bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A208: Comparison of expression and function of two functional RARβ isoforms in human cancer: Clinical implications for the differential splicing of the RARβ gene
Authors: Swift Catherine B. , Varela Victor A. , Graves Jason T. , Dmitrovsky Ethan , Petty W. Jeffrey 
Published: June 2012

Abstract
Purpose: Retinoids are derivatives of vitamin A that are used for treating and preventing certain cancers. Retinoid sensitivity in the lung is linked to expression of a specific isoform of the retinoic acid receptor β (RARβ), termed RARβ1′. This study compared the function of RARβ1′ and RARβ2 and assessed the expression of these isoforms in a panel of cancers. Experimental Design: RARβ1′ and RARβ2 were independently co-transfected into BEAS-2B human bronchial epithelial cells along with a retinoid responsive reporter plasmid. Transfectants were then treated with 4 µM all-trans retinoic acid or control and reporter activation was measured. An isoform-specific antibody for detection of RARβ1′ was also developed and validated. Using this antibody, RARβ1′ expression was evaluated by immunoblot analyses of normal lung versus lung cancer tissue specimens as well as in a panel of cancer cell lines including those of breast, colon, prostate, glioblastoma (GBM) and lung cancer origins. RARβ1′ expression was then examined in an extended panel of GBM cell lines. GBM cell lines were independently treated with 13-cis-retinoic acid, and growth assays and microarray analyses were each performed.
Results: In the absence of retinoid treatment, retinoid reporter activation was increased by co-transfection of RARβ2 (P = .02) but not RARβ1′ (P = .21) in BEAS-2B cells. When treated with the retinoid, transfection of either isoform enhanced reporter activation. RARβ1′ was noted to be expressed in normal lung tissue but absent in tumor tissue from patients with each of the common types of non-small cell lung cancer. Analysis of multiple cancer cell lines revealed RARβ1′ expression only in the GBM cell lines. No appreciable expression was detected in the breast, colon, prostate, or lung cancer cell lines. Analysis of an extended panel of GBM cell lines revealed RARβ1′ expression in all examined GBM cell lines. The examined GBM cell lines were found to be sensitive to treatment with pharmacologically achievable dosages of 13-cis retinoic acid. Microarray analyses revealed several novel candidate retinoid target genes activated in SNB-19 GBM cells.
Conclusions: RARβ1′ and RARβ2 have differing effects on ligand-independent signaling. RARβ1′ was repressed in all examined lung cancer cases and in most of the cancer cell lines studied. RARβ1′ protein was abundantly expressed in GBM cell lines which may help to explain the activity of 13-cis retinoic acid for the treatment of GBM despite the modest single agent activity of retinoids for treating many epithelial cancers. Microarray data of GBM cells have uncovered several candidate retinoid-target genes that may represent novel therapeutic targets.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A208.
Abstract A213: Potent anticancer activity in vitro and in vivo by NMS-E973, a novel synthetic inhibitor of HSP90
Authors: Fogliatto Gianpaolo , Mantegani Sergio , Amboldi Nadia , Ballinari Dario , Brasca Maria Gabriella , Caprera Francesco , Cappella Paolo , Casale Elena , De Ponti Anna , Guanci Marco , Paolucci Mauro , Sola Francesco , Valsasina Barbara , Visco Carlo , Zuccotto Fabio , Colotta Francesco , Felder Eduard , Donati Daniele , Moll Juergen , Galvani Arturo , Pesenti Enrico , Isacchi Antonella 
Published: June 2012

