bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A35: Computer modeling of nocodazole exposure on cell cultures in vitro
Authors: Fernandez Eric , Johnson George , Orrell David , Fell David , Doak Shareen H. , Chassagnole Christophe 
Published: June 2012

Abstract
Nocodazole is an anti-neoplastic agent which reversibly impairs tubulin assembly, resulting in blocking cells in mitosis. At high concentration, nocodazole rapidly depolymerises microtubules in vivo, preventing cells from progressing through mitosis. At lower concentrations, it blocks cells in mitosis by stabilizing microtubules. In vitro, nocodazole is frequently used to synchronise cells, but also leads to aberrant mitoses.
Physiomics and the Institute of Life Science at Swansea University have entered a collaboration to build mathematical models of cell populations in vitro capable of predicting the effect of nocodazole on cell cycle progression, mitotic defects and chromosomal aberrations. Systems biology modelling is a useful method to predict the cell cycle and cell population outcomes which may result from inhibiting cell cycle progression to different degrees with small molecule inhibitors.
In order to simulate the effect of drugs on a cell culture, Physiomics has developed a cell population simulator called SystemCell. Each cell is an instance of an autonomous cell cycle, combined to a discrete event-based state machine, which determines its proliferation state, its ploidy and the multiple stages of apoptosis in a stochastic way. The ILS has provided experimental data on the dose-response relationship of nocodazole exposure with aberrant mitosis. These experimental results have been used as a data set for the calibration of Physiomics models. The cell population simulations were performed on the High Performance Computer available at the ILS, Swansea University.
By accurately model the effect of nocodazole, this simulation platform will be particularly useful to predict the effect and dosing of nocodazole with other antitumor agents in combination.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A35.
Abstract A6: Pazopanib combination with paclitaxel and carboplatin in patients with advanced solid tumors and gynecological cancers: Results of two phase I studies
Authors: Burris Howard , du Bois Andreas , Dowlati Afshin , Gainer Shelby , Park JungWook , Stutts Melissa , Dar Mohammed , Suttle Ben , Mitrica Ionel , Tan Antoinette R. 
Published: June 2012

Abstract
Background: Pazopanib (PAZ) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit with w/ a recommended dose of 800 mg/day as monotherapy. Preclinical activity supports combining PAZ with paclitaxel (P) and carboplatin (C). Safety, PK, and and clinical activity of PAZ with P and and C were evaluated in two Phase I studies.
Methods: Two Phase I studies were conducted using a once daily QD regimen of PAZ (200–800 mg), and once every Q21 days of C (AUC 4–6 mg·min/mL) and P (175 mg/m2) to determine the optimally tolerated regimen (OTR) MTD defined as a dose limiting toxicity (DLT) frequency of &lt;33% in Cycle 1. Study 1 (S1) was a 3 + 3 design expanded at the OTR in patients (pts) with w/ metastatic disease treated with w/ no more than 3 prior lines of therapy. Study 2 (S2) enrolled subjects with w/ gynecological cancer in 2 cohorts of 6 pts each as first-1st line treatment.
Results: In Study 1S1, 34 pts (mean age 54; M/F: 17/17; ECOG 0/1: 19/15) were enrolled. Breast (29%) and esophagus (12%) were the most common primary tumor sites. In Study 2S2, 12 pts (mean age 53.754, M/F: 0/12; ECOG 0/1: 8/4) were enrolled. Ovary (50%) and endometrium/uterus (25%) were the most common primary tumor sites. The frequency of adverse events (AEs), regardless of causality, in the 2 studies (1 vs 2), were similar for neutropenia (82% vs 75%) and fatigue (68% vs 75%) and different for nausea (71% vs 50%), thrombocytopenia (68% vs 33%), anemia (65% vs 25%), and abdominal pain (24% vs 50%). The OTR MTD in Study 1S1 was P 175, C AUC 5, and PAZ 200; an OTR MTD was not determined for Study 2S2 due to poor tolerability. In Study 1S1, in the presence of PAZ 200 mg and 400, mg, the AUC (0–23) of C increased by 41 and 31%, respectively and while the Cmax for P increased by 43 and 40%, respectively. Best response in Study 1S1 at the OTRMTD (n=13) was CR [2 pts (15%); 406 and 446 days] and PR [3 pts (23%); 42–208 days].
Conclusions: Full doses of PAZ and C were not tolerated in combination with w/ P due predominantly to hematologicale toxicities in Study 1S1 and to non-hemeatological toxicities in Study 2S2. A drug interaction between PAZ and P and C along with more extensive prior therapy may explain increased myelotoxicity with this triplet in Study 1S1. Based on this PK interaction, lower doses of P and C may still provide adequate therapeutic exposure and better safety profile when combined with a higher dose of PAZ relative to the OTR MTD in study.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A6.
Abstract A60: Targeting brain tumor stem cells
Authors: Bourseau Erika , Lemaire Laurent , Hervouet Eric , Valette François , Menei Philippe , Berger François , Wion Didier , Benoit Jean-Pierre , Garcion Emmanuel 
Published: June 2012

