bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5763: VCAM1 mediates aggressive bone metastasis outbreak from tumor dormancy by engaging α4β1-positive osteoclast progenitor cells
Authors: Lu Xin , Yang Qifeng , Yuan Min , Mu Euphemia , Reiss Michael , Haffty Bruce , Massagué Joan , Kang Yibin 
Published: February 2011

Abstract
In breast cancer patients, disseminated tumor cells can maintain in dormancy at secondary organs for a long period before relapse into life-threatening metastases. However, the molecular understanding of this process is still very limited. Here, we show that Vascular Cell Adhesion Molecule-1 (VCAM1) is essential for the conversion from dormancy to macrometastasis in a xenograft mouse model of breast cancer bone metastasis. A weakly bone-metastatic subline (SCP6) of the human breast cancer cell MDA-MB-231 was found to give rise to strongly metastatic derivatives after six-month in vivo dormancy in nude mice. Whereas no additional chromosomal alterations were detected by array-CGH, the derivatives significantly upregulated a handful of genes based on microarray analysis. Five candidate genes were evaluated by silencing their expression using short-hairpin RNA in the highly metastatic derivatives and tested by in vivo bone metastasis assay. Only the loss of expression of VCAM1 dramatically reduced the metastasis ability. Ectopic overexpression of VCAM1 in dormancy-prone sublines allowed the outgrowth of bone metastasis. We successfully blocked the initiation and the progression of bone metastasis using purified monoclonal antibodies against VCAM1 or its receptor VLA4 (integrin α4β1). Biochemical analysis showed activated NF-κB pathway is essential for the upregulation of VCAM1. Bone metastases formed by VCAM1-overexpressed tumor cells harbored numerous TRAP-positive osteoclasts and their number was dramatically attenuated with VCAM1 or VLA4 antibodies. Expression analysis using cell lines and fresh murine bone marrow showed progenitor and mature osteoclasts express α4β1. Functional assays found VCAM1 promoted osteoclast differentiation by directly tethering the α4β1-positive osteoclast progenitors. Mice with VCAM1-positive bone metastases showed enriched CD11b-positive α4β1-positive monocytic progenitor cells of osteoclasts in the bone marrow compared with mice free of bone metastases. Finally, tissue microarray analysis showed VCAM1 is upregulated in breast tumor epithelial cells in a subgroup of patients and is associated with early relapse. Overall, our study (1) established a novel mouse model for bone metastasis dormancy of breast cancer; (2) demonstrated VCAM1 as the key mediator for the conversion from dormancy to overt metastasis through engaging α4β1-positive osteoclast progenitors; (3) developed monocloncal antibodies against VCAM1 or VLA4 as promising therapeutic agents for preventing and treating bone metastasis of breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5763.
Abstract 5774: Identification of novel targeted therapies for human triple-negative breast cancer
Authors: Tomlinson Christine C. , Bennett Christina N. , Hollinghead Melinda , Green Jeffrey E. 
Published: February 2011