Abstract
The molecular chaperone heat shock protein 90 (HSP90) is essential for the conformational maturation and stability of a variety of proteins, including kinases, transcription factors, telomerase, and other key proteins implicated in cancer development and progression. The simultaneous block of multiple signaling pathways that is induced by Hsp90 inhibition makes this approach potentially attractive in a broad range of cancer types.
Prototype geldanamicyn-derivative HSP90 inhibitors have already shown efficacy in different types of tumors, but possess liabilities inherent to the class which may ultimately limit their development. Here we describe the in vitro and in vivo characterisation of NMS-E973, representative of a novel class of non-ansamycin Hsp90 inhibitors. NMS-E973 binds HSP90 with picomolar affinity, as revealed by Surface Plasmon Resonance analysis, whereas selectivity screening showed no significant activity against a broad panel of kinases, as well as other ATPases. NMS-E973, when profiled against a panel of 91 tumor cell lines of various tissue origins, showed widespread antiproliferative activity. On-target mechanism was confirmed in multiple cell lines by observation of dose and time dependent degradation of specific oncogenes, parallel blockade of the PI3K and RAF/MEK/ERK pathways, and upregulation of HSP70, a well-known feedback response to HSP90 inhibition. In vivo, NMS-E973 had a favourable pharmacokinetic profile, good tolerability, selective retention in tumors, and induced tumor shrinkage in multiple human xenograft models in nude mice. In the B-RAF V600E driven A375 melanoma model, for which a multi-cycle regimen was adopted, shrinkage was observed both during the first treatment cycle, as well as after successive re-challenge of larger, regrown tumor masses. In conclusion, NMS-E973 is a novel, potent non-ansamycin like inhibitor of HSP90, with efficacy and pharmacokinetic properties compatible with clinical development.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A213.
Abstract A22: Response to the triple VEGFR inhibitor tivozanib (AV-951) in KRAS and EGFR driven lung tumors developed in chimeric mouse models
Authors: Bressel Angela , Zi Tong , Jesmer Kristen , Monti Anthony , Brodeur Joelle , Rideout William , Chiu Maria Isabel , Robinson Murray O. , Heyer Joerg , Zhou Yinghui 
Published: June 2012

Abstract
Lung cancer is one of the most prevalent and deadly malignancies in the world, with more than 213,000 new cases diagnosed each year in the US and a five year survival rate of 15%. Activating mutations in a number of key signaling genes including KRAS, EGFR, and HER2 have been identified. Mutations in EGFR are highly correlated with sensitivity to small molecule EGFR inhibitors, although resistance tends to develop within a short period of time after initiation of treatment. Targeted inhibition of KRAS has not been successful so far, which in turn fueled efforts to identify tractable alternative therapeutic points of intervention.
Because all solid tumors are thought to require neo-vascularization, pharmacologic angiogenesis inhibition may represent an attractive therapeutic strategy for these challenging tumor settings. One attractive anti-angiogenesis agent is the ATP competitive small molecule VEGFR inhibitor tivozanib (AV-951). tivozanib exhibits picomolar inhibitory activity against all three VEGF receptors, a multi-day T1/2 in humans, and demonstrates robust clinical activity demonstrated in renal cell carcinoma, the signal tumor type for VEGF pathway inhibition.
In an effort to recapitulate the stochastic nature of human cancer in genetically engineered mouse models and to maximize their use in preclinical settings, we developed a mouse tumor model strategy involving stepwise genetic manipulation of embryonic stem (ES) cells and chimera formation to enable direct tumor induction in tissues containing both normal and engineered cells. An allelic series of lung cancer models containing EGFR, KRAS, or HER2 oncogenes demonstrated that resultant adenocarcinomas arising within normal lung tissue exhibited features of advanced malignancies.
In this study, we tested the response of KRAS and EGFR driven lung tumors to the VEGFR inhibitor tivozanib in tumor bearing chimeric mice identified by bioluminescent imaging. We demonstrated that tivozanib treatment conferred significant survival benefit to the tumor bearing mice. Consistent with previous reports that tumors become more dependent on neo-angiogenesis for survival and proliferation, we observed sensitivity to tivozanib in advanced adenocarcinomas but not hyperplasia or small adenomas. In addition, we found that upon discontinuation of tivozanib treatment, tumors quickly grew back and became less sensitive to further tivozanib treatment. These results indicate that lung cancer patients could potential benefit from anti-angiogenesis therapy, but sustained inhibition of all VEGF receptors may be important to prevent development of resistance.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A22.
Abstract A226: ImmunoPET with 89Zr-DFO-trastuzumab: Monitoring the pharmacodynamic effects on HER2/neu expression by Hsp90 inhibition in vivo
Authors: Holland Jason P. , Caldas-Lopes Eloisi , Divilov Vadim , Longo Valerie A. , Taldone Tony , Zatorska Danuta , Chiosis Gabriela , Lewis Jason S. 
Published: June 2012

