bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B102: Zibotentan (ZD4054), a specific antagonist of the endothelin A receptor, suppresses the metastatic phenotype of bladder cancer cells in vivo
Authors: Thomas Christopher Y. , Dunlap-Brown Marya , Brautigan David L. , Theodorescu Dan 
Published: June 2012

Abstract
There is mounting evidence that endothelin-1(ET-1) / endothelin receptor axis contributes to the pathogenesis of urothelial bladder cancer. In a previous study, reduced expression of the metastasis suppressor protein RhoGDI2 in bladder cancer cell lines and tumors was associated with increased expression of ET-1 (Titus B et al, Ca Res 65:7320, 2005). This suggests that ET-1 acts down-stream of repressed RhoGDI2 expression to promote the metastatic phenotype. If so, then blocking activation of endothelin receptor A (ETAR) by ET-1 would suppress this phenotype. To test this hypothesis, Zibotentan, a specific inhibitor of ETAR (IC50 = 21 nM), was evaluated for anti-tumor activity in a xenograft metastasis model. To screen for toxicity, 40 athymic nu/nu female received 12.5 to 50 mg/kg/d of zibotentan by gastric lavage for 97 days. The drug was well tolerated at all dose levels and produced no significant changes in body weight, behavior, or general physical condition. In a separate experiment, T24T bladder cancer cells (106 cells suspended in 0.1 mL of medium) were inoculated into the tail veins of a second group of 40 mice. One week later, 20 of animals were treated with zibotentan 50 mg/Kg/d and 20 controls received vehicle only. After 90 days, the animals were euthanized and the lungs were removed, fixed with Bouin's solution, stained, and examined by microscopy to determine the number and size of metastasis (large ≥3mm, small &lt;3mm). Metastases were found in 12/20 (60%) controls and 3/20 (15%) of treated mice (p=0.024); overall, 89 metastases were identified in the controls and 19 in the treated animals (p=0.012). Although the drug-treated mice had fewer metastases, 13/19 (68%) of these were classified as large tumors as compared to 20/89 (22%) in the control group. These results suggest that inhibition of ETAR signaling by zibotentan reduced the frequency and number of metastases, most likely by suppressing metastatic colonization rather than the growth of established metastases. The latter is consistent with earlier data that inhibition of ETAR does not block the proliferation of T24T cells in vitro. Taken together, these and the previous observations provide a rationale for clinical trials to determine if treatment with zibotentan will prevent or delay the development of metastatic disease in patients with clinically localized but high-risk bladder cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B102.
Abstract B11: Preclinical and preliminary phase 1 trial results of JI-101: A novel, oral tyrosine kinase inhibitor that selectively targets VEGFR2, EphB4, and PDGFR
Authors: Velleca Mark , Brittelli David , Elkin Lisa , Klein Udo , Mitchell Scott , Qian Dapeng , Qian Xiaobing , Srinivasa Sreesha , Stephan Thomas , Govindarajan Raman , Stern Warren , Gordon Michael , Sharma Sunil , Miller Linda 
Published: June 2012

Abstract
Introduction: JI-101 is a highly selective and potent angiogenesis inhibitor with unique EphB4 activity that distinguishes it from other agents in clinical development. We report the preclinical pharmacology and early clinical experience with this compound.
Procedures: Lead optimization was used to identify cgi1842 (now JI-101) with a targeted activity profile that is selective and unique. JI-101 was tested in binding, enzymatic, and cell-based assays for activity against kinase and non-kinase targets. Preclinical in vivo testing for PK, PD, efficacy, and safety pharmacology was performed in mouse, rat, guinea pig, and dog. A Phase I clinical trial is underway: 9 patients, 3/cohort, are being treated with 28-day oral daily dosing at 100 mg, 200 mg, and 400 mg. PK, PD, and imaging analyses are being performed.
Data: JI-101 has a MW of 466D and high (&lt;100 nm) potency against VEGFR2, EphB4, and PDGFR in enzymatic and cell-based assays. Broad kinase cross-screening (Ambit KinomeScan, 445 kinases) reveals that JI-101 is highly selective for angiogenic kinases with only 23 kinases demonstrating a Kd 15). JI-101 was co-administered with paclitaxel in a MDA-MB-231 mouse xenotransplant model, resulting in greater efficacy and no increased toxicity. Based on 28-day GLP toxicology studies conducted in rat and dog, a 100 mg qd starting dose (2 × 50 mg capsules) was chosen for Phase I studies. JI-101 appears to be very well-tolerated to date with no dose limiting toxicities. Patients have received 1–8 cycles and 5 remain on study at 100 mg (1 pt), 200 mg (1 pt), and 400 mg (3 pt). Manageable hypertension has been seen in all cohorts indicating a possible PD effect. Further clinical details of the PK, PD, tolerability and efficacy of JI-101 will be presented.
Conclusions: JI-101 potently inhibits 3 critical angiogenic kinases (VEGFR2, EphB4, and PDGFR) and is the only such “triple” angiogenesis inhibitor currently in development. JI-101 shows robust preclinical and clinical pharmacology and is well-tolerated to date in human trials. In tumors where EphB4 may play an oncogenic role, such as head and neck cancer, JI-101 may have anti-proliferative effects in addition to anti-angiogenic effects and should be amenable to combination therapy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B11.
Abstract B13: Identification of a metalloprotease-chemokine signaling system in the ovarian cancer microenvironment: Implications for antiangiogenic therapy
Authors: Agarwal Anika , Tressel Sarah , Kaimal Rajani , Bala Marianthi , Iam Francis , Covic Lidija , Kuliopulos Athan 
Published: June 2012