Abstract
Triple Negative (TN) breast cancers are characterized by the lack of estrogen receptor, progesterone receptor, and Her2 in the tumors. Currently, unlike breast cancers that are hormone responsive or Her2+, there are no targeted therapies for this subtype of breast cancer. Additionally, TN breast cancer is frequently diagnosed in younger women, often prior to the age of routine mammography with young African-American women having a disproportionately higher incidence and mortality from TN breast cancers than Caucasians. Despite advances in the treatment of breast cancer, molecular characteristics of this subtype remain poorly understood and improved therapies are critically needed.
Gene expression profiling has identified genetically engineered mouse (GEM) models that share important correlations with human breast tumor subtypes. In particular, the C3(1)/TAg GEM model appears to best represent basal-like/triple negative human breast cancers in several ways. The C3(1)TAg GEM model develops primary and metastatic mammary tumors following a progressive course characteristic of human breast tumor development, loss of p53 and Rb functions via SV40 T-antigen expression and amplifications of syntenic regions (hu. Chr. 12p12; mus. Chr. 6, a region containing K-RAS.) We have previously identified a critical proliferation/DNA repair/cell cycle gene signature (TAg signature), in primary mammary tumors from SV40 TAg mice that is also characteristic of human basal-like breast cancers. The TAg signature was also found to be highly predictive of human breast cancer prognosis.
By targeting the up-regulated genes identified in the TAg signature, we have identified novel targets for the treatment of TN breast cancer. We have also performed synthetic lethality studies in which gene knockdown has been combined with common chemotherapy agents (cisplatin and paclitaxel) and agents currently in clinical trials (gemcitabine, Chk1 and Notch signaling inhibitors) to identify novel combination therapies. Several combinations are being tested in in vivo tumor transplant and human xenograft experiments.
These studies have shown that the TAg signature can be used for the identification of new targets through siRNA screens of up-regulated genes in the signature and help determine new targets for preclinical testing of candidate drugs in novel combinations for treatment of TN breast cancer. The results of these studies may be translated into potentially effective therapies for women with aggressive forms of TN breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5774.
Abstract 5776: Discovery of AMG 900, a highly selective, orally bioavailable inhibitor of aurora kinases with efficacy in preclinical antitumor models and activity against multidrug-resistant cells
Authors: Geuns-Meyer Stephanie , Cee Victor J. , Deak Holly L. , Du Bingfan , Hodous Brian L. , Nguyen Hanh N. , Olivieri Philip R. , Romero Karina , Schenkel Laurie B. , Patel Vinod F. , Be Xuhai , Bush Tammy L. , Chung Grace , Eden Patrick , Huang Liyue , Kendall Richard , Lin Min-Hwa Jasmine , Radinsky Robert , Ziegler Beth , Payton Marc 
Published: February 2011

Abstract
The aurora family of serine/threonine kinases (Aurora-A, -B, -C) regulate cell-cycle progression in mammalian cells. Whereas aurora kinase C function appears restricted to meiosis in males, aurora kinases A and B are essential for proper chromosome congression, segregation, and cytokinesis during mitosis. Aurora kinases A and B have been implicated in tumorigenesis, with overexpression levels correlating to clinical staging of cancers and poor prognosis. Thus, these mitotic kinases have become the subject of much interest as targets for anticancer therapy.
N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine was a key aurora kinase inhibitor lead, possessing oral bioavailability in rats that was lacking in the anthranilamide compounds from which it was derived. This phthalazine compound possessed a key feature that was deemed important to maintain in a clinical candidate: potency against a model multidrug resistant (MDR) cell line (MES-SA Dx5) commensurate with its activity against a cell line that does not overexpress P-gp (HeLa). Improved in vivo potency was desired, as measured by suppression of the phosphorylation of the aurora kinase B substrate Histone H3 on Ser10 six hours after dosing. SAR from targeting this improvement in in vivo activity uncovered a delicate balance between protein binding, pharmacokinetic parameters, and cell potency in MES-SA Dx5 cells. AMG 900 was identified as a suitable candidate for clinical development based on its low single digit nanomolar potency against MDR cell lines, robust PD response (with complete suppression of Histone H3 phosphorylation at six hours), and high selectivity against other kinases. Oral administration of AMG 900 at a well-tolerated dose of 4 mg/kg BID inhibited tumor growth (83% TGI; p &lt; 0.0001) in an HCT116 xenograft model. AMG 900 is currently undergoing phase 1 clinical evaluation in patients with advanced solid tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5776.
Abstract 5777: EMD 1214063, an exquisitely selective c-Met kinase inhibitor in clinical phase 1
Authors: Schadt Oliver , Bladt Friedhelm , Blaukat Andree , Dorsch Dieter , Friese-Hamim Manja , Fittschen Claus , Graedler Ulrich , Meyring Michael , Rautenberg Wilfried , Stieber Frank , Wilm Claudia 
Published: February 2011

