bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C118: Influence of CYP2D6 phenotype on tamoxifen-treatment outcome in women with metastatic breast cancer
Authors: Lammers Laureen A. , Mathijssen Ron H.J. , van Gelder Teun , Bijl Monique J. , de Graan Anne-Joy M. , Seynaeve Caroline , van Fessem Marianne , Berns Els M. , Vulto Arnold G. , van Schaik Ron H. 
Published: June 2012

Abstract
Introduction: Cytochrome P450 2D6 (CYP2D6) plays a crucial role in the metabolism of tamoxifen into the active metabolite endoxifen. Genetic variation in the CYP2D6 gene and co-administration of CYP2D6 inhibiting medication markedly reduce endoxifen plasma concentrations in patients. The impact hereof on the outcome of tamoxifen therapy in metastatic breast cancer is insufficiently known. In this cohort study, we examined the effect of CYP2D6 predicted phenotype (the combined effect of genetic variants and concomitant use of CYP2D6 inhibiting medication) on time to progression (TTP) and overall survival (OS) in women using tamoxifen for metastatic breast cancer was examined.
Methods: We selected patients treated with tamoxifen (40mg/day) for hormone receptor positive metastatic breast cancer of whom blood samples for pharmacogenetic analysis (CYP2D6*3,*4,*5,*6) were available. Patient charts were reviewed to assess patient and tumor characteristics, TTP, OS, and use of CYP2D6 inhibitors.
Results: Patients with poor CYP2D6 metabolizer phenotype (PMs) had a worse OS compared to extensive metabolizers (EMs) (HR = 2.11; P=0.031; 95% CI: 1.07–4.15, see Table). Patients with an intermediate (IM) and extensive metabolizer (EM) phenotype had comparable TTP and OS, and were further considered as one group in the Kaplan-Meier estimates. For PMs, the Kaplan-Meier estimate demonstrated a shorter TTP compared to the combined group of IMs and EMs: 1.7 years (95% CI: 0.9–2.5) versus 2.9 years (95% CI: 2.3 – 3.6) respectively (P = 0.089). Overall survival of the group of IM/EM patients was significantly longer than for PM patients, being 9.9 years (95% CI: 8.2–11.6) versus 5.4 years (95% CI: 3.7–7.1), respectively (P=0.012). Co-administration of CYP2D6 inhibitors alone was also associated with a worse OS (HR=3.55; P=0.002; 95% CI: 1.59–7.96) and a worse TTP (HR=2.97; P=0.008; 95% CI: 1.33–6.67) compared to patients without CYP2D6 inhibitors.
Conclusions: CYP2D6 phenotype is an important predictor of treatment outcome in women treated with tamoxifen for hormone receptor positive metastatic breast cancer. Co-administration of CYP2D6 inhibitors worsens outcome of tamoxifen therapy, and should therefore be discouraged.
Effect of CYP2D6 phenotype on TTP and OS CYP2D6 phenotype Time to progression (TTP) Overall Survival(OS) Cases (n=99) Cases (n=99) HR (95% CI) HR (95% CI) P-value P-value EM n=50 n=33 HR=1.00 (ref) HR=1.00 (ref) IM n=36 n=22 HR=1.05 (0.67–1.65) HR=0.88 (0.51–1.53) P=0.82 P=0.66 PM n=13 n=12 HR=1.74 (0.92–3.28) HR=2.11 (1.07–4.15) P=0.09 P=0.03
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C118.
Abstract C12: Preclinical characterization of a novel FLIP-targeted antisense phosphorothioate oligonucleotide
Authors: Logan Andrew E. , Wilson Timothy R. , Johnston Patrick G. , Longley Daniel B. 
Published: June 2012

