bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C180: A novel bispecific platform for potent redirected killing of B-cell lymphoma
Authors: Moore Paul A. , Huang Ling , Rainey Jonah , Zhang Wenjun , Burke Steve , Yang Yinhua , Gorlatov Sergey , Li Hua , Alderson Ralph , Tuallion Nadine , Bonvini Ezio , Johnson Syd 
Published: June 2012

Abstract
Despite significant advances in the treatment of B-cell lymphoma, in many cases the disease remains untreatable or displays recurrence after initial response to therapy. The recent clinical success of bi-specific molecules capable of redirecting T-lymphocyte-mediated cytotoxicity (Bi-specific T-cell Engagers, BiTEs) against B-cell lymphoma provides a feasible therapeutic option. We have developed an alternate bi-specific platform of Dual-Affinity Re-Targeting (DART) molecules that is well suited for clinical applications. Compared to BiTEs, which comprise a pair of single-chain Fv domains in a single polypeptide, DARTs contain two separate chains associated into a heterodimeric, covalently linked, ‘diabody’ structure. We show here that DARTs are very stable in vitro and can be built to recruit and retarget different effector cells, including T cells or CD16- (Fc RIII)-positive cells, against B-cell-lineage targets. A CD3xCD19 DART capable of recruiting cytotoxic T cells against CD19-positive targets mediated extremely potent killing of human peripheral blood B lymphocytes or B-cell lymphoma lines in vitro, with an EC50 that compares favorably to that of a BiTE with identical Fv sequences. Redirected killing of Daudi, Raji, or Nalm6 lymphoma lines was observed in the picomolar range using either freshly purified T cells or peripheral blood mononuclear cells (PBMC) as effector populations. In contrast, no killing was observed against a CD19-negative cell line (RPMI-8226) with either resting or stimulated effector populations, indicating a requirement for CD19 engagement for T-cell-mediated killing by the CD3xCD19 DART molecule. Furthermore, a DART constructed with a humanized version of a pan anti-TCR-beta antibody (TCRxCD19 DART) was as efficient against CD19-positive targets as the CD3-based DART. A CD16xCD32B DART was also constructed to redirect CD16-positive NK and/or mononuclear phagocyte effector cells against CD32B-positive B cells, displaying potent killing against Daudi, Raji or RPMI-8226 cells but not against a CD32B-negative cell line (Ramos). Both TCR- and CD16-based DARTs show potent activity in vivo in several mouse models, including autologous B-cell depletion in huCD32B-transgenic mice, tumor reduction in human Raji Burkitt's lymphoma cell xenografts and Raji cell implants in NOD/SCID mice reconstituted with human PBMC. In conclusion, DARTs represent a robust and flexible platform to recruit different cell populations via various cell surface targets for re-directed killing applications against B-cell malignancies.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C180.
Abstract C181: Preclinical efficacy and pharmacodynamics of SCH 900105 (AV-299) an anti-HGF antibody in an intracranial glioblastoma model
Authors: Meetze Kristan A. , Connolly Kelly , Boudrow Andrea , Venkataraman Sriram , Medicherla Satya , Gyuris Jeno , Han May 
Published: June 2012

Abstract
Hepatocyte growth factor (HGF) is a pluripotent growth factor produced predominantly by mesenchymal or stromal cells, and binds to the well-characterized tyrosine kinase receptor, c-Met. The HGF/c-Met pathway is frequently deregulated in different types of human cancers and is thought to play an important role in regulating tumor growth, invasion, metastasis and drug resistance. HGF/c-Met autocrine and paracrine loops have been reported in a number of human cancers including breast, lung, bladder, gastric, head and neck, glioma, multiple myeloma, leukemias, and certain sarcomas.
SCH 900105, formerly known as AV-299, is a potent, humanized anti-HGF antibody. It is currently in phase 1 clinical trials that demonstrated good safety and tolerability. It has been shown to neutralize HGF binding to c-Met and inhibits its biological function in vitro, such as cell signaling, growth, motility, invasion and drug resistance. SCH 900105 was also shown to have potent anti-tumor activity in autocrine and paracrine GBM, NSCLC, pancreatic and multiple myeloma xenograft models both as monotherapy and in combinations with chemotherapeutics or targeted agents.