Abstract
The role of the receptor tyrosin kinase c-Met in tumor progression, metastasis and aggressiveness has been convincingly demonstrated in preclinical and early clinical settings. Several compounds with different selectivity profiles inhibiting c-Met are currently under preclinical/clinical investigation and might emerge as valuable cancer therapeutics in the future. During an HTS run N-(3-(3,6-Dihydro-5-(3,4-dimethoxyphenyl)-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl)-phenyl)-carbaminic acid-(3-(N,N-diethylamino)-propylester) (1) was identified as an attractive lead structure with an interesting overall profile (clogD (7.4): 2.5, S (pH 7.4): &gt;100 µg/ml, IC50 (c-Met in vitro): 30 nM, IC50 (c-Met cellular): 800 nM) providing a valid starting point for lead optimization. The co-crystal structure of 1 revealed the binding mode and the essential structural features. The initial HTS hit was bound in a DFG-in conformation interacting namely with the main chain nitrogen atom of methionine 1160 within the hinge region and with the main chain nitrogen of aspartic acid 1222. After subsequent optimization of potency, efficacy, PK properties and the safety profile of thiadiazinone 1, EMD1214063 was identified as candidate for further development and is currently investigated in a phase 1 clinical trial. The pyridazinone EMD1214063 inhibits enzymatic and cellular c-Met kinase activity with IC50 values in the low nanomolar range. This compound displayed an exquisite selectivity when tested in vitro against a panel of more than 250 potential off-targets, including kinases, GPCRs, ion channels, transporters and various enzymes and demonstrated excellent anti-tumor activity in vivo in a variety of xenograft models. Depending on the particular model, complete regressions were observed with doses as low as 6 mg/kg/d administered per os. The overall profile of EMD1214063 including first time disclosure of the precise structure, synthesis, structure activity relationships, in vitro potency, selectivity profile, pharmacokinetic and in vivo data will be discussed.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5777.
Abstract 5780: Development of potent inhibitors of the DNA-dependent protein kinase (DNA-PK)
Authors: Cano Celine , Bailey Chris , Bardos Julia , Curtin Nicola , Frigerio Mark , Golding Bernard , Hardcastle Ian , Hummersone Marc , Menear Keith , Newell David , Saravanan Kappusamy , Shea K , Smith Graeme , Griffin Roger 
Published: February 2011

Abstract
The cellular response to DNA double-strand break (DSB) formation is an essential component of normal cell survival, following exposure to DNA-damaging chemicals and ionising radiation. The serine/threonine kinase DNA-dependent protein kinase (DNA-PK) is a member of the phosphatidylinositol (PI) 3-kinase related kinase (PIKK) family of enzymes, and plays an important role in DNA DSB repair via the non-homologous end-joining (NHEJ) pathway. DNA-PK inhibitors may, therefore, be useful as agents to improve the activity of radio- and chemo-therapy in the treatment of cancer.
Identification of the lead benzo[h]chromen-4-one DNA-PK inhibitor NU7026 (IC50 = 0.23 uM) guided the development of the potent and selective ATP-competitive chromenone NU7441 (DNA-PK IC50 = 30 nM). Structure-activity relationship studies for DNA-PK inhibition by chromenone-derivatives were conducted in conjunction with homology modelling. Library synthesis was undertaken employing a solution multiple-parallel approach, by O-alkylation or N-acylation of the appropriately substituted NU7441 derivatives, respectively, followed by reaction with a range of amines to afford the target compounds. These studies resulted in the identification of the highly potent inhibitor KU-0060648 (IC50 = 8.6 nM). The further development of KU-0060648 and analogues will be described.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5780.
Abstract 5781: ITRI-260, a new azaazulenone class kinase inhibitor, induces complete tumor regression and prolongs survival in AML mice
Authors: Lee On , Liu Hsingjin Eugene , Ko Ching-Huai , Tsai Yuan-Jang , Liu Chih-Peng , Chen Yen-Chun , Tseng Hsiang-Wen , Shih Ying-Chu , Chen Ting-Shou , Chen Chih-Hung , Chiou Shu-Jiau , Wang Ling-Mei , Hwang Chrong-Shiong 
Published: February 2011

