other CSC characteristics. The putative CSC population was also examined for expression of multidrug resistance (MDR) genes using TaqMan Low Density Arrays.
Results: Pathway analysis showed that MCF-7/ADR cells express ABCB1 as well as genes with patterns similar to breast CSCs. MCF-7/ADR cells grow in 3D cultures as mammospheres, are highly invasive and tumorigenic. In contrast to parental cells, over 30% of MCF-7/ADR cells are CD44+/CD24-. The CD44+/CD24- cells have the ability to self-renew and overexpress many MDR genes when compared to the CD44+/CD24+ population. No enrichment in CD44+/CD24- or CD133+ populations was detected in MCF-7/MDR or other cells with forced expression of the ABCB1 transporter or MDR genes.
Conclusions: Cells with characteristics of CSCs increased in number following selection for doxorubicin resistance. Based on our findings, we speculate that prolonged drug treatment in vivo may result in expansion of a CSC-like population.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-261.
Abstract LB-281: Inhibition of Hedgehog results in altered regulation of c-jun and of ERCC1 in cisplatin-resistant A2780-CP70 human ovarian cancer cells
Authors: Kudo Kenji , Gavin Elaine , Das Shamik , Denny Wesley , Jasmin Martine , Shevde-Samant Lalita , Reed Eddie 
Published: February 2011

Abstract
Cancer stem cells are presumed to be highly resistant to chemotherapy. Activation of the Hedgehog pathway has been reported as necessary, for the cancer stem cell state. A key gene in the Hedgehog pathway is Gli1. Resistance to platinum compounds is due in part, to up-regulated nucleotide excision repair, NER. ERCC1 is a key marker for NER activity. Transcriptional control of ERCC1 occurs in part, through c-Jun. Upon treatment with cisplatin, cisplatin-resistant A2780-CP70 cells normally up-regulate c-jun and c-fos, which then up-regulate ERCC1 and other NER genes. More specifically, the c-jun Ser63/73 cascade is up-regulated, with up-regulation of activator protein 1 (Reed, JBC 1998). We studied the relationship between Gli1 expression, ERCC1 expression, and cisplatin resistance in the human ovarian cancer cell lines A2780 and A2780-CP70. A2780-CP70 cells are 10-15 fold more resistant to cisplatin than A2780 cells. We used two different probes to modulate the Hedgehog pathway: a) cyclopamine as a pharmacologic inhibitor of the Smoothened; and, b) an anti-Gli1 shRNA to specifically inhibit Gli1. At baseline, cisplatin-resistant cells, expressed &gt; 10-fold more Gli1 protein than cisplatin-sensitive cells. In cisplatin-resistant cells, Gli1 protein was down-regulated in response to cyclopamine, and to anti-Gli1 shRNA. When A2780-CP70 cisplatin-resistant cells are pretreated with cyclopamine, or anti-Gli1 shRNA, the following events occur. The c-jun Thr91/93 cascade is upregulated, which is associated with pro-apoptotic processes. The c-jun Ser63/73 cascade is suppressed. This cascade is associated with pro-growth processes. If cisplatin is given after cyclopamine or anti-Gli1 pretreatment; Gli1 protein is down-regulated; the c-jun Thr91/93 cascade is upregulated; the c-jun Ser63/73 cascade is suppressed; and cells do not up-regulate ERCC1, XPD, or XRCC1. Thus, the normal cisplatin-induced up-regulation of these three genes involved in NER (ERCC1, XPD) and in base excision repair (XRCC1), is suppressed by suppression of the Hedgehog pathway. We conclude that Gli1 and/or other genes involved in the Hedgehog pathway (which is critical for cancer stem cells), may play key roles in the up-regulation of DNA repair genes, specifically in response to DNA damaging agents such as cisplatin.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-281.
Abstract LB-285: Pharmacogenomic study to improve sorafenib response in hepatocellular carcinoma
Authors: Kassner Michelle , Kiefer Jeff , Tang Nanyun , Barrett Michael , Han Haiyong , Von Hoff Daniel , Borad Mitesh , Yin Holly 
Published: February 2011

