bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1718: Favorable clinical outcomes of pemetrexed treatment in anaplastic lymphoma kinase positive non-small-cell lung cancer patients were associated with low expression of thymidylate synthase in tumor
Authors: Lee Ha Yeon , Ahn Hee Kyung , Jeong Ji Yun , Kwon Mi Jung , Han Jung-Ho , Sun Jong-Mu , Ahn Jin Seok , Park Keunchil , Cha Joo-Young , Cho Yeoung-Mi , Choi Yoon-La , Ahn Myung-Ju 
Published: August 2012

Abstract
Introduction The purpose of this study was to investigate the clinical characteristics and treatment outcomes of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) to conventional chemotherapy in the pre-ALK inhibitor era Patients and Methods We retrospectively screened 381 consecutive NSCLC patients without known epidermal growth factor receptor (EGFR) or KRAS mutation who were diagnosed between 2007 and 2008 at a single center, and identified ALK rearrangements by fluorescence in situ hybridization Additional 44 ALK-positive patients from other period were included for the analysis of clinical outcomes Results Of the 381 tumors screened, four were excluded because the samples were unevaluable Twenty-one (5 6%) showed ALK rearrangements, with twenty adenocarcinomas and one pleomorphic carcinoma Of the entire 65 ALK-positive patients, 32 patients received pemetrexed as a second- or further-line therapy, in whom response rate was 34 4% (11/32) and median progression-free survival (PFS) was 4 0 months Among these 31 patients, 20 specimens were available for thymidylate synthase (TS) expression analysis Low expression of TS were found in 80% (16/20), with a trend toward longer PFS than TS-positive patients (median PFS 4 0 vs 1 0 months, P = 0 095) Conclusions The prevalence of ALK rearrangement was 5 6% among EGFR and/or KRAS wild-type/unknown NSCLC population Low TS protein expression might be associated with better clinical outcomes in ALK-positive NSCLC patients after pemetrexed given as a second- or further-line therapy
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1718. doi:1538-7445.AM2012-1718
Abstract 1727: Correlation between BRCA1 and LMO4 mRNA expression levels in Erlotinib-treated non small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations
Authors: Costa Carlota , Giménez-Capitán Ana , Benlloch Susana , Tarón Miquel , Jimeno José , Viteri Santiago , Gascó Amaya , Camps Carlos , Carcereny Enric , Massuti Bartomeu , Rosell Rafael 
Published: August 2012

Abstract
Background Advanced NSCLC p harboring EGFR mutations show impressive progression-free survival (PFS) when treated with erlotinib. However, presence of EGFR mutations only imperfectly predicts outcome. We demonstrated that co-existence of the EGFR T790M pretreatment mutation was detected in one-third of p and, in conjunction with elevated BRCA1 mRNA levels, dramatically influenced PFS to erlotinib. Though this model is a breakthrough in outcome of EGFR-mutated NSCLC p treated with TKIs, we choose to analyze the impact of CTIP and LMO4 gene expression levels on p outcome and their correlation with BRCA1. CtIP binds to BRCA1 and LMO4 forming a complex. LMO4 is a negative regulator of BRCA1 function in sporadic breast cancers. Methods mRNA expression of LMO4 and CTIP was examined by RT-PCR in pretreatment tumor biopsies of 72 NSCLC p with EGFR mutations treated with erlotinib. Expression levels were correlated with outcome to erlotinib and BRCA1 expression levels. Results BRCA1 significantly correlated with CtIP (r=0.31;P=0.01) and LMO4 (r=0.32;P=0.02). There was no correlation between CtIP and LMO4 (r=0.09;P=0.49).PFS was not reached for p with high levels of LMO4 vs 13 months for p with low levels (P=0.006). Overall survival (OS) was not reached for p with high levels of LMO4 vs 29 months for p with low levels (P=0.10). Expression levels of CtIP did not correlate with PFS and OS. PFS was not reached for p with low levels of BRCA1 and high levels of LMO4 vs 19 months for p with low levels of both genes (P=0.04). PFS was 8 months for p with high levels of BRCA1 and low levels of LMO4 vs 18 months for p with high levels of both genes (P=0.03). Conclusions BRCA1 and LMO4 mRNA levels examined by RT-PCR could predict PFS to erlotinib in p with EGFR mutations and could be useful for development of new therapeutic strategies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1727. doi:1538-7445.AM2012-1727
Abstract 1750: A phase 3 trial of weekly farletuzumab combined with carboplatin and taxane in subjects with platinum-sensitive ovarian cancer in first relapse
Authors: Weil Susan C. , Jenkins Michele , Hoffman Kimberly 
Published: August 2012