Abstract
The FMS-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation. FLT3 is over-expressed in the majority of acute myeloid leukemia (AML) and the presence of FLT3 active mutations is associated with poor prognosis, implicating FLT3 as a potential target for AML treatment. ITRI-260 is a new azaazulenone class kinase inhibitor that inhibited FLT3-ITD-dependent MV4-11 cell growth with IC50 of 21 nM and cellular phosphorylation with IC50 of 17 nM. In in vivo PK study, ITRI-260 showed favorable oral PK profiles. The maximum concentration of ITRI-260 was 700 nM after a single 100 mg/kg oral dosing in mice, with dose proportional exposure from 10 to 150 mg/kg. ITRI-260 showed therapeutic efficacy in a human AML orthotopic SCID mouse model, following a 100 mg/kg/qd oral dosing regimen. The treatment group showed 100% survival of animals at day 90 after tumor cell inoculation, while the vehicle control group showed 100% mortality. In the other study, ITRI-260 also increased survival in primary tumor cell engraftment model inoculated with cells isolated from sunitinib- and sorafenib-resistant AML patient. Through hERG assay with patch clamp technology, we found higher IC50 of ITIR-260 compared with sunitinib and MLN-518, which indicates that ITRI-260 might arise less cardiotoxic concern. In a 14-day subchronic toxicology study in mice, ITRI-260 was generally tolerated at 300 mg/kg/qd. The most prominent adverse effect appeared at 600 mg/kg/qd group is starry sky appearance in spleen, which is moderate and reversible. No specific clinical signs or body weight loss were attributed to the test article. In conclusion, the in vitro/in vivo PK/PD/toxicology studies have provided the basis for the clinical developmental potential of ITRI-260 in AML. The bridge studies from discovery to development such as CMC, GLP toxicology/safety pharmacology and pre-formulation are now in progress.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5781.
Abstract 5783: In vitro ADME properties of ARQ 621: A specific Eg5 inhibitor
Authors: Savage Ronald E. , Zhong Caiyun , Hall Terence , Bresciano Karen , Song Pengfei , Wang Yunxia , Chan Thomas C.K. 
Published: February 2011

Abstract
ARQ 621 is a potent and selective allosteric inhibitor of Eg5, a microtubule-based ATPase motor protein involved in cell division. Eg5 inhibition is recognized as a potential therapeutic strategy in cancer, supported by the observation that over-expression of Eg5 causes genomic instability and tumor formation in mice. ARQ 621 is currently being tested in a Phase I clinical trial in cancer patients. Prior to its entry into the clinic, the in vitro ADME properties of ARQ 621 were studied. Data from these studies showed that ARQ 621 had a t1/2 of 53 min in human liver microsomes. The t1/2 of ARQ 621 in male and female mouse, rat, dog and monkey liver microsomes was similar to that of human liver microsomes with t1/2 values of 43, 53, 56, 53, 47, 44, 36, and 32 minutes, respectively. Consistent with the microsomal stability data, in vitro metabolic studies conducted with individual human CYP P450 isoforms indicated that ARQ 621 was relatively stable with t1/2 values all greater than 27 min. IC50 values of ARQ 621 were measured for CYP 1A2, 2C9, 2D6, 3A4, 2C19, and 2C8 and determined to be &gt;20, &gt;20, &gt;20, 4.1, 4.0, and 15 µM, respectively. ARQ 621 was found to modestly induce 1A2 but not 2A6 or 3A4. Data from in vitro Caco 2 studies demonstrated that ARQ 621 has poor GI absorption potential with a Papp value of 0.69 × 10−6 cm/s. Additionally, Caco 2 bi-directional experiments suggested that ARQ 621 may be a P-glycoprotein substrate with an efflux ratio of 45. These data are consistent with rat in vivo oral bioavailability studies in which the bioavailability of ARQ 621 was determined to be approximately 9%. Hence, ARQ 621 was subsequently developed for IV administration only. Protein binding studies conducted in human plasma showed that ARQ 621 is highly bound (∼96.4-99.2%) to plasma proteins.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5783.
Abstract 579: Chinese herbal mixture LQ inhibits tumor growth and metastasis and increases survival in orthotopic and other mouse models of human and mouse cancer
Authors: Zhang Lei , Wu Chengyu , Zhang Yong , Wang Xiaoen , Reynoso Jose , Liu Fang , Zhao Ming , Hoffman Robert M. 
Published: February 2011