Abstract
Hepatocellular carcinoma (HCC), the primary malignancy of the liver, is the fourth leading cause of cancer deaths worldwide, with a 5-year survival rate of∼10%. Recently, a new multikinase inhibitor, sorafenib (Nexavar®), which mainly targets the VEGFR and the Raf/Mek/Erk pathways, has shown limited response rate and modest survival benefits in patients with advanced stage HCC. We hypothesize that there exist genetic alterations or contexts of vulnerability (COV) in cancer cells that dictate sensitivity to sorafenib. In order to identify specific COVs and obtain an increased understanding of drug's mechanism of action, we performed a custom chemosensitization high-throughput siRNA screen. We developed and optimized a sorafenib chemosensitization assay in 3 HCC cell lines, one of which, Hep3B, a AFP and HBsAg positive cell line, was selected for primary RNAi screening with a kinase siRNA library, which covers 700 genes (4 siRNA sequences per gene). Primary screen data was rigorously evaluated for multiple quality control metrics (transfection efficiency, CV values, accessing plate-to-plate and set-to-set variation) and found to exceed all expected performance parameters. The top sorefenib sensitizing hits were identified and supplemented with additional genes selected based on related biological concepts. This sensitization effect of the genes was further tested and compared in two additional HCC cell lines (HepG2 and PLC). Additionally, based on the sensitizer list from the RNAi screening, 11 chemical compounds were tested for synergistic combination with sorafenib. Notable synergism with sorafenib was observed in the combination with erlotinib or doxorubicin. More strikingly, we also observed synergy between sorafenib and multiple MEK inhibitors as well as gemcitabine in the selected HCC cell lines. Our data suggest that MEK inhibitors might improve the efficacy of sorafenib in HCC treatment in the clinic. Further mechanistic studies are being conducted for this particular combination.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-285.
Abstract LB-294: Development and characterization of novel orally available hypoxia-inducible factor (HIF) signaling inhibitors as dual-mechanism cancer therapeutics
Authors: Schultes Christoph , Alonso Jorge , Encinas-Lopez Arantxa , Leber Blanka , Mülbaier Marcel , Wawro Sabine , Janssen Bernd , Lewis Joe 
Published: February 2011

Abstract
The HIF signaling pathway is a crucial way in which tumors can circumvent the constraints of regions of low oxygen (hypoxia) to induce angiogenesis and maintain proliferation. The oxygen regulated subunit of the transcription factor hypoxia-inducible factor 1 (HIF1), HIF1αlpha, is a positive factor in tumor growth and its expression has been correlated with poor patient prognosis in a number of settings.
We here present in vitro and in vivo data for a novel series of orally available small-molecule HIF signaling modulators that show nanomolar inhibition of the HIF signaling pathway in addition to potent anti-proliferative activity against a large number of cell lines derived from solid and blood tumors (EC50 in the range 1-100nM). Phenotypically, the compounds elicit an initial G2/M arrest, followed by the induction of caspase-3/7 and the onset of apoptosis.
The in vitro results also translate into in vivo animal models. The lead compounds from the series show efficacy in tumor xenograft mouse models, with dose-dependent tumor growth inhibition of 60-70% after oral dosing (MDA-MB-231 xenograft). Structural optimisation has additionally allowed us to improve the PK and physicochemical characteristics of the compounds, with a lead candidate currently in formal pre-clinical development with the aim of entering a Phase 1 clinical trial in multiple myeloma at the end of 2010.
In conclusion, we believe that the development towards clinical Proof-of-Concept of this new class of dual-mechanism inhibitors of HIF signaling and cell proliferation presents a promising new option for cancer therapeutics.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-294.
Abstract LB-302: Activity of PF-04691502, A dual PI3K/mTOR inhibitor in breast cancer cell lines and models discriminates between ER, PR and HER2 positive and negative segments
Authors: Yuan Jing , Van Lee Nathan , Pavlicek Adam , Ching Keith , Cao Joan , Garza Scott , Hook Kenneth E. , Ozeck Mark , Marx Matthew A. , Christensen James G. , Kan Julie L.C. 
Published: February 2011

Abstract
The PI3K pathway plays a role in key cellular functions that include regulation of cell growth, proliferation, survival, angiogenesis, and motility. PI3K/AKT pathway aberrations are common in cancer comprising PTEN loss of function through mutations, deletion, and methylation events and gain of function at the PIK3CA locus including mutations and amplification events resulting in deregulation of this pathway. Thus, pharmacological intervention of this pathway should impact cellular functions central to survival of cancer cells. PIK3CA mutations/amplification and PTEN loss of heterozygosity have been reported to occur in approximately 35-40% and 20% of breast cancer, respectively and suggest this patient population could benefit from treatment using a small molecule inhibitor that targets the PI3K pathway. PF-04691502 which is a potent inhibitor of all PI3K isoforms and mTOR (TORC1 and TORC2) presently in Phase 1 trials was evaluated for its growth inhibitory or cytoreductive activity over a panel of 30 breast cancer cell lines. PF-04691502 had robust &lt;300nM (IC50%) antiproliferative activity across the panel of breast cell lines. We observed a trend whereby cell lines that were hormone receptor (ER and/or PR) and HER2 negative (triple negative) were least sensitive and cell lines that were HER2(+) and/or hormone receptor positive (ER and/or PR) were more sensitive to PF-04691502. These studies were extended in vivo with PF-04691502 as a single agent and in combination in a HER2, ER and PR positive xenograft model with robust tumor growth inhibition in combination with docetaxel or with the pan-HER inhibitor, PF-00299804. In a xenograft that was triple negative, administration of single agent PF-4691502 at the MTD resulted in 60% tumor growth inhibition. In conclusion, our findings suggest that the ER/PR and/or HER2 positive breast cancer segment may particularly benefit from PI3K/mTOR inhibitor based treatment regimens.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-302.
Abstract LB-314: Patients with inflammatory breast cancer have significant reductions in immune cells responsible for adaptive immunity
Authors: Lee Bang-Ning , Gao Hui , Cohen Evan N. , Andreopoulou Eleni , Jackson Summer A. , Parker Charla , Tin Sanda , Galland Matthew , Ueno Naoto , Valero Vicente , Alvarez Ricardo H. , Cristofanilli Massimo , Reuben James M. 
Published: February 2011

