bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3550: Curcumin suppresses growth of human mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis
Authors: Wang Ying , Rishi Arun K. , Wu Wenjuan , Polin Lisa , Sharma Sunita , Levi Edi , Albelda Steven , Pass Harvey I. , Wali Anil 
Published: June 2012

Abstract
Malignant Pleural Mesothelioma (MPM) is an aggressive, asbestos-related malignancy of the thoracic pleura. Although platinum-based agents are the first line of therapy, there is an urgent need for second-line therapies to treat the drug-resistant MPM. Cell cycle as well as apoptosis regulatory pathways are frequently altered in MPM and thus remain attractive targets for therapeutic intervention strategies. Curcumin, the major component in the spice turmeric, alone or in combination with other chemotherapeutics has been under investigation for a number of cancers. Here we investigated the biological and molecular responses of MPM cells to Curcumin treatments and the mechanisms involved. Flow-cytometric analyses coupled with western immunoblotting and gene-array analyses were conducted to determine mechanisms of Curcumin-dependent growth suppression of human (H2373, H2452, H2461, and H226) and murine (AB12) MPM cells. Curcumin inhibited MPM cell growth in a dose and time dependent manner while pretreatment of MPM cells with Curcumin enhanced Cisplatin efficacy. Curcumin activated stress-activated p38 kinase, caspases 9 and 3, caused elevated levels of proapoptotic proteins Bax, stimulated PARP cleavage, and apoptosis. In addition, Curcumin treatments stimulated expression of novel transducers of cell growth suppression such as CARP-1, XAF1, and SULF1 proteins. Oral administration of Curcumin inhibited growth of murine MPM cell-derived tumors in vivo in part by stimulating apoptosis. Thus, Curcumin targets cell cycle and promotes apoptosis to suppress MPM growth in vitro and in vivo. Our studies provide a proof-of-principle rationale for further in-depth analysis of MPM growth suppression mechanisms and their future exploitation in development of effective therapeutic treatment options against resistant MPM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3550. doi:10.1158/1538-7445.AM2011-3550
Abstract 3568: Characterization of AZD4547: An orally bioavailable, potent and selective inhibitor of FGFR tyrosine kinases 1, 2 and 3
Authors: Gavine Paul R. , Mooney Lorraine , Kilgour Elaine , Thomas Andrew P. , Al-Kadhimi Katherine , Beck Sarah , Coleman Tanya , Baker Dawn , Mellor Martine J. , Brooks Nigel AN , Klinowska Teresa 
Published: June 2012

Abstract
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signalling axis plays an important role in normal organ, vascular and skeletal development. Deregulation of FGFR signalling through genetic modification or over-expression of the receptors (or their ligands) has been observed in numerous tumour settings, whilst the FGF/FGFR axis also plays a key role in driving tumor angiogenesis. A growing body of data demonstrates that inhibition of FGFR signalling can result in anti-proliferative and/or pro-apoptotic effects, both in vitro and in vivo, thus confirming the validity of FGFR as a therapeutic target.
AZD4547 is a small molecule inhibitor which competes with ATP for binding to FGF receptors 1, 2 and 3, thus inhibiting autophosphorylation and downstream signalling. Using in vitro kinase assays, we demonstrate that AZD4547 is a potent inhibitor of FGFR's 1,2 and 3 with IC50 values of 0.2, 2.5 and 1.8nM respectively. AZD4547 is also highly selective vs a panel of over 70 other kinases (no activity at 10μM) and importantly vs Kinase Insert Domain Receptor (KDR) (&gt;120-fold window in cellular assays vs. FGFR2). In vitro treatment of a large panel of cell lines (&gt;100) with AZD4547 resulted in varying anti-proliferative responses, the most potent of which were almost exclusively confined to those cell-lines in which FGFR signalling was de-regulated. Treatment of these sensitive cell lines with AZD4547 for 1hr, demonstrated potent inhibition of phosphorylation of FGF receptors and downstream substrates including p44/42 MAPK. The anti-proliferative effects of AZD4547 appear to be cell line dependent and vary between potent G1-phase cell cycle arrest and apoptotic induction. Chronic in vivo dosing of AZD4547 up to 12.5mg/kg qd was well tolerated and resulted in dose-dependent growth inhibition in a KMS11 tumour xenograft model. This in vivo anti-tumor activity is correlated with exposure to AZD4547 and associated pharmacodynamic modulation of phospho-FGFR. These data confirm the novelty of AZD4547 as a potent and selective agent for the therapeutic treatment of tumors with deregulated FGF/FGFR signalling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3568. doi:10.1158/1538-7445.AM2011-3568
Abstract 3582: Targeting the FAK amino terminus F2 subdomain to disrupt growth factor receptor protein interactions, signaling and function
Authors: Ucar Deniz A. , Magis Andrew , He Di-Hua , Ostrov David , Hochwald Steven N. 
Published: June 2012