Abstract
FLIP (FLICE-inhibitory protein) is a major inhibitor of death receptor-mediated activation of caspase 8 (FLICE, Fas-associated death domain-like interleukin-1 -converting enzyme). We have previously found that FLIP is not only a key regulator of death receptor-mediated apoptosis, but also inhibits chemotherapy-induced apoptosis in several cancers. Furthermore, we found that silencing FLIP expression using siRNA approaches was in itself sufficient to induce apoptosis in several different cancer models. These results suggest that FLIP is a promising therapeutic target in several cancers. In this study, we describe the pre-clinical characterisation of a novel FLIP-targeted antisense phosphorothioate oligonucleotide (AS PTO). Of 5 potential sequences identified, one AS PTO potently down-regulated FLIP. Down-regulation of FLIP by this AS PTO resulted in caspase 8 activation and apoptosis induction in non-small cell lung (NSCLC), colorectal and prostate cancer cell lines. Furthermore, the FLIP AS PTO sensitized cancer cells to apoptosis induced by the clinically relevant death ligand TRAIL (TNF-related apoptosis-inducing ligand). Moreover, the FLIP AS PTO also sensitized NSCLC cells to apoptosis induced by the chemotherapeutic agents cisplatin and taxol. Importantly, compared to a control non-targeted PTO, the FLIP-targeted AS PTO demonstrated in vivo antitumor activity against NSCLC xenografts and enhanced the antitumor effects of cisplatin. In summary, we have identified a novel FLIP-targeted AS PTO that has in vitro and in vivo activity and which may therefore have potential for clinical development.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C12.
Abstract C126: Exposure-response (E-R) relationship in ABT-263-induced thrombocytopenia and the effect of platelet transfusion in dogs
Authors: Xiong Hao , Noertersheuser Peter A. , Pradhan Rajendra S. , Mittelstadt Scott W. , Marsh Kennan C. , Humerickhouse Rod A. , Awni Walid M. 
Published: June 2012

Abstract
Background: Thrombocytopenia is the most prominent dose-limiting toxicity in animals and humans following ABT-263 administration. ABT-263 induces apoptosis, rather than lysis, of circulating platelets resulting in premature platelet senescence. This differs from typical chemotherapy induced thrombocytopenia, which is related to myelosuppression. Bcl-XL is believed to play a key role in the thrombocytopenia induced by ABT-263. Platelet transfusion has been widely adopted in clinical practice when platelet count drops below 10,000/ L. The effect of platelet transfusions on circulating platelet levels have been examined in four studies in dogs.
Methods: Pharmacokinetic (PK) and pharmacodynamic (PD) data from a total of 76 dogs from the four studies were analyzed sequentially. First, ABT-263 plasma concentration data in dogs were described using a two-compartment model with first-order absorption (for oral dosing only) and elimination. Then, the time courses of circulating platelet levels were described using a semi-physiological model. The model includes a progenitor compartment for proliferating blood cells linked to a series of three compartments representing the maturation chain in the bone marrow and the central circulation compartment. A feedback system is included in the model to allow the system to respond to disturbances in the platelet concentrations. It is assumed that ABT-263 increases the degradation rate of circulating platelets in a concentration-dependent manner.
Results: The medians of the E-R model parameters were comparable among the studies, indicating that the E-R relationships between ABT-263 concentrations and platelet response are consistent across all four studies in dogs. Simulations using the model further supported that platelet transfusion is an effective rescue method for low platelet counts caused by ABT-263 treatment both at clinically-relevant ABT-263 concentrations (∼4 g/mL) and at the higher ABT-263 concentrations (7 g/mL) in dogs. The effects of platelet transfusion were smaller and more transient when the transfusion was administered at higher ABT-263 concentrations (7 g/mL) compared to those administered at lower ABT-263 concentrations (∼4 g/mL). Multiple transfusions are expected to produce larger and more prolonged effects on circulating platelet levels than a single transfusion.
Conclusion: Thrombocytopenia induced by ABT-263 in dogs is dependent on ABT-263 concentrations and could be well described by a semi-physiological E-R model. Platelet transfusion should be started after ABT-263 concentration has dropped and multiple transfusions are needed to produce larger and more prolonged effects on circulating platelet levels.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C126.
Abstract C133: Effect of casopitant, a novel neurokinin-1 receptor antagonist, on the pharmacokinetics (PK) of the oral contraceptive pill (OCP)
Authors: Adams Laurel M. , Zamuner Stefano , Fina Paolo , Peroni Michela , Johnson Brendan M. , Fernandes Sofia 
Published: June 2012