In vivo efficacy of systemically administered SCH 900105 was evaluated in an intracranial autocrine U87MG model. In these studies, SCH 900105 treatment resulted in significant survival benefit over an IgG treated control group. Immunohistochemistry staining for SCH 900105 in the intracranial tumor tissue suggested adequate tumor penetration of the antibody. Treatment also led to significantly decreased tumor phospho-c-Met, increased cleaved caspase-3, as well as decreased Ki67 and CD31 staining. Greater survival benefit was also seen when SCH 900105 was combined with temozolomide in U87 intracranial model. These findings suggest evaluating SCH 900105 in GBM is warranted.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C181.
Abstract C194: In vivo characterization of AMG 900, an orally active small molecule inhibitor of aurora kinases in phase 1 clinical trials
Authors: Bush Tammy L. , Ziegler Beth , Chung Grace , McElroy Patricia L. , Kendall Richard , Radinsky Robert , Geuns-Meyer Stephanie , Payton Marc 
Published: June 2012

Abstract
Background: The aurora family of serine-threonine kinases (Aurora-A, -B, -C) regulate cell-cycle progression in mammalian cells. Aurora kinases A and B are essential for proper chromosome congression, segregation, and cytokinesis during mitosis, whereas aurora kinase C function appears restricted to male meiosis. Aurora kinase B is responsible for the direct phosphorylation of histone H3 on serine-10 (p-histone H3). Aurora kinase A and B expression is elevated in a variety of human cancers and is associated with advanced clinical staging and poor prognosis. The emergence of aurora kinases as key mitotic regulators and their potential role in tumorigenesis has focused substantial interest in developing selective small molecule inhibitors for the treatment of human cancers. AMG 900 is a novel ATP competitive small molecule inhibitor that is highly potent and selective for aurora kinases A, B, and C.
Objective: The aim of this study was to characterize the in vivo effects of AMG 900 by establishing a pharmacokinetic-pharmacodynamic relationship and profiling its antitumor activity across multiple human xenografts models using a variety of dosing schedules.
Results: In nude mice, oral administration of AMG 900 inhibited phosphorylation of histone H3 in tumors and bone marrow in a time- and dose-dependent manner. The degree of p-histone H3 suppression in cells correlated with plasma drug concentrations. The effect of AMG 900 was tested in a panel of human tumor xenograft models. Oral administration of AMG 900 at 15 mg/kg BID for two consecutive days per week or 3 mg/kg BID every day inhibited tumor growth (50–97% inhibition; p ≤ 0.0044) in all nine of the xenograft models tested compared with the vehicle control group. Importantly, three of these xenograft models are resistant to paclitaxel, docetaxel, and doxorubicin. Mice treated with efficacious doses of AMG 900 showed a transient loss of body weight (0–10%) and bone marrow cellularity, consistent with its on-mechanism effects on normal proliferating cells. Since aurora kinase inhibitors are known to cause neutropenia, studies were performed to investigate the effects of prophylactic treatment of PEGylated-G-CSF (SD/02). In mice, administration of SD/02 shortened the duration of AMG 900-induced neutropenia.
Conclusion: Based on these preclinical activities, AMG 900 has the potential to treat advanced cancers, including tumors resistant to standard-of-care chemotherapeutic agents such as paclitaxel and docetaxel. AMG 900 is currently undergoing phase 1 clinical evaluation in patients with advanced solid tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C194.
Abstract C196: Co-treatment with NVP-BEZ235 and heat shock protein (hsp) 90 or pan-deacetylase (DAC) inhibitor is synergistically active against non-small cell lung cancer (NSCLC) cells with mutant RAS and LKB1
Authors: Upadhyay Sunil , Fiskus Warren C. , Rao Rekha , Joshi Atul , Koul Sanjay , Balusu Ramesh , Mudunuru Uma , Buckley Kathleen M. , Quadt Cornelia , Atadja Peter , Garcia-Echeverria Carlos , Bhalla Kapil N. 