Abstract
Introduction: Focal adhesion kinase (FAK), IGF-1R and the c-MET are tyrosine kinases that induce cell proliferation, invasion, metastases and survival. We have previously shown that FAK physically interacts with growth factor receptors in pancreatic cancer cells and is involved in tumor progression. Since IGF-1R and c-MET have significant structural similarity, we hypothesize that both interact with a similar conserved amino acid “patch” on FAK. We also hypothesize that this patch can be targeted with small molecules to inhibit pancreatic cancer essential signaling pathways and induce apoptosis.
Methods: Based on Lipinski rules, we screened a chemical library of 240,000 compounds against a conserved patch on the F2 subdomain of FAK using in silico high throughput screening. We obtained the top scoring compounds from the National Cancer Institute Developmental Therapeutics Program and evaluated their effects on: 1) FAK protein interactions with c-MET and IGF-1R, 2) FAK, IGF-1R and c-MET kinase activity, 3)cell viability and apoptosis, and 4) growth of Panc-1 and Miapaca-2 pancreatic cancer cells in both orthotopic and direct xenograft mouse tumor models.
Results: Based on co-immunoprecipitation assays, our lead compound blocked the interaction of FAK with both c-MET and IGF-1R in pancreatic cancer cells, without altering their kinase activity. Treatment with our lead compound led to decreased phosphorylation of AKT, inhibited cell viability and induced apoptosis in a dose-dependent manner (range 2-20μM). In addition, the combination of our lead compound with either 5-FU or gemcitabine chemotherapy resulted in a synergistic decrease in pancreatic cancer cell viability. More importantly, 10mg/kg of lead compound via subcutaneous injection, effectively (p&lt;0.05) caused pancreatic tumor regression in vivo in both an orthotopic and direct xenograft model of pancreatic cancer. Conclusions: Our data suggest that targeting the protein interactions of FAK with growth factor receptors including c-MET and IGF-1R has specific therapeutic effects that can increase the sensitivity of pancreatic cancer cells to conventional chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3582. doi:10.1158/1538-7445.AM2011-3582
Abstract 3596: SCH727965, a cyclin-dependent kinases inhibitor, induces apoptosis in sarcoma cells through caspase 3- dependent pathway
Authors: Fu Wei , Ma Le , Chu Baoky , Wang Xue , Bagui Tapan K. , Bui Marilyn M. , Gemmer Jennifer , Altiok Soner , Letson Douglas G. , Pledger W. Jack 
Published: June 2012

Abstract
Sarcoma is a rare cancer in adults (1% of all adult cancers), but rather prevalent in children (about 15% of all childhood cancers). Toward the goal of developing new treatment options for sarcoma, we show that the cyclin dependent kinase inhibitor SCH 727695 (SCH) induces the apoptosis of several sarcoma cell lines including those resistant to doxorubicin and dasatinib. Also responsive to SCH were cell lines prepared in our laboratory from patients who had received adjuvant chemotherapy and explant derived from a human sarcoma xenograft in mice. Apoptosis occurred at low nanomolar concentrations of SCH, as did CDK inhibition. SCH activated the mitochondrial pathway of apoptosis as evidenced by caspase-9 cleavage and accumulation of cytoplasmic cytochrome c. SCH induced cell death in sarcoma cells that differ in RB and p53 expression. Amounts of the apoptotic proteins Bax and Bim increased in mitochondria, whereas amounts of the anti-apoptotic proteins Mcl-1 and Bcl-xL declined. Sarcoma cells apoptosed when co-depleted of CDK1 and CDK2 but not when depleted of other CDK combinations. We suggest that SCH triggers the apoptosis of sarcoma cells by inactivating CDK1 and CDK2 and that SCH may be useful for treatment of drug-resistant sarcomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3596. doi:10.1158/1538-7445.AM2011-3596
Abstract 3603: Development of novel small molecule PIM kinase inhibitors
Authors: Baldino Carmen M. , Caserta Justin , Lee Chee-Seng , Flanders Yvonne , Dumas Stephane , Li Jixian , Xu Chunping , Ning Jinying , Chen Taiping , Chen Yiyou 
Published: June 2012