Abstract
Background: Ovarian cancer is the leading cause of death among women with gynecologic malignancies in North America. Despite advances in treatment, only 15%-30% of patients survive long term, underscoring the need for more effective regimens. Folate receptor ≤ (FRα) is highly expressed on all epithelial ovarian cancer (EOC) cells but largely absent from normal tissue. This study examines the efficacy and safety of farletuzumab, a monoclonal antibody that binds FRα, when combined with standard chemotherapy, in platinum-sensitive subjects with ovarian cancer after first relapse. Methods: This phase 3, randomized, double-blind, placebo-controlled trial is ongoing at 375 sites globally. Eligible subjects are β18 years of age, with a histologically confirmed diagnosis of non-mucinous EOC, including primary peritoneal and fallopian tube malignancies. Subjects must have undergone debulking surgery and achieved an objective response lasting 6-24 months following first-line platinum and taxane chemotherapy, followed by relapse confirmed by computed tomography or magnetic resonance imaging. Approximately 1080 subjects will be randomized to receive weekly intravenous farletuzumab (1.25 mg/kg or 2.5 mg/kg) or placebo, plus standard carboplatin (area under the curve [AUC] 5-6) and taxane (paclitaxel at 175 mg/m2 or docetaxel at 75 mg/m2) every 3 weeks for 6 cycles. Maintenance treatment follows, with weekly single-agent farletuzumab or placebo administered until disease progression. The primary end point is progression-free survival (PFS) based on Response Evaluation Criteria in Solid Tumors (RECIST). Secondary outcomes are overall survival, CA-125-defined PFS (based on Rustin criteria) and serologic response, best objective response and time to response, duration of first vs current remission (by RECIST), subject-reported quality of life, and resource utilization (hospitalizations, unscheduled office visits, and admissions to hospice or nursing home). Molecular markers are being sought that may be predictive of response to farletuzumab. Pharmacokinetic analysis is performed to assess interactions between agents. Safety will be evaluated by review of physical assessments, laboratory data, and adverse events; review is overseen by an independent data monitoring committee. As of November 7, 2011, 957 (of 1080 planned) subjects have enrolled in the study. The last subject will likely be enrolled by March 2012.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1750. doi:1538-7445.AM2012-1750
Abstract 1758: A podophyllotoxin derivative, Adva-27a, is more potent at killing multi-drug resistant breast cancer cells than etoposide
Authors: Young Rebecca S. , Liao Si , Slilaty Steve N. , Gal Susannah 
Published: August 2012