Abstract
The brain tumor stem-cell (BTSC) hypothesis proposes with acquired self-renewal properties establish a brain tumorigenic-behavior (1). Thus, failure to cure brain cancer has been attributed to the fact that typical cytotoxic therapies target rapidly proliferating brain tumor cells, while sparing the BTSC compartment, which has a low proliferation rate and high tumorigenic potential. Taking advantage of the recent development of nanotechnologies that may offer innovative drug-delivery systems for improved efficacy, specificity and biological safety (2), the aim of our work is to develop nanoparticle-based treatments targeting BTSCs.
The first part of our work represents a comprehensive study of the aggressiveness of the BTSC was shown to be associated with the expression of the neural precursor cell marker AC133. Hence, the percentage of AC133 expressing glioma cells is increased after maintenance or exposure to moderately low oxygen levels (3). Our data indicate that cells maintained at 3% oxygen express more AC133 and are more aggressive after in vivo xenograft than cells cultured at 21% oxygen. Thus, oxygen pressure represents a major parameter in the expression of the AC133 molecule but is also important in aggressiveness of glioma cells. The mechanism that links hypoxia, AC133 expression and the tumorigenic behavior of BTSC has been studied. Our results, including CoCl2 induction and shRNA knockdown, suggest a role for HIF-1α in the regulation of AC133 in glioblastoma cells. The second part of our work, immunonanoparticules (ILNC) that target AC133 were synthesized by conjugation of thiolated AC133 or IgG1 isotype control immunoglobulins to lipid nanocapsules (LNC) (4) by linkage through incorporation of lipid PEG(2000) functionalized with reactive-sulfhydryl maleimide groups (DSPE-PEG(2000)-maleimide) on the surface of LNC by using a post-insertion procedure (5). Our results indicate a fixation yield of antibodies on LNC varying from 6 to 60% representing 70 antibodies per LNC. To evaluate the selectivity of immunonanoparticles binding and resulting uptake by cells a second in vitro model has been developed. Human Caco-2 cells, previously described to express AC133, were used and exposed to siRNA targeting the CD133 gene to dispose of two types of Caco-2 cells: Caco-2-AC133high and Caco-2-AC133low. We are now testing ILNC uptake in our Caco-2 cell model. We will test if ILNC are able to bind to AC133 epitope on Caco-2 cells and if they are able to be internalized in cells.
Accumulated results must allow us to extend our knowledge on glioma aggressiveness and to adapt our vectors to resolve the BTSC targeting problem and their death.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A60.
Abstract A70: A genome-wide siRNA screen for modulators of cell death induced by the proteasome inhibitor bortezomib
Authors: Chen Siquan , Blank Jonathan L. , Peters Theodore , Liu Jane , Rappoli David M. , Pickard Michael D. , Menon Saurabh , Yu Jie , Driscoll Denise L. , Lingaraj Trupti , Burkhardt Anne L. , Chen Wei , Sappal Darshan S. , Gray Jesse , Garcia Khristofer , Hales Paul , Leroy Patrick J. , Ringeling John , Rabino Claudia , Spelman James J. , Morgenstern Jay P. , Lightcap Eric S. 
Published: June 2012