Abstract
The PIM family of serine/threonine kinases, regulated by cytokines and growth factors, is over-expressed in multiple cancer types, including prostate tumors and hematologic malignancies. Recent reports of PIM kinase inhibitors have been implicated with anti-tumor growth activity in cancer cells and xenograft models, thus providing evidence that PIM kinases are attractive targets for anticancer drug development. Jasco Pharmaceuticals has developed a proprietary focused screening library of small molecules designed to inhibit PIM kinase activity. Kinase panel screening of the focused set identified nanomolar inhibitors from a novel chemical series. To further characterize the compounds, Jasco Pharma has established a research partnership with Crown BioScience for access to its cancer cell line and human primary tumor (HuPrime) xenograft models. The initial efforts of this partnership involved the identification of cancer cell lines which express high levels of PIM kinases for anti-proliferation studies and MOA exploration. Medicinal chemistry optimization provided a cluster of compounds with low single-digit micromolar anti-proliferation activity. These improved compounds have been demonstrated to act through a PIM driven mechanism of action, decreasing the levels of the proto-oncogene c-myc and the phosphorylation of the proteins BAD and 4E-BP1. In order to select the compounds with better in vivo drug activity, we performed in vivo PK followed by plasma protein binding assay (PPB) and drug-drug interaction (DDI) analysis instead of the whole series of in vitro ADME property assays. Four compounds were picked up for in vivo efficacy study according to their potency, in vivo pk characteristics, results of PPB and DDI. Preliminary results indicated that one compound had significant anti-tumor activity in MV-4-11 tumor models.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3603. doi:10.1158/1538-7445.AM2011-3603
Abstract 3605: KW-2450, a novel orally-active dual IGF1R/IR inhibitor: Antitumor effects in vitro and in vivo
Authors: Maekawa Yoshimi , Koizumi Fumito , Kashima Naomi , Suzuki Masayo , Umehara Hiroshi , Takahashi Hiroko , Nakamura Hiroaki , Nara Shinji , Nakazato Tomoyuki , Kanda Yutaka , Takahashi Takeshi , Akinaga Shiro , Shiotsu Yukimasa , Soga Shiro 
Published: June 2012