Abstract
Background: Clinical studies suggest that casopitant, a novel neurokinin-1 receptor antagonist in development for prevention of postoperative and chemotherapy-induced nausea and vomiting (PONV and CINV, respectively), is a mild to moderate inhibitor of CYP3A4. However, in cultured human hepatocytes, induction of CYP3A4 and UGT enzymes also has been observed. Since casopitant is intended for use in women receiving moderately emetogenic chemotherapy for breast cancer, the current studies evaluated the pharmacokinetics (PK) of a combined monophasic oral contraceptive pill (OCP) coadministered with repeat-dose casopitant.
Methods: Healthy female subjects of non-childbearing or of childbearing potential taking OCP were enrolled. Study 1 (N=11) was a randomized, double-blind, placebo-controlled, repeat-dose, crossover study. OCP containing 30 µg ethinylestradiol (ETE) and 150 µg levonorgestrel (LEV) was administered for 2 complete menstrual cycles (21 days + 7-day washout), plus oral placebo or 60 mg casopitant on days 1–14 of each cycle. Study 2 (N=61) was a single-blind, placebo-controlled, repeat-dose, single-sequence study. OCP was administered for 2 complete cycles as above with oral casopitant (30 mg or 120 mg) or placebo administered for cycles 1 and 2, respectively. Casopitant or placebo was administered for 28 consecutive days, beginning 7 days before OCP administration. The geometric least squares mean ratios and 90% confidence intervals (CI) for ETE and LEV AUC and Cmax were calculated to compare OCP + casopitant vs OCP + placebo.
Results: In study 1, ETE AUC(0−) and Cmax were decreased on average by 16% and 17%, respectively, when the OCP was coadministered with 60 mg casopitant vs placebo. Geometric mean LEV AUC(0−) increased 4%, and Cmax decreased 17%. In study 2, for ETE, OCP + casopitant decreased AUC(0−) on average by 15% and 40%, and Cmax by 24% and 32% with 30 mg and 120 mg, respectively. For LEV, the largest mean change in exposure was a 13% decrease in Cmax with 120 mg casopitant given daily for 14 days. Coadministration of casopitant with the combined OCP was well tolerated in both studies.
Conclusions: Continuous coadministration of casopitant for 14 or 28 days with a combined monophasic OCP resulted in only a small change in LEV exposure, but a dose-dependent reduction in ETE exposure that may reduce the efficacy of hormonal contraceptives. The effect of a single oral dose of casopitant on hormonal contraceptives has not been studied.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C133.
Abstract C137: Pinpointing a protein-protein interaction site of focal adhesion kinase and VEGFR-3 suppresses cancer growth in vivo
Authors: Kurenova Elena V. , Hunt Darrell , Ucar Deniz , He Dihua , Nyberg Carl , Hochwald Steven , Magis Andrew , Ostrov David , Cance William G. 
Published: June 2012

Abstract
Tumor cell survival depends on activation of signaling pathways that suppress the apoptotic stimuli of invasion and metastasis. FAK and VEGFR-3 are tyrosine kinases that have been identified as critical signaling molecules for these processes. Previously we have shown that VEGFR-3 and FAK physically interact and are overexpressed in cancer cells to provide a significant survival advantage for the tumor cells. We subsequently identified a novel small molecule inhibitor that targeted VEGFR-3-FAK site of interaction and disrupted the survival function of these two proteins. We utilized the crystal structure of the FAK focal adhesion targeting (FAT) domain for molecular docking of small molecules that targeted the VEGFR-3 binding site on FAK. We identified a small molecule C4 (Chloropyramine hydrochloride), that disrupted VEGFR-3-FAK binding, and abrogated the phosphorylation of VEGFR-3 while reducing the phosphorylation of FAK. In vitro testing of this compound resulted in the selective growth inhibition, reduction in motility and invasion, and induction of apoptosis in a time- and dose-dependent manner in many cancer cell lines, especially those that overexpressed VEGFR-3. In vivo, C4 showed a marked reduction of tumor growth and was synergistic with doxorubicin chemotherapy in breast cancer xenograft models, with dacarbazine in melanoma xenograft models, and with gemcitabine in pancreatic cancer xenograft models. These results demonstrate that targeting the FAK-VEGFR-3 interaction with a small molecules inhibited the survival function of these two tyrosine kinases, representing a unique approach for molecular-targeted highly-specific cancer therapeutics.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C137.
Abstract C145: The nonredundant oncogenic role of miR-17-5p in gastric cancer in vitro
Authors: Lee Seok Cheol , Kim Chang Hee , Green Jeff , Kim Hark Kyun 
Published: June 2012