Abstract
A novel non-ester GEM-difluorinated C-glycoside derivative of podophyllotoxin, Adva-27a, had been designed and synthesized. The growth inhibitory properties of this drug compared to the currently used Topoisomerase II inhibitor etoposide was evaluated in MCF-7 breast cancer cells and in a multi-drug resistant (MDR) variant of this cell line. These cells were cultured in the presence of the drugs at different concentrations (0.1-100μM) for various times (1-9 days) and analyzed for viability using a mitochondrial metabolic activity dye, Alamar blue versus solvent (DMSO) treated cells. The MCF-7 cells were sensitive to Adva-27a and etoposide, resulting in an IC50 of less than 10μM for etoposide and 20μM for Adva-27a, while the IC50 for the MDR MCF-7 cells was 25μM with Adva-27a, but greater than 100μM for etoposide. The timing for killing by Adva-27a of the MDR MCF-7 cells appeared significantly different than for the MCF-7 parent cells. In this case, 100μM drug resulted in less than 50% of viability at day 3 for the MDR MCF-7 cells, while the same concentration of drug required 5-6 days to cause the same level of killing of the parent cells. To determine the mechanism of action of the drug, we analyzed the Adva-27a treated cells by flow cytometry using propidium iodide staining. We found that after 24 hours with 30μM of the drug, both MCF-7 and the MDR MCF-7 cells were accumulating in the G2/M phase of the cell cycle. Both cells are similarly killed after 7 days by this concentration of the drug. Etoposide is known to cause accumulation of cells at a similar phase, implying the Adva-27a has a similar drug target. Thus, the mechanism for the difference in sensitivity of the MDR MCF-7 cells for Adva-27a relative to etoposide is not yet understood, but will be explored in the future.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1758. doi:1538-7445.AM2012-1758
Abstract 1766: Persistence of drug-induced DNA interstrand cross-links distinguishes bendamustine from conventional DNA cross-linking agents
Authors: Bagnobianchi Alessia , Spanswick Victoria J. , Bingham John P. , Kiakos Konstantinos , Suarez-Henriques Paula , Smith Dean , Yong Kwee , Hochhauser Daniel , Hartley John A. 
Published: August 2012

Abstract
Bendamustine has demonstrated substantial clinical efficacy in the treatment of hematologic malignancies and continues to distinguish itself from other alkylating agents. The mechanistic and clinical differences associated with bendamustine may be directly related to its unique structural features, although the precise mechanism of action is still poorly understood. We have undertaken a detailed study of the drug-DNA interactions of bendamustine. It alkylates DNA primarily at guanine-N7 positions with a sequence selectivity similar to other nitrogen mustards. It produces DNA interstrand cross-links (ICLs) in both solid tumor and hematological tumor cells at doses that cause growth inhibition. ICLs peak at 8h following a 1h treatment and persist over 48h in tumor cells including those that are proficient at repairing (unhooking) ICLs formed by melphalan or cisplatin. This persistence of ICLs is also observed in multiple myeloma cells from patients who have relapsed on melphalan therapy and which efficiently repair melphalan-induced ICLs compared to cells from treatment naive patients. The peak γ-H2AX response follows the ICL peak and also persists beyond 48h. Cells defective in ICL unhooking proteins ERCC1 and XPF, or defective in homologous recombination repair, show increased sensitivity to bendamustine, but at a level less than observed for other nitrogen mustards or cisplatin. Real time PCR profiling showed that at equivalent peak levels of DNA ICLs bendamustine induced fewer changes in DNA damage signaling and DNA repair gene expression compared to either cisplatin or melphalan. These data suggest that the critical DNA damage produced by bendamustine induces a different signaling and repair response to conventional cross-linking agents, including other nitrogen mustards, which may be an important contribution to its clinical efficacy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1766. doi:1538-7445.AM2012-1766
Abstract 1769: Significant in vivo activity of an APE1/Ref-1 redox inhibitor, E3330, alone and in combination with Bevacizumab in a glioblastoma mouse model analyzed by a whole slide digital imaging system and quantitative immunohistochemistry
Authors: Kumar Krishan , Jackson Jessica L. , Kelley Mark R. , Ivan Mircea , Sandsuky George 
Published: August 2012