Abstract
KW-2450 is an orally active, multi-kinase inhibitor which inhibits both insulin-like growth factor receptor (IGF-1R) and insulin receptor (IR) with an IC50 of 7.39 nmol/L and 5.64 nmol/L, respectively. KW-2450 also exhibits inhibitory activities (&gt;90% at 100 nmol/L) against several protein tyrosine kinases such as FAK, FLT1, FLT3, JAK2, KDR, TRKA, and Aurora A. KW-2450 inhibited the growth of various types of malignant cells, and the reduction of phosphorylated IGF-1R or IR and their downstream signalling such as phosphorylation of AKT and ERK were observed from 10 to 30 nmol/L in vitro.
The PK/PD study of KW-2450 was conducted in a human colon cancer HT-29/GFP xenograft model. The plasma concentrations of KW-2450 were measured by LC/MS/MS method and the phosphorylation status of IGF-1R (P-IGF-1R) and AKT (P-AKT) in tumor tissue were examined by Western blotting. A single oral administration of KW-2450 showed inhibition of P-IGF-1R and P-AKT in tumor tissue in accordance with the increasing plasma concentration and peaked 2 hours after the administration of the drug at doses of 10 to 80 mg/kg. In this model, KW-2450 showed a statistically significant suppression of tumor growth by oral administration at a dose of 40 mg/kg once a day for 14 days. In addition, KW-2450 at a dose of 10 mg/kg showed a potent growth inhibitory activity against a human myeloma KMS-12-BM xenograft model, which is sensitive to the compound in vitro.
In mice, KW-2450 induced an increase of plasma glucose levels at 20 mg/kg and higher in a dose-dependent manner. However, the increase in glucose was transient and it returned to normal levels within 2 hours at 20 mg/kg, 4 hours at 40 mg/kg and 8 hours at 80 mg/kg. A similar trend was seen in insulin levels which return to normal levels within 4 hours at 10 mg/kg, 8 hours at 20 and 40 mg/kg, and 24 hours at 80 mg/kg. In summary, these pharmacological studies revealed that KW-2450 could act as a potent and selective dual IGF-1R/IR inhibitor and exert antitumor effects on various types of malignant cells in vitro and in vivo, although this compound shows multi kinase inhibitory activity in a cell free system.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3605. doi:10.1158/1538-7445.AM2011-3605
Abstract 3607: MET inhibitor sensitivity and resistance
Authors: Krumbach Rebekka , Kelter Gerhard , Maier Armin , Fiebig Heinz-Herbert , Beckers Thomas 
Published: June 2012

Abstract
MET, the receptor for HGF regulates proliferation, migration and metastasis of tumor cells. However, similar to EGFR-targeted drugs, highly sensitive tumors are rare, and the reasons for response to MET targeting agents are not yet clear.
In this study we identified patient-derived tumor xenografts and cell lines sensitive to the clinically developed small molecule MET inhibitors SGX-523, PF-04217903 and JNJ-38877605. Two different assays were applied, namely a monolayer assay measuring cell proliferation and a soft agar assay measuring colony formation of xenografts derived tumor cells ex vivo. In the monolayer assay out of a panel of 42 cell lines of 15 histotypes only the Asian gastric cancer cell line MKN45 was strongly affected by MET inhibition. The NSCLC cell lines LXFA 526L and LXFL 1121L showed moderate inhibition. In the colony formation assay 68 tumors of 15 histotypes were tested. The most sensitive tumor was the xenograft GXA MKN45, which was potently inhibited by all compounds. Other tumors sensitive to at least two of the MET inhibitors were from various tumor entities: NSCL adenocarcinoma (LXFA 526, LXFA 1647) and large cell carcinoma (LXFL 1121), renal cancer (RXF 616) and liver cancer (LIXF 658). Consistent with the function of MET in anchorage independent growth, the growth inhibiting effect of the compounds on tumor cells was more pronounced in the colony formation assay compared to the monolayer assay, highlighting the importance of a three dimensional matrix for MET inhibitor efficacy.
Molecular characterization of the tumors was done to understand the basis for sensitivity or resistance. We identified LXFA 526 and LXFA 1647 with high levels of phosphorylated MET, whereas LXFL 1121 produces large amounts of the ligand HGF. Nevertheless, tumors like LXFL 1176 or RXF 1220 with activated MET were resistant. LXFL 1176 carries an activating mutation of KRAS which could cause independence from MET signaling.
For tumors which responded only weakly to small molecule MET inhibitors, combinations of MET inhibitors with selected standard-of-care chemotherapeutic drugs and targeted agents were studied and data are presented.
In conclusion, only selected NSCL and gastric cancer are sensitive to MET inhibition due to defined genetic alterations. Although MET inhibitors are not broadly active as single agents, combinations with selected drugs have high clinical potential.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3607. doi:10.1158/1538-7445.AM2011-3607
Abstract 3609: Homology structure-based design, synthesis and biological evaluation of a series of novel Axl and Mer kinase inhibitors
Authors: Mollard Alexis , Warner Steven L. , Call Lee , Wade Mark , Bearss Jared , Verma Anupam , Yang Mei , Sharma Sunil , Bearss David J. , Vankayalapati Hariprasad 
Published: June 2012