Published: June 2012

Abstract
Inactivating somatic mutation of LKB1 is found in approximately 30% of NSCLC and is often coincident with activating K-RAS mutation. In a mutant K-RAS-driven model of mouse lung cancer, strong cooperation and aggressive phenotype was seen with hemizygous inactivation of LKB1. Loss of LKB1 results in activation of mTOR pathway while somatic activating mutation in K-RAS results in activation of PI3K/AKT and RAS/RAF/ERK. Therefore therapeutic stratagies which target these pathways may have significant affect on the outcome of these cancers. NVP-BEZ235 is a dual PI3K and mTOR inhibitor and panobinostat (PS) (Novartis Pharmaceuticals Inc) is a pan-histone deacetylase (HDAC) inhibitor, which has been shown to induce proteasomal degradation and depletion of the levels of hsp90 client proteins, including AKT and c-RAF. Here, we determined the effects of BEZ235 and/or PS or AUY922 (an hsp90 inhibitor) on NSCLC A549 and H460 cells with LKB1 and K-RAS mutations (A549 and H460). Treatment with BEZ235 (200 to 1000 nM), PS (25 to 50 nM) or AUY922 (25 to 100 nM) dose-dependently increased % of cells in G2/M and decreased % of cells in S phase of cell cycle, as well as induced apoptosis of the NSCLC cells. Co-treatment with AUY922 or PS increased BEZ235 mediated depletion of p-AKT, p-4EBP1 and p-p70S6K levels, as well as synergistically induced apoptosis of A549 and H460 cells (combination indices &lt; 1.0). Combined therapy with BEZ235 (25 mg/Kg) and PS (10 mg/Kg) or AUY922 (20 mg/Kg) resulted in significantly more tumor growth delay than treatment with each of the agents alone of A549 cell xenografts in nude mice (p &lt; 05). We also determined the activity of BEZ235 and/or PS in the NSCLC H368 cells with mutant K-RAS and either wild-type (H358 cells) or stable knock down of LKB1 expression (H358/LKB1-KD cells), achieved by shRNA against LKB1, mimicking the presence of mutant LKB1. As compared to each agent alone, co-treatment with BEZ235 and PS exhibited a higher level of antitumor synergy against H358/LKB1-KD versus H358 cells. These pre-clinical in vitro and in vivo studies demonstrate that combined treatment with the dual PI3K/mTOR inhibitor BEZ235 and PS or AUY922 could potentially be a promising targeted therapy for NSCLC that harbors K-ras and LKB1 mutations.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C196.
Abstract C202: Targeting the mitotic checkpoint for cancer therapy with NMS-P715, a novel MPS1 kinase inhibitor
Authors: Colombo Riccardo , Caldarelli Marina , Mennecozzi Milena , Giorgini Maria L. , Sola Francesco , Cappella Paolo , Ballinari Dario , Perrera Claudia , Re Depaolini Stefania , Rusconi Luisa , Avanzi Nilla , Volpi Daniele , Bossi Roberto , Bertrand Jay A. , Pesenti Enrico , Isacchi Antonella , Donati Daniele , Moll Jurgen 
Published: June 2012

Abstract
The Spindle Assembly Checkpoint (SAC) is a mitotic mechanism specifically required for proper chromosomal segregation ensuring that cells do not divide until all sister chromatids correctly align to the metaphase plate. MPS1 kinase, (also known as TTK) is a key regulator of SAC functions and it has been found to be up-regulated in a number of tumors of different origins. The hypothesis is that SAC activity could be highly required to sustain aneuploid tumor growth and MPS1 inhibitors may have a therapeutic benefit in the treatment of certain cancers.