Abstract
Multiple pathways have been proposed as the mechanism by which proteasome inhibition induces cell death. To clarify their relative importance, we performed a genome-wide siRNA screen to evaluate the genetic determinants that confer sensitivity of the HCT-116 colon cancer cell line to bortezomib (VELCADE®, PS-341). The screen identified 100 genes whose knock-down affects the lethality of bortezomib. From this list, the accumulation of the proteins ASF1B, Myc, ODC1, PMAIP1 (Noxa), BNIP3, Gadd45α, p-SMC1A, SREBF1, and p53 by proteasome inhibition was linked to the induction of cell death. Fifty-nine genes in the A375 melanoma cell line and 56 genes in the HeLa cervical cancer cell line showed similar interactions with bortezomib to those seen in HCT-116 and a subset of 39 genes were common to all three cell lines. Finally, knockdown of these 100 genes in HCT-116 cells similarly affected their responsiveness to a structurally diverse set of proteasome inhibitors. Our results suggest that proteasome inhibition promotes cell death primarily by dysregulating Myc and polyamines, interfering with protein translation, and disrupting essential DNA damage repair pathways, leading to programmed cell death.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A70.
Abstract B1: Antiangiogenic activity of AG-13736, a selective inhibitor of VEGFR-1, -2, -3, in human neuroblastoma
Authors: Rossler Jochen , Farace Francoise , Monet Yann , Opolon Paule , Vassal Gilles , Geoerger Birgit 
Published: June 2012

Abstract
Tumor angiogenesis in neuroblastoma, the most frequent extracranial solid tumor in childhood, has been shown to be an important prognostic factor. High vascularity is reported in aggressive and disseminated neuroblastoma and we previously described all known mechanisms of angiogenesis present, including sprouting of new vessels by angiogenesis growth factors as well as integration of circulating endothelial cells from bone marrow origin. Despite multimodal therapy protocols including surgery, high dose chemotherapy with stem cell support, radiotherapy and differentiating agents, the prognosis of advanced disease remains poor suggesting the evaluation of new therapeutics with distinct mechanism of action like anti-angiogenic agents for neuroblastoma.
We evaluated the new oral pan-VEGFR tyrosine kinase inhibitor AG-13736 in the IGR-N91 xenograft model derived from a primary neuroblastoma bone marrow metastasis. Oral treatment with 30 mg/kg BID during 2 weeks at advanced tumor stage yielded significant tumor growth delay in median time to reach 5 times initial tumor volume of 11.4 days compared to controls (p=0.0006; Mann-Whitney test). AG-13736 treatment down-regulated VEGFR-2 phosphorylation in IGR-N91 and resulted in significantly decreased vessel density and overall surface fraction of tumor vessels in all xenografts as measured by immunohistochemistry using CD34 antibody (mean OSFV at 14 days was 0.56% in treated tumors versus 1.29% in controls; p=0.0006; Mann-Whitney test). We further evaluated the effects of AG-13736 on circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CEPs) measured by flow cytometry. While only a transient reduction was observed in CECs, CEPs were significantly reduced during at least 28 days after treatment (0.40 +/−0.08 cells/ L before treatment compared to 0.02 +/−0.003, 0.00 +/−0.01 and 0.03 +/−0.02 at days 7, 14 and 28, respectively). The mTOR inhibitor rapamycin at 20 mg/kg once weekly resulted similarly to AG-13736 in significant tumor growth delays in IGR-N91 xenografts, however its combination to AG-13736 did not further increase their single agent activities. Thus, AG-13736 is a very potent anti-angiogenic new agent and demands further evaluation in neuroblastoma.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B1.
Abstract B104: The orally bioavailable proteasome inhibitor PR-047 inhibits metastasis in a mouse mammary carcinoma model
Authors: Jiang Jing , Kirk Christopher J. , Muchamuel Tony , Swinarski Debbie , Bennett Mark K. 
Published: June 2012