Abstract
Objectives: The positron-emitting radionuclide 89Zr (t1/2 = 3.17 days) has been isolated in high specific-activity and was used to prepare 89Zr-radiolabeled monoclonal antibodies (mAbs) for use as immunoPET imaging agents. The work presented describes the preparation of 89Zr-DFO-trastuzumab for use as a radiotracer for delineating HER2/neu positive tumors for the non-invasive imaging of breast cancer in vivo. In addition, pharmacokinetic studies on HER2/neu expression levels in response to administration of therapeutic doses of PU-H71 (a specific inhibitor of heat-shock protein 90 [Hsp90]) were conducted.
Methods: 89Zr was prepared via the 89Y(p, n)89Zr transmutation with high radiochemical yields (1.52±0.11 mCi/ Ah) and purity (&gt;99.99%). Trastuzumab was functionalized with the tris-hydroxamate chelate, desferrioxamine B (DFO) and radiolabeled with [89Zr]Zr-oxalate at room temperature. ImmunoPET imaging experiments in female, athymic nu/nu mice bearing sub-cutaneous BT-474 (HER2/neu positive) and/or MDA-MB-468 (HER2/neu negative) were conducted. The change in 89Zr-DFO-trastuzumab tissue uptake in response to high- and low-specific-activity formulations and co-administration of PU-H71 (a Hsp90 chaperone inhibitor) was measured by using both acute biodistribution studies and Western blot analysis.
Results: 89Zr-DFO-trastuzumab radiolabeling proceeded in high radiochemical yield and specific-activity of 2.82±0.05 mCi/mg. In vitro assays demonstrated &gt;99% radiochemical purity with an immunoreactive fraction of 0.87±7. In vivo biodistribution experiments revealed high and specific tumor uptake after 24, 48 and 72 h (64.68 ± 13.06 %ID/g; 71.71 ± 10.35 %ID/g and 85.18±11.10 %ID/g, respectively) with retention of activity for over 120 h. Pre-treatment with PU-H71 was followed by quantitative biodistribution and 89Zr-DFO-trastuzumab immunoPET imaging. Expression levels of HER2/neu were modulated during the first 24 and 48 h post-administration (29.75 ± 4.43 %ID/g and 41.42 ± 3.64 %ID/g, respectively). By 72 h radiotracer uptake studies (73.64 ± 12.17 %ID/g) and Western blot analysis demonstrated that HER2/neu expression recovered to baseline levels.
Conclusions: The results indicate that 89Zr-DFO-trastuzumab provides quantitative and highly-specific delineation of HER2/neu positive tumors and may be used to monitor treatment with Hsp90 inhibitors. Efforts towards the “current Good Manufacturing Process” (cGMP) production and clinical translation of 89Zr-DFO-trastuzumab are underway.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A226.
Abstract A24: Establishment and characterization of multi-drug resistant HER-2/3 expressing and triple-negative breast tumor xenograft models
Authors: Moore Mitchell M. , Estrada Vanessa A. , Kelly Scott G. , Nieves Francis E. , Bruckheimer Elizabeth , Papadopoulos Kyriakos P. , Patnaik Amita , Tolcher Anthony W. , Hidalgo Manuel , Wick Michael J. 
Published: June 2012

Abstract
Breast cancers demonstrate marked heterogeneity in clinical presentation where classification and treatments are based on the presence or absence of several protein and genetic markers. The human epidermal growth factor-2 (HER-2) receptor is a surface-bound receptor tyrosine kinase overexpressed in some cancers, especially breast and ovarian, and is a target for several approved therapies including the α-HER-2 antibody trastuzumab and duel (EGFR/HER2) kinase inhibitor lapatinib. However, many of these cancers develop resistance to these agents leaving patients with few effective alternative treatments. Lack of validated preclinical models of HER-2 targeted drug resistance impairs drug development in this area. Furthermore, breast cancers lacking expression of HER-2, progesterone (PR), and estrogen receptors (ER-α), referred to as “triple negative (TN)”, represent a minority of diagnosed cases each year but are responsible for a disproportionate number of breast cancer deaths. Few advances have been made in the treatment of TN compared with other types of breast cancer. Thus the development of effective screening tools for promising agents in these HER2 and TN subgroups is warranted.
To address these unmet needs, we have established and characterized a cell-based, HER-2/3 expressing xenograft model in both mice and rats and a panel of cell-based and low passage human tumor models representing TN breast cancer. Chronic treatment with trastuzumab or lapatinib was ineffective in the HER 2/3-expressing model in mice. In the TN panel, cell-based models showed varying sensitivity to standard platinum or taxane treatments while the CBI-0810 low passage TN model was sensitive to liposomal doxorubicin and a cisplatin/irinotecan regimen but not the α-EGFR antibody cetuximab or mTOR inhibitor temsirolimus.
Results from these studies confirm HER-2 targeted drug resistance in this breast cancer model and benchmark its value as a screening tool for agents targeting trastuzumab/lapatinib-refractory breast cancer. In addition, data demonstrate that the TN panel is a novel and highly beneficial tool for screening potential therapies for this form of breast cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A24.
Abstract A247: Preclinical antitumor activity of the MEK inhibitor RO5068760 in human tumor xenograft models
Authors: Brian Higgins , Kolinsky Kenneth , Daouti Sherif , Rizzo Christine , Wang Huisheng , Huby Nicholas , Niu Huifeng , Packman Kathryn 
Published: June 2012