Abstract
Ovarian cancer is a lethal gynecologic malignancy with poor survival, hence it would benefit from therapies that block key signaling pathways involved in tumor-stromal interactions and tumor vascularity. We previously showed that Protease Activated Receptor 1 (PAR1) is an important regulator of angiogenesis, ascites and metastasis in peritoneal mouse models of ovarian cancer. In this study we tested the hypothesis that matrix metalloprotease1 (MMP-1) activates PAR1 which stimulates angiogenesis and tumorigenesis in ovarian cancer through its paracrine control of the endothelial CXCR1/2 receptors. We demonstrated that MMP-1-PAR1 stimulation leads to a 2–5 fold increase in several angiogenic factors including IL-8 and GRO from ovarian cancer cells. These secreted factors then act on endothelial CXCR1/2 receptors to cause endothelial cell proliferation, tube formation and migration. A cell penetrating pepducin, PZ-206, that targets the third intracellular loop of CXCR1 and CXCR2 receptors (also known as X1/2pal-i3) can significantly inhibit both endothelial cell proliferation and tube formation. Avastin-the VEGF blocking antibody was unable to inhibit IL-8 and GRO- stimulated tube formation. To validate our in vitro observations we injected matrigel plugs containing MMP-1 stimulated/unstimulated ovarian cancer (OVCAR-4) conditioned media into the flanks of nude mice. After 7 days, the matrigel plugs were harvested and stained for CD31 and whole mount confocal microscopy was done in a blinded manner. Mice injected with MMP-1 stimulated, OVCAR-4 CM showed an 8 fold increase in blood vessel formation which was significantly inhibited by injecting mice with CXCR1/2 inhibitor PZ206 (5mg/kg/d) as compared with control pepducin or vehicle. These studies will help us validate novel therapeutic targets such as CXCR1/2 pepducins for ovarian cancer that block angiogenesis and tumor progression to improve survival in this lethal disease.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B13.
Abstract B133: SEA technology: A novel strategy for enhancing antibody effector function
Authors: Alley Stephen C. , Sussman Django R. , Jeffrey Scott C. , Torrey Lindsay , Burke Patrick J. , Klussman Kerry , Okeley Nicole M. , Senter Peter D. , Benjamin Dennis R. 
Published: June 2012

Abstract
The activity of monoclonal antibodies (mAbs) can be enhanced by a number of chemical and genetic strategies. We describe a novel strategy for enhancing antibody-dependent cellular cytotoxicity (ADCC) through modification of the mAb carbohydrate during expression, designated Sugar Engineered Antibody (SEA) technology. A series of small molecule fucose analogs were added to mAb-expressing Chinese hamster ovary (CHO) cells, with the resulting mAbs showing a significant reduction in their carbohydrate fucosylation. We demonstrate that these mAbs show a substantial increase in ADCC activity and an improvement in CD16 binding. We find that the mechanism of action is inhibition of GDP-mannose dehydratase (GMD), the first enzyme in de novo synthesis of GDP-fucose, leading to a depletion of substrate for the fucosyltransferase responsible for mAb carbohydrate fucosylation. We also demonstrate that this strategy yields mAbs with significantly reduced fucosylation in large scale CHO cell culture as well as in additional expression systems such as hybridomas and transient transfectants. Since genetic modification of the mAb-producing cell line is not required, SEA technology can be readily applied from the mAb screening to manufacturing stage to generate effector function enhanced therapeutic antibodies.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B133.
Abstract B140: In vitro sensitivity profiling identifies selectively responsive tumor types and molecular subtypes to the PI3K inhibitor GSK2126458
Authors: Greshock Joel , Hardwicke Mary Ann , Conway Theresa , Degenhardt Yan , Cartee Leanne , Moy Christopher , Lager Joanne , Wooster Richard , Bachman Kurtis 
Published: June 2012