Abstract
Background: Cell-mediated immunity is essential for maintaining immune surveillance against tumor progression. Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer, yet there is a paucity of information on peripheral blood leukocyte immunophenotypes of these patients. Therefore, we enumerated the immune cells of IBC patients with or without metastasis.
Methods: This ongoing prospective study consists of 43 IBC patients, 22 with non-metastatic IBC and 21 with metastatic disease (MIBC). Peripheral blood was collected prior to starting a new therapy and analyzed to determine the immunophenotype of T cells, B cells, regulatory T (TR) cells, natural killer cells (NK), and dendritic cells (DC) by 6-color flow cytometry. The Kruskal-Wallis and Mann-Whitney U tests were used to determine the differences between healthy donors (HD, N=15), non-metastatic IBC and MIBC patients.
Results: Among the 43 IBC patients, 22 are hormonal receptor (HR)+ with 11 HER-2+, 8 are HR- but HER2+, and 13 are triple receptor negative. Non-metastatic IBC patients have significantly lower median percentages (%) of lymphocytes (P=0.018), B cells (P=0.028), and myeloid DC (P=0.049), and higher median % TR cells (P=0.039) when compared with those of HD. In addition, non-metastatic IBC patients have significantly lower median counts of B cells (P=0.003), myeloid DC (P=0.009), and plasmacytoid DC (P=0.037) when compared with those of HD. Moreover, compared with non-metastatic IBC patients, MIBC patients were significantly older (P=0.029) and have significantly lower median % and absolute counts of lymphocyte and B cells (all P&lt;0.02), lower median ratio of CD4+/CD8+ T cells (P=0.028), and lower median number of TR cells (P=0.013).
Conclusion: This preliminary cross-sectional analysis suggests that non-metastatic IBC patients have significant reductions in various effector cells, in particular, B-cells and antigen-presenting DC that may lead to compromised adaptive immunity. Moreover, metastatic IBC patients are more immunocompromised than non-metastatic IBC patients. Longitudinal study is warranted to further assess the role of humoral and cell-mediated immunity in the pathogenesis of IBC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-314.
Abstract LB-321: Changing the route of immunization determines outcome in immunotherapy of experimental brain tumors: Translation in development
Authors: Darabi Anna C. , Sande'n Emma , Eberstål Sofia , Janelidze Shorena , Visse Edward , Siesjö Peter 
Published: February 2011

Abstract
Introduction: Based on our previous experimental result we have performed a clinical trial at the Lund University Hospital, with immunotherapy using IFN transduced autologous tumor cells for intradermal (i.d.) immunizations in adult patients with glioblastoma multiforme. Eight patients have been treated with an increase in overall survival by more than six months as compared to age-matched controls. The trial has shown that the therapy has no side effects and that an immune activation can be detected. Current experimental results show that by changing the route of immunization from i.d. to sub-cutaneous (s.c.) immunization, a substantial increase in survival time of animals is seen. The mechanisms behind this are now under investigation.
Experimental Procedures: We are currently investigating the therapeutic efficacy of i.d. or s.c. administerd IFN transduced irradiated tumor cells (N32-IFNγ) against intra cerebral tumors in the rat glioma model (N32) syngeneic with the Fisher 344 rat. The rats are immunized day 1, 15 and day 29 after tumor inoculation. The induction of the immune response is studied by tracing irradiated CFDA-SE stained tumor cells from the immunization site (i.d. or s.c.) to secondary lymphoid organs using immuno-histochemistry. The immune response is studied at different time-points after the first and after the third immunization.
Preliminary Results: S.c. immunization with N32-IFNγ cured 53% of the tumor bearing animals compared to i.d. immunization where only 6% of the rats survived for 100 days, when the study was finalized. After the first immunization, tumor cell debris can be traced to inguinal lymph nodes of i.d. immunized animals, but not of s.c. immunized animals. After the third immunization tumor debris is found in inguinal lymph nodes both after i.d. and s.c. immunization. No other secondary lymphoid tissues tested contain tumor debris. Mononuclear phagocytes expressing MHC class II are responsible for engulfing tumor cells at the immunization site of both i.d. and s.c. immunized animals. Cells that strongly express the enzyme cyclooxygenase-2, the rate-limiting enzyme for production of prostaglandine E2, are seen after s.c. immunization but not after i.d. immunization. Further studies are ongoing to reveal possible differences in kinetics and antigen presenting cells.
Conclusions: To our knowledge, no systematic comparison has been performed between different immunization routes using whole tumor cells as immunogen. If these results are further confirmed, the route of immunization will be altered from i.d. to s.c. in future clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-321.