Abstract
Background: Proteasome inhibitors, such as bortezomib and the tetrapeptide epoxyketone carfilzomib, have shown strong antitumor activity in patients with multiple myeloma and mantle cell lymphoma. Anti-tumor responses are due to direct tumor cell cytotoxicity but may also involve effects on growth factors, angiogenesis and stromal cell interactions. The effect of proteasome inhibitors on metastatic spread has not been well studied in pre-clinical models. PR-047 is a novel orally bioavailable inhibitor of the 20S proteasome, that is structurally related to carfilzomib. PR-047 has demonstrated potent anti-tumor activity in mice bearing subcutaneous tumors of multiple histotypes.
Aim: To evaluate the effect of PR-047 on metastatic spread in mice bearing tumors of the 4T1 mammary carcinoma, an invasive tumor cell line that can spontaneously metastasize from the primary tumor to multiple sites.
Methods: 6–8 week old female BALB/c mice were challenged in the mammary fat pad (metastatic spread model) or via intravenous administration (micro-metastasis model) with 4T1 cells (1 × 105/mouse). Treatment was initiated on Day 3 post tumor challenge in both models. PR-047 was administered orally at 30 or 40 mg/kg on a weekly schedule of QDx2 or QDx5. The cytotoxic agent cyclophosphamide (CY) was used as a positive control. Primary tumors in the mammary fat pad and metastases in lungs were measured.
Results: In the metastatic spread model, PR-047 treatment reduced the number of metastases in the lung by ∼50% without an effect on the growth of the primary tumor. CY reduced the growth of the primary tumor and metastases in the lung. Both dose schedules and dose levels of PR-047 were effective in blocking metastasis. To rule out a direct cytotoxic effect on tumor cells in the lung, we assessed the effect of PR-047 treatment in mice intravenously challenged with 4T1 cells. Unlike CY, which inhibited the growth of micro-metastases, PR-047 treatment had no effect in this model, ruling out a direct cytotoxic effect.
Conclusion: PR-047 blocked the spread of 4T1 tumor cells from the mammary fat pad to the lung without an effect on primary tumor cell growth. This is the first report that an orally bioavailable proteasome inhibitor can block metastasis in vivo. These data support the further evaluation of PR-047 as a novel therapeutic agent for the treatment of metastatic breast cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B104.
Abstract B106: Nedd9 null status initially delays mammary tumor growth, then selects for hyper-aggressive mammary tumors
Authors: Singh Mahendra K. , Izumchenko Eugene , Klein-Szanto Andres JP , Golemis Erica A. 
Published: June 2012

Abstract
Altered expression of the HEF1/CAS-L/NEDD9 scaffolding protein has recently emerged as a candidate mechanism controlling tumor development, progression and metastasis. While some studies have identified elevated NEDD9 expression as pro-metastatic, other works have suggested a negative role in tumor progression. We have recently reported that the Nedd9 null genetic background significantly limits mammary tumor development in the MMTV-polyoma virus middle T (PyVmT) genetic model. Late-developing tumors are characterized by depressed activation of proteins including AKT, SRC, FAK, and ERK, emphasizing an important role of NEDD9 as a scaffolding protein for these pro-oncogenic proteins. However, NEDD9 is also regulates activation of the Aurora-A mitotic kinase (AurA). In vitro, knockdown of NEDD9 reduces AurA activation, suggesting in vivo loss of NEDD9 might be a potential source of genomic instability. We have evaluated a panel of cell lines derived from mammary tumors of MMTV-PyVmT;Nedd9−/− mice. Nedd9−/− cells injected orthotopically in mammary fat pads of SCID mice exhibited significantly faster growth of mammary tumors, and in a tail vein injection assay yielded a dramatically enhanced metastasis to the lungs. As hypothesized, Nedd9−/− cell lines had lower AurA kinase activity than Nedd9+/+ cells, and also had evidence of centrosomal and spindle abnormalities associated with deficient AurA function. Interestingly, the sensitivity of Nedd9−/− cells to small molecule inhibitors targeted at specific partner kinases and to chemotherapeutic agents used in breast cancer notably differed from that of Nedd9+/+ cells. Together, these data support the use of NEDD9 expression as a novel biomarker in establishing prognosis and drug responsiveness of tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B106.
Abstract B107: Targeting metastatic tumor cell functions by Src signaling interference using the small molecule Src inhibitor, saracatinib (AZD0530)
Authors: Siemann Dietmar W. , Dong Meiyu 
Published: June 2012