Abstract
Human apurinic endonuclease/redox factor 1 (APE1/Ref-1) mediates the repair of baseless sites in DNA caused by alkylation and oxidative DNA damage as well as regulates the function of various transcription factors (TF) under redox signaling control (p53, NFkB, HIF-1, AP-1, and others). High levels of APE1 expression have been reported in numerous cancers (glioblastoma, ovarian, pancreatic, prostate, and others) such that APE1 is an emerging target for a variety of novel anticancer drugs. E3330 targets the redox signaling function of APE1 and its activity was studied in vivo using a glioblastoma xenograft mouse model. This preclinical xenograft model evaluated the use of dual anti-angiogenic agents, Bevacizumab (Bev) and E3330, in glioblastoma implanted Nude mice. Four mice groups were used to determine drug effects: E3330, Bev, a combination of E3330 and Bev, and an untreated vehicle control group. Immunohistochemistry (IHC) was used to predict the effectiveness of treatment for glioblastoma based on caspase-3, Ki67, and CD31 biomarker expression. IHC slides were quantified using both a traditional pathology hand count and an image system analysis. The positive pixel data closely mirrored the hand count for all three biomarkers. At the combined dosage, hand count data demonstrated that CD31 levels decreased significantly from the vehicle control group. Ki67 decreased slightly, and caspase-3 was not increased in any of the drug treatment groups. While each drug independently had anti-angiogenic effects, the combined drug group, E3330 and Bev, had anti-angiogenic effects that were greatly enhanced. These results support previous studies demonstrating the anti-angiogenic activity of E3330 and its enhancement of Bevacizumab.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1769. doi:1538-7445.AM2012-1769
Abstract 1776: Antitumor activity of Chk1 inhibitor LY2606368 as a single agent in SW1990 human pancreas orthotopic tumor model
Authors: Wu Wenjuan , Bi Chen , Bence Aimee K. , Um Suzane L. , Yan Betty , Starling James J. , Marshall Mark S. , Beckmann Richard P. 
Published: August 2012

Abstract
ChK1 is a key kinase in the DNA damage response signaling network, including cell cycle checkpoints, DNA repair, apoptosis and transcription, thus emerging as an attractive target in anti-cancer therapy. LY2606368, a potent and selective ATP competitive inhibitor of the Chk1 protein kinase, is currently in clinical development. LY2606368 has been reported to inhibit Chk1 auto-phosphorylation activated by DNA damaging agents, and induce phosphorylation of H2AX, a DNA damage maker in multiple cancer cell lines in vitro. In addition, LY2606368 has demonstrated potent single agent activity and potentiates the anti-tumor activity of DNA damaging agents in vivo. Pancreatic cancer is one of the least curable cancers, with an approximate 5% overall 5-year survival for all patients. In the current study, we evaluated the efficacy of LY2606368 (as its methanesulfonate salt, hydrate; LY2606368.MeSO3H.H2O = LY2940930) in pancreatic cancer cell lines in vitro and xenograft tumors (including subcutaneous and orthotopic models) in vivo. LY2606368 alone significantly inhibited the cell proliferation in a variety of pancreatic cell lines (SW1990, SU86.86, Bx-PC3, AsPC-1, CFPAC-1, Capan-2, HPAF-II) with SW1990 being the most sensitive (IC50=1.5 nM). In SW1990 subcutaneous xenograft model, LY2606368 showed substantial dose-dependent inhibition of tumor growth. In SW1990 pancreas orthotopic model, which represents the local and metastatic growth pattern seen in pancreas cancer patients, LY2606368 treatment resulted in over 92% inhibition of primary tumor growth as well as 100% inhibition of metastasis to lymph node, spleen and intestine. The anti-tumor effect of LY2606368 treatment was further demonstrated in comparing with gemcitabine (the standard of care for pancreas cancer patient) in SW1990 orthotopic model. The anti-tumor and/or anti-metastasis mechanism of LY2606368 was also investigated, including phosphorylation of H2AX, cell proliferation, cell survival, and soft agar anchorage-independent growth. Together, our findings demonstrate the therapeutic potential of LY2606368 as a single agent in the treatment of pancreatic cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1776. doi:1538-7445.AM2012-1776
Abstract 1796: SAR302503: A Jak2 inhibitor with antitumor activity in solid tumor models
Authors: Greco Rita , Hurley Raelene , Sun Fangxian , Yang Lu , Yu Qunyan , Williams Juliet , Dorsch Marion , Cohen Pamela , Adrián Francisco 
Published: August 2012