Abstract
MicroRNAs are non-coding RNA molecules that consist of 19 to 25 nucleotides. Overexpression of miR-17-92 cluster is reported in many human cancers including gastric cancers, the second most common cause of cancer mortality worldwide. While the data in the literature predominantly supports the oncogenic role of miR-17-92 cluster, some studies suggested tumor suppressor role of the miR-17-92 cluster. Given that function of a given microRNA is context-dependent, the exact function of miR-17-92 cluster in gastric cancer cells should be experimentally documented in order to validate this microRNA as a novel therapeutic target. MiR-17-5p is one member of the miR-17-92 cluster, the other members of which are miR-18a, miR-19a, miR-20a, miR-19b and miR-92. Although knockdown of mir-17-5p is reported to inhibit the growth of neuroblastoma and breast carcinoma cells, the intracluster redundancy has not been fully evaluated in gastrointestinal cancers. We tested a functional role of miR-17-5p in gastric cancer cells, given our patient data that miR-17-5p is significantly overexpressed in gastric cancer patients, compared with healthy volunteers. MiR-17-5p knock-down was performed in KATO-III human gastric cancer cell line, using commercially available lentiviral vectors targeting specifically miR-17-5p. Knock-down of miR-17-5p significantly decreased the proliferation rate of KATO-III cells. A smaller number of KATO-III colonies were formed in soft agar after miR-17-5p knock-down, suggesting a critical role of miR-17-5p in anchorage-independent cell growth. On the other hand, there was no change in the sensitivity of KATO-III cells to either fluorouracil or cisplatin after miR-17-5p knock-down, consistent with our patient data showing no association of miR-17-5p expression with chemotherapy response. These data suggests the non-redundant oncogenic function of miR-17-5p in vitro, leading to increased growth, but not decreased apoptosis of gastric cancer cells. Thus, inhibiting miR-17-5p is a promising therapeutic strategy against gastric cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C145.
Abstract C148: LNA (locked nucleic acid)-based RNA antagonists mediate target mRNA silencing without transfection by simple addition to cell culture media
Authors: Zhang Yixian , Qu Zhengxing , Kim Steven , Shi Victoria , Liao Baisong , Kraft Patricia , Bandaru Raj , Sapra Puja , Greenberger Lee M. , Horak Ivan D. 
Published: June 2012

Abstract
Background: Since oligonucleotides do not penetrate cells well, most RNA-based therapies, such as antisense molecules and siRNAs use transfection conditions in tissue culture and delivery technologies in animals to facilitate entry of oligonucleotides into target cells. However, such vehicles are known to substantially alter cellular function and thereby significantly confound analyses. We have been developing LNA-based RNA antisense molecules to key cancer targets including survivin, HIF-1α, androgen receptor, GLI2, β-catenin, HER3, p110 alpha, and HSP27. LNA-based oligonucleotides were choosen since these molecules are highly stabile in plasma, have extraordinary high affinity to mRNA, and potently silence mRNA in cells under transfection conditions (IC50 in the high picomolar - low nanomolar range). We now report that LNA based RNA antagonist, when used in the high nanomolar - low micromolar range readily down modulate mRNA and protein of interests in multiple cell lines without any delivery means.
Material and Methods: In vitro, the ability of the antagonists to down modulate mRNA and cell growth was evaluated by qRT-PCR and MTS respectively. Cellular localization of the antagonists was evaluated by examining a FAM-labeled HER3 antagonist EZN-3920 under fluorescent microscope. In vivo, HER3 mRNA down-modulation and protein levels in tumors, which were grown on the flank of nude mice, were evaluated after intravenous administration of the antagonists.
Results: The down-modulation of mRNA in tissue culture-treated cells was quick, robust, long lasting, and specific followed by potent protein inhibition. Importantly, we show that mechanisms underlying the down-modulation correlated with nuclear localization of the LNA-ASO, suggesting that RNas H was the primary mechanism involved in target inhibition. Using this simple and effective approach, we were able to demonstrate that HER3, GLI2, and β-catenin were likely crucial growth and survival factors for certain cancer cells.
Conclusions: LNA-based RNA antagonists down-modulate target mRNA and protein in the absence of any agent to facilitate cell penetration. Such antagonists represent an attractive option for rapid, simple, and specific determination of gene function, target validation, and identification of drug-sensitive tumors for further in vivo evaluation. Beyond this, these results helps validate the use of intravenously administered LNA oligonucleotides simply prepared in saline, as is being done in on-going clinical trials with LNA-based RNA antagonists to HIF-1α and survivin.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C148.
Abstract C15: A novel panel of serum biomarkers distinguishes asthma from non-small cell lung cancer
Authors: Izbicka Elzbieta , Streeper Robert , Diaz Armando , Campos David , Long Thomas , Baek Sung , Mussman Rhys 
Published: June 2012