Abstract
The phosphoinositide 3-kinase (PI3K) signalling pathway is activated in a broad spectrum of human cancers. Activation of this pathway often occurs indirectly by somatic aberrations of receptor tyrosine kinases, or directly by mutations in PI3K genes, such as PIK3CA. GSK2126458 is a novel, orally administered inhibitor of wild type phosphoinositide 3-kinase alpha (PI3K) and the common activation mutants of p110 found in human cancers that has recently entered Phase I clinical trials. In order to determine histological and genetic profiles of patients that are more likely to gain clinical benefit from GSK2126458, the compound was tested in a 3-day continuous exposure proliferation assay on a panel of 198 genetically characterized human cancer cell lines derived from a diversity of tissue types. Cells originating from bladder, breast, and ovarian cancers are most responsive based on growth inhibition metrics (gIC50's). Breast cancer cell lines harboring activating mutations of PIK3CA are associated with increased levels of response (p = 0.027); an observation which was validated in an independent cohort of 53 breast cell lines (p = 0.021). While colon cancers exhibit an intermediate level of sensitivity compared to other tumor types, specific exon 5 G12/13 hotspot mutations of the KRAS gene are predictive of decreased cellular response (p = 0.025). Additionally, a comparison of these cell line proliferation data to a similarly-assayed panel of 19 compounds of diverse target class shows that while the overall pattern of cellular response to GSK2126458 resembles other inhibitors or the PI3K/AKT/mTOR pathway, distinctions emerge that correlate with pathway targeting strategy. For example, while breast cancers are preferentially responsive to GSK2126458 and other inhibitors of this pathway, cell lines harboring PTEN mutations are less responsive to GSK2126458 than to compounds directly targeting AKT. Collectively these data suggest a unique profile for GSK2126458 among compounds that inhibit the PI3K/AKT/mTOR pathway. Positive predictors of response, such as PIK3CA mutations in breast cancer, may identify patients who are most likely to benefit from GSK2126458. The use of this predictor to select patients has the potential to reduce the size of a clinical registration trial for GSK2126458 by approximately 25%, thereby limiting cost and accelerating the development of this compound.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B140.
Abstract B142: PKI-402, a dual PI3K/mTOR inhibitor
Authors: Mallon Robert G. , Holland Irwin , Feldberg Larry , Lucas Judy , Abraham Robert , Gibbons Jay , Dehnhardt Christoph , Venkatesan Aranapakam , Santo Efren Delos , Chen Zecheng , Santos Oswaldo dos , Ayral-Kaloustian Semiramis , Brooijmanns Natasja , Mansour Tarek 
Published: June 2012