We have identified NMS-P715, a potent and selective oral bioavailable small-molecule MPS1 kinase inhibitor with an ATP-competitive bindingmode. Treatment of cells with NMS-P715 accelerates mitotic exit with an IC50 of 53 nM. This is accompanied by reduction of the mitotic length, MPS1 dephosphorylation, chromosomal mis-alignment, delocalization of kinetochore components and massive aneuploidization, which ultimately leads to cell death.
Proliferation data performed on a large panel of 126 cell lines shows a wide range of activity and indicates selective activity against tumoral cells compared to normal cells. Oral administration of NMS-P715 in tumor xenografted mice resulted in potent tumor growth inhibition in an ovarian cancer xenograft model and was accompanied by biomarker modulation, confirming the expected MOA.
Our data provide evidence that inhibition of MPS1 kinase and SAC abrogation could represent a new promising approach to cancer therapy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C202.
Abstract C209: Inhibition of both c-Met and EGFR signaling shows synergistic antitumor activity in non-small cell lung cancer model
Authors: Tammam Jennifer G. , Davis Lenora , Ware Chris , Reilly John F. , Deshmukh Sujal V. , Dinsmore Christopher , Marshall Gary , Harrington Elizabeth A. , Pan Bo-Sheng , Lutterbach Bart A. , Majumder Pradip K. 
Published: June 2012

Abstract
c-Met and ErbB family of receptors including EGFR, ErbB-2, ErbB-3 and ErbB-4 are co-expressed in many human tumors including Non-Small Cell Lung Cancers (NSCLC). Several reports suggest that the activation of c-Met and ErbB family receptors is associated with poor prognosis in multiple tumors types. Recently it has been shown that activation of c-Met is common in Erlotinib and Gefitinib-resistant NSCLC patients. Combining c-Met and EGFR inhibitors has been proposed as a strategy for treatment in EGFR inhibitor-refractory lung cancers. To understand the cooperation of these pathways, we used a c-Met activated human NSCLC cell line (EBC-1), where EGFR signaling network is also active. In vitro treatment of EBC-1 cells with a combination of Erlotinib and MK-8033 (an inhibitor of c-Met and RON kinases) resulted in greater growth inhibition relative to treatment with either agent alone. In order to validate these in vitro data, we have tested MK-8033 and EGFR inhibitors (Erlotinib and Gefitinib) in vivo. The data suggests the effect of MK-8033 with Gefitinib or Erlotinib on tumor growth is greater when combined as compared to monotherapy in this preclinical xenograft model. PK data suggests no drug-drug interaction of MK-8033 and EGFR inhibitor when administered together. Exposure of these agents was sufficient to inhibit both kinases in tumors. Our studies provide a rationale for the combination of MK-8033 and Erlotinib or Gefitinib in EGFRi refractory patients with NSCLC.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C209.
Abstract C219: Molecular and cellular pharmacology of the novel non-camptothecin topoisomerase I inhibitor, GENZ644282
Authors: Sooryakumar Dhriti , Dexheimer Thomas , Teicher Beverly A. , Pommier Yves 
Published: June 2012

Abstract
Camptothecin (CPT) derivatives are powerful anticancer drugs because of their ability to trap topoisomerase I (Top1)-DNA cleavage complexes. However, they exhibit clinical limitations due to the instability of their α-hydroxylactone six-membered E-ring structure, which is essential for trapping Top1-DNA cleavage complexes. Additionally, they exhibit bone marrow and intestinal toxicity in adults and are drug efflux substrates. Here, we report a Top1 inhibitor, Genz644282. In the cell lines studied, we find that Genz644282 as well as its metabolites induce Top1 cleavage at similar, as well as unique genomic positions, compared with CPT. The compound also induces protein-linked DNA breaks and Top1-DNA cleavage complexes that persist longer after drug removal than CPT. Concentration-dependent and persistent H2AX formation was readily observed in cells treated with Genz644282, and was present in greater than 50% of the cell population following 24 hours drug treatment. The compound shows partial cross-resistance in cell lines resistant to CPT. These cell lines include the prostate cancer cell line (DU145RC0.1), and human leukemic (CEM/C2) cells. Genz644282 demonstrated limited cross-resistance in Top1-knockdown colon cancer (HCT116) and breast cancer (MCF7) cells. The compound also demonstrated limited resistance in human lung cancer cells (H460/MX20). These lung cancer cells express (BCRP, ABCG2), a member of the ATP-binding cassette family of cell surface transport proteins known to have ABCG2 drug-efflux pumps.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C219.