Abstract
RO5068760 is a representative member of a new class of potent, highly selective, non-adenosine triphosphate (ATP) competitive MEK inhibitors. In tumor cells, RO5068760 selectively blocked MAPK pathway signaling by inhibiting the phosphorylation of both ERK1/2 and MEK1/2. Human tumor cell lines bearing MAPK pathway gene mutations such as B-Raf and Ras were preferentially sensitive to RO5068760 treatment in vitro. When administered orally to tumor-bearing mice, RO5068760 demonstrated dose-dependent anti-tumor activity in a variety of human xenograft models including melanoma, colorectal, pancreatic, and non-small cell lung cancer (NSCLC). RO5068760 elicited statistically significant tumor growth inhibition in all models tested when administered once daily (qd) or twice daily (bid). At an optimal dose of 100 mg/kg bid, partial regressions (PRs) were demonstrated in 3/4 tumor models, and complete regressions (CRs) in 1/4 models tested. Antitumor efficacy was proportional with drug plasma exposure and inhibition of ERK1/2 phosphorylation, with slightly better efficacy observed with bid vs qd administration in the MiaPaCa-2 (pancreatic) and H460a (NSCLC) models. In the Lox melanoma model, animals treated at doses as low as 12.5 mg/kg bid exhibited CRs, which further supported the observation made in vitro that tumor cells bearing B-Raf mutations had the greatest sensitivity to RO5068760. Combination treatment of mice bearing MiaPaca-2 xenografts with 2/3 optimal doses (ODs) of RO5068760 and Gemcitabine significantly enhanced the antitumor activity as compared to either monotherapy. These results suggest that RO5068760 is a promising candidate for further development in the treatment of human cancers with aberrant MAPK pathway activation.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A247.
Abstract A249: Potent protein kinase inhibitors block Pim kinase-mediated increase in prostate epithelial cell migration, regulation of p27 protein half-life, and secretion of hepatocyte growth factor
Authors: Kraft Andrew S. , Cen Bo , Zemskova Marina , Beharry Zanna , Smith Charles D. 
Published: June 2012

Abstract
Pim-1 proto-oncogene encodes a serine/threonine protein kinase that regulates apoptosis, cell cycle progression, and transcription. The expression of this protein kinase is elevated in both prostate intraepithelial neoplasia (PIN) and prostatic adenocarcinoma, suggesting an important role for Pim-1 kinase in prostate cancer development and growth. To investigate the role of Pim-1 in controlling tumor growth we have synthesized novel benzylidene-thiazolidine2, 4-dione (J. Med. Chem. (2009) 52:74) inhibitors of this kinase. The most potent members of this chemotype have IC50s of 13 nM for Pim-1. To examine the activity of these agents in prostate cancer we have first set out to define the biochemical activity of Pim-1 in epithelial cells. We have expressed Pim-1 in a mouse prostate epithelial cell (MPECs) line that demonstrates stem cell characteristics. We find that Pim-1 expressing cells produce and secrete markedly increased levels of hepatocyte growth factor/scatter factor (HGF/SF), and this protein kinase stimulates increases in HGF/SF mRNA. Additionally, expression of Pim-1 markedly increases HGF/SF induced migration of MPECs. The contribution of Pim-1 kinase to this biochemical pathway is confirmed in murine embryonic fibroblasts (MEFs) that are deficient for all three Pim protein kinases (TKO) and evidence reduced level of HGF mRNA in TKO versus wild type MEFs. The Pim-1-stimulated migration of MPECs is inhibited by two benzylidene-thiazolidine-2, 4-diones, SMI-4a and 16a, as well as known inhibitors of the HGF receptor, c-Met. HGF treatment of MPECs induced p27 upregulation that could be inhibited by the expression of Pim-1, thus allowing cell cycle progression. Further studies showed that expression of Pim-1 did not alter the mRNA level of p27, but enhanced the cell cycle-dependent degradation and thus decreased the half-life of the p27 protein. Consistent with this finding, p27 ubiquitination assays showed that Pim-1 increases this modification in vivo. We found that the Pim-1-mediated ubiquitination is regulated by complex formation between Pim-1 and Skp2, a protein component of the SCF complex, which is known to regulate the ubiquitination and degradation of p27. Pim-1 does not affect Skp2's E3 ligase activity, but appears to inhibit the degradation of Skp2 through phosphorylation. Incubation of these cells with the Pim protein kinase inhibitor, SMI-4a, decreased Skp2 expression and increased p27 and cyclin E expression. Together our data demonstrates the complex pathway by which Pim-1 protein kinase regulates HGF/SF and p27 levels, thus controlling cell migration, proliferation, and potentially transformation. Potent Pim kinase inhibitors block these two signaling pathways thus inhibiting prostate epithelial cell migration and growth.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A249.
Abstract A31: Human prostate cancer transcriptome reveals distinct signaling pathway dysregulations associated with TMPRSS2:ERG fusion
Authors: Bhasin Manoj , Lu Bin , Arredouani M. Simo 
Published: June 2012