Abstract
Natural products have been used as sources of first-line cancer chemotherapeutic agents, including vinca alkaloids, taxanes, podophyllotoxin and camptothecin. However, Traditional Chinese Medicine (TCM) combinations (Fufang), which have been widely used in China for over 5000 years, are still poorly understood with regard to the types of cancer they are effective against as well as their mechanism of action. We report here on the use of patient-like orthotopic nude-mouse models of metastatic cancer and other mouse tumor models to obtain proof-of-concept that TCM (Fufang) combinations have anti-tumor and anti-metastatic activity. In the present study, human and mouse lung, pancreatic and prostate cancer cell lines (H460, Lewis lung carcinoma [LLC) MIA-PaCa-2 and PC-3, respectively), labeled with red fluorescent protein (RFP) or green fluorescent protein (GFP), were orthotopically implanted or injected subcutaneously, or injected in the tail vein in nude mice to evaluate anti-tumor and anti-metastatic efficacy of the Fufang LQ, which contains a mixture of herbs. Results showed that LQ (gavage, 600 mg/kg/day) significantly inhibited prostate, pancreatic and lung cancer tumor growth as measured by imaging, tumor size and weight, in both subcutaneous and metastatic models. LQ was efficacious against primary and metastatic cancer without weight loss in contrast to drugs such as doxorubicin and cisplatin, which caused significant weight loss. Survival of tumor-bearing mice was also prolonged by LQ treatment. Furthermore, in vitro experiments demonstrated that LQ inhibited proliferation of tumor cells (LLC, H460, PC-3 and MIA-PaCa-2) in a dose-dependent manner. Those results indicate that LQ has efficacy against metastatic pancreatic and lung and prostate cancer which demonstrates its clinical potential. The results also suggest that GFP- and RFP-expressing tumors in orthotopic and other nude mouse models can be widely used for in vivo evaluation of TCM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 579.
Abstract 58: Hyaluronan metabolism enhances the Warburg effect and provides an alternate energy source in the breast cancer microenvironment
Authors: Thomas Natalie K. , Waltham Mark , Udabage Lishanthi , Brown Tracey J. 
Published: February 2011

Abstract
Introduction: A hallmark of cancer is a shift in cellular metabolism away from oxidative phosphorylation of glucose towards aerobic glycolysis thereby facilitating the rapid generation of energy required for proliferation. In breast cancer, the overproduction of hyaluronan (HA) is associated with poor disease outcomes where its metabolism is a finely regulated equilibrium between rapid synthesis and degradation. Synthetic products are involved in the structural integrity of the tumoral architecture while catabolic intermediates contribute to cell proliferation, neovascularisation and metastasis but little is known about their role in the generation of intratumoral energy.
Methods: A hyaluronanhigh producing cell line was generated by the stable transfection of HAS2 into the ZR-75-1 breast cancer cell line. The HA metabolism and expression of the HA receptor, CD44 was characterised in the parental, vector- and HAS2-transfected cell lines. The effect of elevated HA synthesis on the glycolytic phenotype was determined by quantitation of phosphoinositide 3-kinase/Akt pathway activation, transketolase-like protein 1 (TKTL1), pyruvate kinase M2 (PKM2), glucose transporter 1 (GLUT1), aerobic glycolysis, cell proliferation and metastasis both in vitro and in vivo.
Results: Compared to the controls, HAS2-transfected cells liberated up to 10-fold more HA and had increased expression of CD44s and CD44v9. The resultant increase in CD44-HA interactions mediated in vitro activation of the PI3K/Akt pathway, enhanced proliferation and metastatic capacity, increased propensity for aerobic glycolysis and a higher HA metabolic index. High levels of HA production conferred a characteristic glycolytic phenotype to HAS2 transfectants where Akt and TKTL1 were up-regulated and PKM2 reduced. Unlike the classic glycolytic phenotype, GLUT1 was not increased, but down-regulated 3-fold in the HAS2 cells. HA-induced enhancement of the glycolytic phenotype was confirmed in vivo by a &gt;6 fold increase in endpoint tumor volume and reduced overall survival in an animal model of metastases.
Conclusions: Elevated HA production confers an aggressive phenotype to breast cancer where CD44-HA interactions alter the metabolic fate of the cell driving it into an aerobic glycolytic pathway. This study has provided preliminary evidence that in highly proliferative breast cancer glucose may not be the sole catabolic substrate and hyaluronan may contribute to this process.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 58.