Abstract
Numerous studies have recognized the critical role of STAT3 in malignant transformation and tumor progression. Constitutive STAT3 activation is frequently found in cancer cell lines and tumor samples and it is usually linked to the presence of IL-6. Autocrine or paracrine IL-6 loops have been described to provide tumor cells with the ability to proliferate, survive, migrate and metastasize. At the molecular level, IL-6 binding to its receptor results in activation of Jak/STAT3 signaling and other signaling cascades, namely PI3K/Akt, MEK/ERK1-2, with a well established role in cancer. We have evaluated the ability of SAR302503, a selective Jak2 inhibitor entering a PhIII clinical trial in myelofibrosis patients, to block these pathways in a panel of ∼20 tumor cell lines representing different cancer types (prostate, breast, lung, colorectal, pancreas, hepatocellular, etc). A 45 minutes treatment with different concentrations of SAR302503 (0.1-10 µM) was sufficient to block both basal or IL-6 induced STAT3 phosphorylation in a dose dependent manner. Compound concentrations equal or greater than 0.1 µM were able to reduce the phosphorylation levels of STAT3 by an extent greater than 50% in all the cell lines included in the study. The impact of SAR302503 in tumor cell proliferation and survival was evaluated using different assays including clonogenic assays. Complete inhibition of colony formation was achieved at concentrations of SAR302503 below 1 µM in most of the cell lines. The antitumor activity of SAR302503 was evaluated in mice xenotransplanted subcutaneously with DU145 human prostate cancer cells. Oral administration of SAR302503 for 10 days resulted in significant dose dependent tumor growth inhibition, near to stasis at the highest dose (T/C=19% at 100 mg/kg, bid). In summary, we demonstrate that SAR302503 negatively impacts the proliferation and survival of different solid tumor cells and our data supports a role for a selective Jak2 inhibition in treating solid tumors with activated Jak/STAT signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1796. doi:1538-7445.AM2012-1796
Abstract 1797: Preclinical evaluation of HM-018, a potent and selective JAK inhibitor in the treatment of myloproliferative disorders
Authors: Ren Yongxin , Deng Wei , Gu Weihua , Shen Wuzhong , Yu Youjun , Yang Xiaoning , Zhang Zhixiang , Fan Shiming , Sai Yang , Wang Jian , Yan James , Li Jia , Zhao Helen , Qing Weiguo , Su Weiguo 
Published: August 2012

Abstract
JAK2 kinase mutation V617F is prevalent in myeloproliferative diseases (MPD), including polycythemia vera (PV, 81-99%), essential thrombocytosis (ET, 41-72%) and primary myelofibrosis (PMF, 39-57%). This point mutation constitutively activates the JAK kinase and leads to oncogenic potential of host cells, and thus making JAK2 a promising molecular target for MPD therapy. HM-018 is a small molecule inhibitor against JAK kinase and the compound's preclinical anti-MPD effects from signal transduction to biological consequences were investigated. HM-018 was found to inhibit JAK kinase 1, 2, 3 and TYK with IC50 of 0.010, 0.006, 0.040 and 0.047 μM, respectively. The compound demonstrated &gt;100 folds selectivity against a panel of 63 kinases. In accordance with enzymatic activity, HM-018 suppressed ligand dependent or constitutive JAK activation in multiple cell lines as evidenced by the decrease of STAT3/5 phosphorylation. As a result, JAK dependent cell proliferation was significantly inhibited by HM-018. EPO-mediated mouse PV model was utilized to evaluate the in vivo efficacy of the compound. HM-018 could shrink enlarged mouse spleen, a typical symptom of PV, in a dose dependent manner accompanied with decreased STAT5 phosphorylation both in animal spleen and in bone marrow after oral dosing for 7 days. To better mimic MPD development in a more clinically-relevant manner, JAK2-V617F-tranfected 32D cells were injected into mice intravenously, and it was observed that oral treatment of HM-018 not only prolonged the animal's life span, but also reduced MPD-related symptoms, such as spleen weight increase and organ invasion by malignant cells. Meanwhile, HM-018 exhibited a favorable pharmacokinetic profile and acceptable safety window in rats. Based on the preclinical data, HM-018 demonstrated anti-MPD potency both in vitro and in vivo, and the studies have provided rationale to further develop this compound as possible MPD therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1797. doi:1538-7445.AM2012-1797