Abstract
Introduction: The gene rearrangement leading to the fusion of the TMPRSS2 and ERG genes on chromosome 21 occurs in about 50% of prostate cancer cases. TMPRSS2:ERG fusion is believed to contribute to prostate tumorigenesis in mice and has been shown to be associated with aggressive disease in patients with prostate cancer. However, the molecular mechanisms driving the clinical aggressivity of fusion-positive prostate cancer remain unknown.
Hypothesis: We postulate that dissecting the molecular events taking place in prostate tumors with or without ERG fusion might lead to the discovery of novel targets for prostate cancer therapy.
Methods: RNA was purified from benign (n=8) and malignant (n=13) human prostate specimens. Malignant specimens were previously tested for the occurrence of ERG fusion and included 6 fusion(+) and 7 fusion(−) samples. We performed gene expression profiling using cDNA microarrays, and conducted in silico analysis of gene expression data, followed by detailed canonical pathway analysis and regulatory network identification.
Results: Gene expression data revealed differential expression of 3039 genes in fusion positive cancer, while only 2386 genes were differentially expressed in fusion negative cancer. Among these genes, 1096 were differentially expressed regardless of the fusion status of the tumor. Pathway analysis performed on differentially expressed genes showed that fusion positive tumors showed the highest impact occurred on genes classified in the Nitric Oxide Signaling in the Cardiovascular System Pathway and the Cardiac β-Adrenergic Signaling Pathway, while the most impacted pathways in the fusion negative tumors were the Ephrin Receptor Signaling Pathway and the Fatty Acid Biosynthesis Pathway.
Conclusion: TMPRSS2:ERG gene fusion highlights a distinct molecular subtype of prostate cancer. A better understanding of the molecular consequences of the fusion will lead to the identification of new molecular targets for diagnosis and therapy of prostate cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A31.
Abstract A34: Conquering resistance to targeted therapies through system-based analysis of clinico-molecular information
Authors: Stein Martin A. , Brems Stefanie , Seifarth Wolfgang , Zien Alexander , Frank Oliver , Jackson David B. 
Published: June 2012

Abstract
While the advent of targeted therapies has promised to revolutionize the success of cancer treatment, a critical review of clinical response rates provides a sobering perspective on the challenge at hand. New levels of discovery innovation are urgently required to redress this enormous medical need. Focusing on primary imatinib resistance in chronic myeloid leukemia, we demonstrate that the systems-based modeling and analysis of clinico-molecular information from responder and non-responder patients can provide unique molecular insights into the sources of therapy resistance. By then utilizing these models to prioritize therapeutic drug space, the strategy elaborates rational multi-component therapies to potentially redress the issue. Moreover, by hypothesizing that co-medications may perturb the activity of resistance model components, we utilize prescription information to “probe” the functional network in search of key resistance associated targets. Not only does this method provide a novel approach to the analysis of patient information, it also permits the repositioning of drugs from independent therapeutic areas within predicted combinatorial regimens. Taken together, our results provide an exciting new approach to the computational analysis of clinico-molecular data, and suggest a future where rationally designed theranostic-linked combination therapies could significantly address the non-responder problem.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A34.