Abstract
Introduction: The metastatic spread of cancer cells remains the principal cause of treatment failure. Src is a non-receptor tyrosine kinase that is frequently over-expressed in malignances, and increased Src activity may be associated with poor patient prognosis. Src tyrosine kinase plays an important role in tumor cell survival, proliferation, migration and invasion. Since these cellular functions are key components of the metastatic cascade, Src may be a novel target for cancer therapy. The present studies were undertaken to investigate whether molecular intervention in Src associated signaling could reduce the metastatic spread of tumor cells. Specifically, the efficacy of saracatinib a potent, selective and orally available Src inhibitor, was evaluated in the highly metastatic rodent KHT sarcoma cell line.
Methods: The effect of saracatinib treatment on tumor cell functions, including viability, migration, invasion, and attachment, were examined by clonogenicity, migration/invasion and attachment assays, respectively. To assess saracatinib therapeutic effects on metastatic growth, tumor cells were either pretreated with saracatinib prior to intravenous injection or injected intravenously and then the mice were treated with saracatinib. In the latter case three protocols commencing immediately after tumor cell inoculation were investigated: a single 10 mg/kg dose of saracatinib; four 10 mg/kg doses of saracatinib given at 24 hr intervals; daily 10 mg/kg doses of saracatinib administered over a period of 3 weeks; in all protocols saracatinib was administered p.o. Twenty-one days after cell injection the number of lung metastases were determined.
Results: In vitro saracatinib doses ranging from 0.5–5.0 µM significantly reduced Src phosphorylation and functionally inhibited KHT cell proliferation, migration, invasion and adhesion. Pretreating KHT cells with saracatinib (1 or 5 µM, 24 hr) also reduced (2–4-fold) the ability of these cells to form lung metastases when injected into C3H mice via the tail vein. In vivo, daily doses of saracatinib (10 mg/kg) reduced the number of metastases formed at the end of a 3 week period by a factor of ∼2. A similar reduction in lung colonies was achieved with four 10 mg/kg doses of saracatinib given daily commencing immediately after tumor cell injection, or even a single 10 mg/kg treatment administered immediately after tumor cell inoculation.
Conclusions: The present studies explored the possibility of utilizing a molecular targeting strategy directed against key aspects of the metastatic cascade. The present findings demonstrate that saracatinib treatment significantly inhibits the ability of the cancer cells to escape the blood stream and invade at a secondary site supporting the notion that Src signal inhibition may hold considerable promise in impairing metastases formation.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B107.
Abstract B108: Inhibition of osteoblastic tumorigenesis of a novel human prostate cancer cell line by the blockade of TGF-β signaling
Authors: Sun LuZhe , Tang Yuping , Mishra Sweta , De Graffenried Linda , Werner Sherry , Troyer Dean , Thompson Ian 
Published: June 2012

Abstract
The skeleton is the most common site of prostate cancer metastasis, which often results in osteoblastic lesions. The associated fractures and pain are major causes of morbidity and mortality in prostate cancer patients. Transforming growth factor-beta (TGFβ) signaling has been shown to developmentally regulate bone mass and bone matrix properties. It has also been shown to promote osteolytic metastasis induced by breast cancer through its regulation of some secreted proteins that are involved in bone resorption. However, its role in prostate cancer-induced osteoblastic metastasis is much less clear. This is in part due to a lack of prostate cancer cell lines that can efficiently induce bone metastasis and osteoblastic lesions in animal models. We found that a newly established human prostate cancer PacMetUT1 cell line produces copious amounts of active TGFβ1 and induces extensive bone metastases in calvaria, rib, femur, and tibia when inoculated in the left cardiac ventricle of male nude mice. Histology revealed extensive bone formation in the metastatic lesions of the calvaria and femur with some areas showing bone resorption. Stable knockdown of TGFβ1 with a shRNA in the PacMetUT1 cells resulted in significantly reduced TGFβ1 secretion and decreased tumor incidence when the cells were directly injected into the tibiae of male nude mice. Systemic administration of either a small inhibitor of TGFβ type I receptor kinase or a pan TGFβ binding protein also decreased osteoblastic intratibial tumor incidence and growth. PacMetUT1 is a novel prostate cancer cell line for the investigation of mechanisms that regulate formation of metastatic osteoblastic bone lesions. Future studies will reveal whether targeting the TGFβ signaling pathway is feasible for the prevention and treatment of prostate cancer-induced bone metastasis.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B108.