Abstract
Axl and Mer kinases belong to the TAM family that was first identified as a transforming gene in chronic myeloid leukemia. Its intracellular region has the typical receptor tyrosine kinase (RTK) structure and its extracellular domain is similar to cadherin-type adhesion molecules in that it is composed of fibronectin type II and immunoglobulin (Ig) motifs. Axl binds various growth factors, with vitamin K-dependent protein growth-arrest-specific gene 6 (GAS6) being the best studied. Axl is involved in mesenchymal and neuronal development as well as in cell survival, adhesion and blood vessel function. High levels of Axl are found in various tumors, including malignant glioma and metastatic colon, ovarian and breast cancers, and it plays a role in cancer invasion. Recent development of Axl inhibitors suggested that inhibition of Axl activity may be impact both tumor angiogenesis and tumor growth. We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, inhibitors of Axl and Mer kinases. Our initial lead compound was identified via cross-docking experiments utilizing the homology model of Axl kinase and screening of a diverse in-house chemical library. We subsequently carried out structure-activity relationship studies and optimized the lead structure which has 2 to 6.1 μM inhibition activity to 2-fold improvement in the Axl and Mer kinase activities to 730 nM. As a starting point for further optimization, it was considered that the modest of these series could be improved by introducing a spacer at the aryl piperazine moiety and focused on maximizing the in vitro potency, addressing the SAR and molecular properties. We further explored Leu620, hydrophobic, Gly543, Phe547 and DFG motif sites through scaffold hoping lead to the identification of an electron-withdrawing functional groups lead to the compound HCI-2084 and HCI-2091 which exhibited potent Axl kinase inhibition activity of 7 and 12 nM in Axl kinase assay and 30-50 nM is panel of cancer cell lines. These novel series of compounds were synthesized in two-step procedure via a standard cross-coupling reaction or with various substituted aryl amine derivatives under amination conditions. In a subsequent step we employed Buchwald-Hartwig amination reaction to prepare target molecules. Due to the ready synthesis accessibility, we extensively investigated the SAR improving the RO5, solubility and permeability parameters. The details of these results will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3609. doi:10.1158/1538-7445.AM2011-3609
Abstract 3624: Therapeutic targeting of glioblastoma multiforme using anti-EMP2 antibodies
Authors: Fu Maoyong , Goodglick Lee , Gordon Lynn K. , Braun Jonathan , Wadehra Madhuri 
Published: June 2012

Abstract
Despite recent advances in molecular classification, surgery and radiotherapy, and the integration of novel molecular targeted therapies, the clinical outcome of patients with malignant brain tumors remains extremely poor. In particular, the prognosis for patients with glioblastoma multiforme (GBM), the most common and aggressive form of brain tumors, yields only a median survival of 12 months; the 5-year survival rate of less than 5%. In this report, we show that epithelial membrane protein-2 (EMP2) is a novel tetraspan protein upregulated at both the mRNA and protein levels in 95% of patients with GBM.
We have started to characterize the functional consequence of EMP2 up-regulation in GBM cells. Within these cells, EMP2 appears to orchestrate the membrane expression of proteins required for cell migration and invasion. Specifically, our past results as well as our current preliminary results strongly suggest that EMP2 modulates the repertoire of integrin heterodimers on the cell surface and stabilizes the FAK complex and signaling required for cell migration and GBM progression. We further show that this upregulation is sufficient to induce tumor growth in a number of xenograft models using immunocompromised mice.
The high expression of EMP2 on the membrane of GBM cells caused us to predict that we could exploit this increase in expression using anti-EMP2 recombinant antibodies. Using both anti-EMP2 antibody fragments (diabodies) as well as a humanized anti-EMP2 IgG1, we show that anti-EMP2 antibodies specifically induce apoptosis both in vitro and in vivo using GBM xenograft models. We have also started characterizing any potential toxicity that may arise from anti-EMP2 therapy. Importantly, no systemic or histological toxicity was observed at therapeutic doses. Thus, we predict that EMP2 expression can be targeted in GBM to develop a novel therapeutic strategy, and it may have broad applicability given that EMP2 expression is upregulated in a number of other tumors such as ovarian and breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3624. doi:10.1158/1538-7445.AM2011-3624