Abstract C29: Bladder cancer-associated single nucleotide polymorphisms of vascular endothelial growth factor in 12 human cell lines
Authors: Lainesse Karine , Menard Sonia , Ke Danbing , Khan Salim A. , Prevost Gabrielle , Filion Mario C. , Phillips Nigel C. 
Published: June 2012

Abstract
Introduction: Vascular endothelial growth factor (VEGF), critical in angiogenesis, is important for solid tumor growth and metastasis. Three single nucleotide polymorphisms (SNP) in the promoter (rs833052, rs1109324 and rs1547651) and one in the 5′-UTR regions (rs25648) of VEGF have been associated with increased risk for bladder cancer, and one at intron 2 (rs3024994) with decreased risk in a large-scale case-control study. The genotype frequency of the five bladder cancer-associated SNPs among various ethnic groups is similar based on the dbSNP and the SNP500Cancer databases. The objective of this study was to determine the presence of these variants in a panel of 12 human bladder cancer cell lines.
Methods: Twelve bladder cancer cell lines, commonly used in urological research and derived from various ethnic groups, were included in the study. Genotypes of the five SNPs were determined for the12 cell lines by direct PCR sequencing. The basal VEGF secretion by these cell lines in culture was measured by ELISA using a microsphere-based array (Millipore) and Luminex® xMAP technology.
Results: The SNP genotype frequency was in agreement with that reported in the databases. The only bladder cancer-associated variant (rs833052: C&gt;A) was detected in UM-UC-3, a cell line with many other genetic alterations. The secreted VEGF level in these cell lines as determined by ELISA varied considerably. No correlation between VEGF production and any particular SNP genotype could be established.
Conclusions: The reported bladder cancer associated variants in VEGF was detected in only one of the twelve cell lines. Though these SNPs are all located in the regulatory regions, it appears that they have no effect on basal VEGF production in the cultured cells. Considering the low prevalence of these variants reported, the role of these SNPs in VEGF production and bladder cancer remains to be defined.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C29.
Abstract C36: MBP-426, a novel liposome-encapsulated oxaliplatin, in combination with 5-FU/leucovorin (LV): Phase I results of a Phase I/II study in gastro-esophageal adenocarcinoma, with pharmacokinetics
Authors: Senzer Neil N. , Matsuno Kazuhiko , Yamagata Nobuyuki , Fujisawa Tadashi , Wasserman Ernesto , Sutherland William , Sharma Sunil , Phan Alexandria 
Published: June 2012

Abstract
Background: MPB-426 is a new transferrin-conjugated liposomal formulation of oxaliplatin, which can provide preferential tumor targeting and better bioavailability through the EPR effect and binding of transferrin receptors, respectively. In a recent phase I study, single agent MBP-426 given q3w showed thrombocytopenia as DLT, with 226 mg/m2 being the recommended phase II dose (RDP2). The current phase I–II study was designed to establish the RDP2 of MPB-426 in combination with 5-FU/LV (de Gramont schedule) and assess the efficacy of this combination in pretreated patients with gastro-esophageal (GE) adenocarcinoma.
Methods: MBP-426 IV was given q3w at two dose levels: 226 and 170 mg/m2 with fixed doses of 5-FU/LV. LV (400 mg/m2) was given concurrently with MBP-426 followed by IV bolus 5-FU (400 mg/m2), and then by 5-FU 2400 mg/m2 by continuous IV (CIV) infusion over 46 hours. The phase I dose assessment part was conducted in solid tumor patients. The phase II part will be limited to second line patients with gastric, gastro-esophageal or esophageal adenocarcinoma.