Abstract
We have developed small molecule inhibitors of the PI3K/mTOR signaling pathway. An example is PKI-402. This compound is a reversible, ATP competitive, and equipotent inhibitor of class I PI3Ks, including the E545K and H1047R mutant forms of PI3K- , and mTOR (IC50 vs PI3K- = 1nM). Selectivity of PKI-402 was established in a screen against 236 diverse human kinases. PKI-402 caused in vitro growth inhibition of human tumor cell lines derived from breast, brain (glioma), pancreas, and non small cell lung cancer (NSCLC) tissues. In many cases IC50 values were &lt;100 nM. In vitro, PKI-402 suppressed phosphorylation of PI3K and mTOR effector proteins, particularly p-Akt at threonine 308 (T308), at concentrations that closely matched those that inhibited tumor cell growth. In MDA361, a breast tumor line with elevated levels of Her2 receptor, and mutant PI3K- (E545K), 30 nM PKI-402 induced cleaved PARP, a marker for apoptosis. This occurred after an exposure time of 4 h. In vivo, PKI-402 displayed anti-tumor activity when administered by IV route in glioma (U87MG, PTEN), NSCLC (A549; K-Ras, STK11), and breast (MDA361: Her2+, PIK3CA [E545K]) xenograft models. A key question about PI3K/mTOR signaling inhibitors is: can they cause tumor regression in pre-clinical models? At 25, 50, and 100 mg/kg PKI-402 caused regression of MDA361 tumors. PKI-402 effect was most pronounced at 100 mg/kg (daily for 5 days [dx5], 1 round), which reduced an initial tumor volume of 260 mm3 to 129 mm3, and prevented tumor re-growth for 70 days. Tumor re-growth occurred between days 16–20 when PKI-402 was administered at 25 and 50 mg/kg (dx5, 2 rounds). However, when PKI-402 was re-administered at 100 mg/kg (dx3, 1 round) at day 37 (25 mg/kg group), large tumors (∼600 mm3) were reduced in volume by 69%. In MDA361 tumor tissue PKI-402 at 100 mg/kg (single dose) caused sustained suppression of Akt phosphorylation at both the T308 and S473 sites, and induced cleaved PARP. Suppression of p-Akt was complete at 8 h, and still evident at 24 h; while cleaved PARP was evident at both 8 h and 24 h. In vivo biomarker analysis of heart and lung tissue showed minimal effect on p-Akt and no induction of cleaved PARP by PKI-402 at 100 mg/kg. Preferential accumulation of PKI-402 in tumor tissue was observed. It may be that complete and sustained suppression of p-Akt is needed to cause tumor regression in the MDA361 and other tumor xenograft models. We are testing whether dual PI3K/mTOR inhibitors can durably suppress p-Akt, induce cleaved PARP, and cause tumor regression in a diverse set of human tumor xenograft models.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B142.
Abstract B144: NVP-BEZ235, a dual inhibitor of PI3K and mTOR, induces MAPK phosphorylation in HER2-positive cells
Authors: Elizalde Violeta Serra , Eichhorn Pieter JA , Scaltriti Maurizio , Prudkin Ludmila , Rodriguez Olga , Guzman Marta , Baselga José 
Published: June 2012

Abstract
The PI3K pathway is highly deregulated in human cancer with the most common alterations being amplification of the receptor tyrosine kinases (RTKs) EGFR and HER2 and mutations in PI3K itself or inactivation of the tumor suppressor PTEN. Thus, the rationale exists to develop therapeutic agents targeting the PI3K/AKT pathway. Several small molecule inhibitors targeting PI3K, AKT and mTOR are now in clinical trials. However, these novel compounds may interfere with regulatory feedback loops. One such example involves the activation of AKT following rapamycin analogues treatment, such as everolimus, an allosteric mTOR inhibitor. Blocking mTOR signaling also alters the regulation of other signaling pathways, like the MAPK cascade. The aim of this study was to investigate the mechanism/s by which inhibition of the PI3K pathway leads to activation of MAPK kinase signaling in breast cancer cell lines and its relevance in tumor treatment. We have observed an increased MAPK phosphorylation in HER2 positive BT474, SKBR-3, MDA-361 and MCF-7HER2 cells when treated with NVP-BEZ235, a dual inhibitor of both mTOR and p110, the catalytic component of PI3K. The increase of P-MAPK was observed by western blot and correlated with hyperphosphorylation of several RTKs. PD325901, a MEK1/2 inhibitor, or lapatinib, a HER1/2 tyrosine kinase inhibitor, reverted the NVP-BEZ235-induced MAPK phosphorylation. On the other hand, NVP-AEW541, an IGFR-1 tyrosine kinase inhibitor, did not prevent NVP-BEZ235-dependent HER2 phosphorylation and downstream MAPK activation. Activation of MAPK upon administration of NVP-BEZ235 was also observed in vivo. We are currently investigating the possible involvement of known regulatory feedback loops as well as the individual RTK contribution. Activation of parallel pathways in a condition of PI3K inhibition may reduce potential benefits of these anti-cancer treatments. For this reason, we propose the combination of an anti-HER2 therapy together with PI3K inhibitors for the treatment of HER2 positive tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B144.
Abstract B162: Differential stress-induced CXC-chemokine expression, signaling and responses in PTEN-deficient prostate tumors
Authors: Waugh David J. , Maxwell Pamela , McClatchey Ashleigh 
Published: June 2012