Abstract
Purpose: Asthma affects an increasing proportion of the population and may predispose sufferers to lung cancer. Frequent misdiagnosis of asthma and lack of early detection tests for lung cancer might be mitigated by better diagnostic tests. We used multiplexed immunoassays and mass spectrometry to identify serum biomarkers capable of distinguishing asthma from non-small cell lung cancer, the most common type of lung cancer.
Methods: Sera from normal subjects (NO; n = 300), patients with asthma (AST; n=180), and non-small cell lung cancer (LC; n = 334) were acquired from commercial vendors. Levels of 58 cytokines, chemokines and growth factors were quantified using multiplexed immunoassays. For biomarker discovery, specimens were digested with trypsin and analyzed by liquid chromatography electrospray ionization MS (LC ESI MS/MS). Proteins were identified using Mascot search software. Validation of select biomarkers identified by MS was achieved by immunodetection of target proteins in serum specimens. Data were reduced using inter-pathology comparisons with statistical significance determined using Student's t-test.
Results: Multiplexed immunoassays identified 29 analytes with significant (t&lt;0.05) inter-pathology differences; 14 of these were highly significant (t &lt; 0.0001). We fund a subset of biomarkers with unexpectedly large inter-gender differences and distinct gender-specific expression patterns. Serum levels of interleukin-13 and small inducible cytokine b11 (I-TAC) showed the greatest difference between AST, LC, and NO sera. MS analysis to date identified 11 differentially expressed proteins that included 3 putative yet unnamed proteins identified by gene sequencing and 1 protein product corresponding to chromosome X open reading frame 38. The presence of select proteins discovered by MS (syntaxin 11, cAMP-specific 3′,5′-cyclic phosphodiesterase type 7, and arginase) was confirmed and quantified by immunobloting.
Conclusion: We have identified a group of serum biomarkers having high inter-pathology discrimination power that are capable of differentiating AST and LC from normal controls and that may potentially be used in diagnostic tests for early detection of lung pathologies. Our experimental strategy is widely applicable to discovery and validation of biomarkers for diverse human diseases, response to a therapy, or pre-selection of patients for clinical trials.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C15.
Abstract C152: Therapeutic potential of histone deacetylase inhibitors in human liposarcomas
Authors: Mühlenberg Thomas , Pedeutour Florence , Fletcher Jonathan A. , Schuler Martin , Bauer Sebastian 
Published: June 2012

Abstract
Introduction: Systemic treatment of dedifferentiated liposarcomas (LPS) is limited to classical cytotoxic drugs, such as doxorubicin, ifosfamid or trabectedin. Recently, HSP90 inhibitors have shown evidence for clinical activity in patients with LPS. Histonedeacetylase inhibitors (HDACI) have been shown to disrupt hsp90 chaperone function with a favourable toxicity profile. Most LPS exhibit MDM2 amplification, resulting in p53 inhibition as important oncogenic event. We therefore sought to evaluate the therapeutic potential of HDACi alone and in combination with MDM2/p53 modulating drugs.
Materials and Methods: HDACi SAHA and LBH589 were evaluated in 4 liposarcoma cell lines (T449, T778, LPS141 and SW872). Biological consequences of HDAC inhibition alone and in combination with MDM2 inhibitors (nutlin-3 and RITA) were determined by cell viability assays, immunoblotting for p53- -related signalling pathways, effects on cell cycle and apoptosis as measured by flow cytometry and luminescence-based caspase activation assays.
Results: HDACi treatment (3 days) resulted in IC50 (cell viability) between 4µM and 8µM for SAHA and 25nM and 110nM for LBH589. Nutlin-3 showed strong antiproliferative effects in T449, T778 and LPS141 (IC50: 2–3µM), but not in SW872 (&gt;10µM). Interestingly, SW872 exhibited a high sensitivity to RITA (IC50: 140nM) while all other liposarcoma cell lines were less sensitive (IC50 RITA: &gt;10µM). Combinations of HDACI and Mdm2 inhibitors showed minor additive effects in cell viability assays.
Notably, HDACi treatment (SAHA 5µM, LBH589 50nM) resulted in substantial (80–90%) downregulation of p53 as measured by western blotting (after 24h) in all cell lines accompanied by induction of p21 (6- to 9-fold), and caspase 3 cleavage (9- 10-fold).
Nutlin-3 mediated induction of p53, p21 and Mdm2 was reduced when combined with SAHA or LBH589, while induction of apoptosis was strongly enhanced (40-fold) compared to baseline levels. Reactivation of p53 was less pronounced with RITA and no induction of p21 was observed.
Combination of nutlin-3 with SAHA or LBH589 resulted in a 2–3-fold increase of apoptotic cells (50–60%) compared to treatment with HDACi (10–30%) or nutlin-3 (32%) (alone). RITA exhibited only minor induction of apoptosis (6%) but showed similar additive effects when combined with HDACI (SAHA: 54%) and (LBH589: 40% apoptotic cells).
Conclusion: HDACi show antiproliferative and proapoptotic effects in liposarcoma cell lines. Notably, HDACi result in p53 inactivation. Combinations of HDACi with MDM2 inhibitors may greatly enhance the proapoptotic effects at doses that seem therapeutically achievable. RITA and nutlin-3 may exhibit differential activity in liposarcoma cell lines.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C152.