Results: The phase I part has been completed. Nine patients (pts) were included and treated. Median age: 61 years (55–67), gender M/F: 5/4, ECOG PS 0/1: 2/7, diagnosis: colorectal 4, pancreas 2, bladder 1, H&N 1 and cervix 1. Median number of prior lines: 4 (2–10). Four patients received a total of 11 cycles at the first dose level (MBP-426 226 mg/m2), in which two dose limiting toxicities (DLTs) were observed: grade 3 nausea and vomiting (1 pt) and grade 3 back pain (1 pt). Additional grade 3–4 toxicities were thrombocytopenia (3 pts), neutropenia (2 pts), transient rise of bilirubin (1 pt), and skin toxicity (1 pt with grade 3 erythema multiforme at cycle 4). To date, six patients (7 cy) have been explored at a lower dose level of 170 mg/m2. No DLTs were observed, establishing 170 mg/m2 as the RDP2. Grade 3–4 toxicity was limited to neutropenia in 1 pt. Oxaliplatin-induced peripheral neuropathy was not reported at either dose level, with 5 pts receiving an oxaliplatin equivalent dose ≥ 500 mg/m2. Efficacy: early data show 2 SD (4 cycles, 4+) and 1 PD (2 cycles) in 3 evaluable colorectal pts, all resistant to prior exposure to oxaliplatin. Pharmacokinetic data will be available for the meeting.
Conclusion: MBP-426 at 170 mg/m2 is the RDP2 for use in combination with 5-FU/LV (de Gramont schedule) every 3 weeks. Treatment at this dose was well tolerated. No peripheral neurotoxicity has been reported with this new formulation of oxaliplatin. Potential activity was observed in 2 oxaliplatin-resistant patients.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C36.
Abstract C38: Immunosuppression by indoleamine 2,3-dioxygenase in mesenchymal stem cells derived from adult human tissues
Authors: Lee Myoung Woo , Jang In Keun , Noh Yoo Hun , Kim Dae Seong , Kim Hye Ryung , Cheuh Hee Won , Lee Soo Hyun , Jung Hye Lim , Sung Ki Woong , Koo Hong Hoe 
Published: June 2012

Abstract
Mesenchymal stem cells (MSCs), which evoke only minimal immune reactivity, may have anti-inflammatory and immunomodulatory effects. In this study, we conducted a comparative analysis of the immunomodulatory properties of MSCs derived from adult human tissues including bone marrow (BM), adipose tissues (AT), umbilical cord blood (CB), and cord Wharton's jelly (WJ). Using a multiple cytokine detection assay, we showed that there were no significant differences in levels of secreted factors from non-stimulated MSCs. We compared the immunosuppressive effect of BM-MSCs, AT-MSCs, CB-MSCs, and WJ-MSCs on phytohemagglutinin (PHA)-induced T-cell proliferation. AT-MSCs, CB-MSCs, and WJ-MSCs effectively suppressed PHA-induced T-cell proliferation as effectively as did BM-MSCs. Levels of interferon (IFN)-γ secreted from activated T-cells increased over time, but these levels were significantly reduced when cocultured with each type of MSCs. In addition, the expression of hepatocyte growth factor, interleukin-10, transforming growth factor-β1, cyclooxygenase (COX)-1, and COX-2 were unchanged in MSCs treated with IFN-γ, while that of indoleamine 2,3-dioxygenase (IDO) increased. Use of an antagonist, 1-methyl-L-tryptophan, restored T-cell proliferation and confirmed an IDO contribution to IFN-γ-induced immunosuppression by MSCs. Addition of tryptophan catabolite, such as kynurenine, 3-hydroxykynurenine, or quinolinic acid, significantly decreased PHA-induced T-cell proliferation. These data indicate that IFN-γ produced by activated T-cells were correlated with induction of IDO expression by MSCs, which, in turn, suppressed T-cell proliferation through tryptophan depletion and the local accumulation of tryptophan catabolites. Our findings suggest that MSCs derived from AT, CB, or WJ could be substituted for BM-MSCs for treatment of allogeneic conflicts.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C38.