Abstract
We have shown that expression of the proinflammatory CXC chemokine, interleukin-8 (IL-8) and its receptors CXCR1 and CXCR2 is elevated in malignant prostate cancer (CaP) epithelium. Published studies confirm that hypoxia and/or chemotherapy-induced stresses underpin AP-1, HIF-1 and NFκB-mediated transcription-driven increases in IL-8, CXCR1 and CXCR2 expression in CaP cells. The current study determines the relevance of PTEN, a commonly mutated or deleted tumor suppressor gene in CaP, in regulating the induction of CXC-chemokine signaling and the cellular response of stressed CaP cells. Time-dependent increases in CXCL8, CXCR1 and CXCR2 mRNA were observed in PTEN-deficient LNCaP and PC3 cells. ELISA confirmed increased IL-8 secretion following hypoxia, while immunoblotting confirmed elevated CXCR1 and CXCR2 expression in both cells. In contrast, CXCL8, CXCR1 and CXCR2 expression was only marginally up-regulated in PTEN wild-type DU145 and 22Rv1 cells under hypoxia. Subsequently, PTEN status was shown to regulate the magnitude and duration of CXC-chemokine-promoted signaling and altered gene expression profiles. For example, CXCL8 administration increased expression of HIF-α and increased the activity of this transcription factor in PTEN-deficient LNCaP and PC3 cells but not in PTEN wild-type cells. Furthermore, expression of HIF-1 target genes (VEGF, TGF) was also induced following CXCL8 stimulation in PTEN deficient but not PTEN wild-type cells. Attenuation of PTEN in the DU145 and 22Rv1 cells using siRNA revealed the CXCL8-induced responses including the increase in HIF-1 expression and activation. Functionally, the transcription-mediated elevation in IL-8 signalling underpins an increased survival of hypoxic prostate cancer cells to DNA-damage-based chemotherapy. Additionally, CXCL8 signaling was shown to induce cysteine cathepsin and serine protease expression in CaP cell lines and stromal cells, indicating a capacity to promote tumor invasion. In summary, our studies suggest that the magnitude of CXC-chemokine signaling and its subsequent effects are enhanced in PTEN-deficient prostate tumors, promoting proliferation, survival, chemoresistance, androgen-independent transition and changes in the tumor microenvironment.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B162.
Abstract B170: Downregulation of Yes-associated protein 1 (YAP1) expression reduces cell proliferation and clonogenicity of pancreatic cancer cells
Authors: Diep Caroline H. , Zucker Kelly , Watanabe Aprill , Hostetter Galen , Munoz Ruben , Von Hoff Daniel D. , Han Haiyong 
Published: June 2012

Abstract
Recent genetic studies in Drosophila have shown the Hippo pathway to be a potential tumor suppressor pathway that could play vital role(s) in mammalian cancer development. The Hippo pathway regulates organ size by inhibiting cell proliferation and promotes cell apoptosis upon its activation. The Yes Associated Protein 1 (YAP1) is a nuclear effector that promotes cell growth as a transcription co-activator. In human cancer, YAP1 has been shown to be a candidate oncogene as the chromosomal region containing YAP1 (11q22) has been reported as amplified and over-expressed in several tumor types, such as colon, liver, and lung (Overholtzer et al. 2006 PNAS, 103: 12405–12410). To determine the role of YAP1 in the tumorigenesis and progression of pancreatic cancer, here we examine YAP1 protein expression in pancreatic tumors and investigate the phenotypic effects of YAP1 down-regulation in cultured pancreatic cancer cells. Initially, we evaluated YAP1 expression in pancreatic tumors through immunohistochemistry (IHC) using tissue microarrays (TMA) to determine relative protein abundance and localization at the tissue and cellular level. YAP1 staining intensities were moderate to strong in the nucleus and cytoplasm of the cells, whereas the companion normal pancreas tissue showed negative to weak staining. In cultured cells, YAP1 expression and localization was modulated by cell densities. YAP1 total protein expression and Ser127 phosphorylation increased concurrently with cell density in whole cell lysates and cytosolic fractions, but does not in nuclear fractions. Additionally, transfection of YAP1-targeting siRNA oligonucleotides within pancreatic cancer cell lines, BxPC-3 and PANC-1, significantly decreased cell viability and reduced cell proliferation in vitro. An additional observation was the diminished anchorage-independent growth on soft agar of BxPC-3 and PANC-1 cells upon transfection with YAP1 siRNA oligonucleotides. The number of colonies formed were approximately 5% in BxPC-3 (p&lt;0.007) and 20% (p&lt;0.04) in PANC-1 compared to the negative siRNA control. Furthermore, the reduction of YAP1 protein expression by siRNA oligonucleotides correlates with the reduced growth on soft agar. The silencing of YAP1 abated clonogenicity of pancreatic cancer cells, suggesting a role of YAP1 in tumorigenesis. In summary, we demonstrate that YAP1 is overexpressed in pancreatic cancer and potentially plays an important role in the tumorigenesis and growth of pancreatic cancer. (This work was supported by a grant from the National Foundation for Cancer Research.)
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B170.